Skip to content

Advertisement

  • Review
  • Open Access

Minimal residual disease in prostate cancer patients after primary treatment: theoretical considerations, evidence and possible use in clinical management

Biological Research201851:32

https://doi.org/10.1186/s40659-018-0180-9

  • Received: 21 March 2018
  • Accepted: 28 August 2018
  • Published:

Abstract

Minimal residual disease is that not detected by conventional imaging studies and clinically the patient remains disease free. However, with time these dormant cells will awaken and disease progression occurs, resulting in clinically and radiological detectable metastatic disease. This review addresses the concept of tumor cell dissemination from the primary tumor, the micrometastatic niche and tumor cell survival and finally the clinical utility of detecting and characterizing these tumor cells in order to guide management decisions in treating patients with prostate cancer.

Keywords

  • Prostate cancer
  • Circulating tumor cells
  • Tumor cell dissemination
  • Dormancy
  • Micrometastasis
  • Phenotype
  • Treatment

Background

With the worlds demographic changes and aging population prostate cancer has become the most common non-skin cancer in developed countries, 1,094,916 new cases were diagnosed and 307,481 deaths were reported worldwide in 2012 [1]. The natural history of untreated prostate cancer is one of evolution to a metastatic disease, especially disseminating to bone, over a variable time period. With advent of prostate cancer screening using the prostate specific antigen (PSA) there has been a migration to earlier stage cancers localized to the prostate gland [2]. Radical prostatectomy (RP) is a standard treatment option for these patients; however, 4–32% of these men with eventually relapse following radical prostatectomy (RP) [35]. In patients who achieve a PSA nadir of < 0.01 ng/ml post-surgery the failure of curative surgery is hard to explain. Although the peak time to relapse is 2 years, the majority will do so within 5 years [6, 7] but many patients remain clinically disease free for years until there is an increase in the serum PSA or overt metastasis are detected. One in five men have disease recurrence after 5 years and one in twenty after 10 years [6, 7].

Although an erroneous pathological classification of the tumor; in terms of either the cancer penetrating the prostate capsule (pT3) or an anatomically incorrect dissection plane (unrevealed positive margin), which left behind microscopic amounts of PC which subsequently progressed may explain some cases, this is not the case in the majority. The presence of sub-clinical micrometastasis (mM) not detected by conventional imaging is a more logical explanation of these cases. A positive bone scan has been reported in between 6 and 9% of patients with biochemical failure; however most of these studies are more than 15 years old, with median PSA levels of over 5 ng/ml [8, 9]. Similarly CT scanning fared little better with a detection frequency of 14% [8]. Since 2013 the use of Gallium-68-prostate specific membrane antigen (68Ga-PMSA) position emission tomography/computed tomography (PET/CT) has changed clinical practice and is incorporated in the Australian guidelines for prostate cancer restaging after biochemical failure [10]. It has a specificity of over 98% for prostate tissue; however the sensitivity is dependent on PSA levels. With PSA levels between 0.05 and 0.09 ng/ml 8% of patients had a positive PET/CT; 23% in the range 0.10–0.19 ng/ml and rising to 58% of patients with a PSA level of 0.20–0.29 ng/ml [11]. The 50% positive detection rate in patients with a PSA of 0.2–0.5 ng/ml is similar across differing studies [12, 13]. However, a systemic review of 37 published studies found a positive scan rate of 11–75% in patients with a PSA level of < 0.5 ng/ml [14]. Importantly this resulted in significant changes in the management of patients, in terms of local versus systemic rescue therapy in 29–87% of patients [14]. Limitations of the test include the 10% of prostate cancers that do not express PMSA [15] and nonspecific labeling of lymph nodes, especially those with follicular hyperplasia [16, 17]. However, with these advances there are more patients with “less indemonstrable minimal residual disease”.

Although new techniques are detecting smaller micrometastasis, there is a limit to image resolution, the undetected microscopic foci not removed by curative surgery are termed minimal residual disease (MRD) previously called micrometastatic disease. Minimal residual disease was first used to describe patients with hematological malignancies in complete clinical and hematological remission post bone marrow transplant yet using molecular techniques such as polymerase chain reaction had small numbers of leukemic cells detected in bone marrow. The term has been used increasingly in patients with solid tumors, especially breast cancer [1820]. Minimal residual disease encompasses residual tumor cells which can persist locally as cancer stem cells, in the circulation as circulating tumor cells and in distant organs such as bone marrow as disseminated tumor cells or micrometastasis, the three faces of minimal residual disease [21].

The following databases were systemically searched during January 2018; Pubmed, Medline, SCOPUS, Web of Science, no language restriction, date restriction or publication status restriction were used. The reference lists of all included articles were hand checked for additional relevant articles not identified in the database searches. Full text articles were retrieved for any articles deemed potentially eligible.

Primary dissemination

The metastatic process by which cancer cells disseminate from the primary tumor, survive in the circulation, implant in distant tissues, survive and grow is multistage and complex. To explain the presence of treatment failure in men with pathologically organ confined prostate cancer dissemination of tumor cells must be an early event, prior to treatment.

Circulating tumor cells (CTCs) were first described in 1869 by Ashworth [22] although only in the last few decades methods have been developed to detect these cells, defined as primary (pre-treatment) or secondary (post curative therapy) circulating prostate cells (CPCs).

Tumor cells are thought to enter the circulation passively, actively or both [23], as single cells, in clusters, in strands or in single files of cells.

Passive entry into the circulation occurs as a result of primary tumor growth, mechanical forces or friction which causes the cells to enter the circulation. Little is known about passive entry into the circulation, it has been postulated that cancers induce new blood vessel formation by the secretion of vascular endothelial growth factor (VEGF), this process of angiogenesis often results in leaky vessels as a consequence of weak interconnections of the endothelial cells and intercellular openings [24]. The endothelial cells do not form a normal monolayer and as such do not have a normal barrier function [25]. Thus with tumor growth, single or clusters of cancer cells may be pushed through these leaky intercellular openings and enter the circulation. This leakiness may be enhanced by the secretion of inflammatory mediators and the migration of leukocytes through the vessel wall [26]. The secretion of inflammatory cytokines which increase these endothelial openings [27] is one explication why epithelial cells may be detected in non-malignant disease [28, 29].

Passive dissemination may also occur as a result of tumor manipulation, either during surgery [30, 31], seed implantation during brachytherapy [32] and prostate biopsy [33]. Tumor cells may be passively moved through micro-tracks created by other tumor cells that are actively migrating into the circulation, as a result of proteolysis [34].

Active dissemination of tumor cells requires specific phenotypic characteristics which confer the ability to the tumor cell to detach from the surrounding cells, survive free of them, migrate towards the blood vessels where they cross the capillary endothelial wall to enter the circulation. Epithelial cells are anchored to other cells via adhesion molecules such as cadherins, claudins and plakoglobin. Normal epithelial cells show plasticity and undergo dynamic and reversible transitions between epithelial and mesenchymal cell phenotypes [35]. This epithelial to mesenchymal transition (EMT) is seen during embryogenesis, wound healing and tissue regeneration [36]. Cancer cells exhibit a decreased expression of anchor proteins such as E-cadherin [3739] and beta-catenin [37], a loss of cytokeratins and EpCAM (epithelial cell adhesion molecule) [4042] with upregulation of mesenchymal markers such as vimentin, N- and O-cadherins [43, 44]. E-cadherin is a calcium dependent cell–cell adhesion molecule, essential in maintaining the cellular polarity and architecture; its dysregulation modulates various signaling mechanisms including Wnt [45], RhoGTPase [46] and NF-kB pathway [47].

Single cells have been shown to exhibit these EMT changes while cell clusters detected in the blood only show a partial EMT, permitting them to enter the circulation while retaining some of the cell-to-cell interaction profiles of epithelial cells [48]. EMT can be initiated by paracrine signaling of TGF-Beta, WnT, platelet derived growth factors and interleukin 6 [35, 49] which in turn trigger the activation of the transcription factors Snail, Twist and Zeb thus maintaining the phenotype of a mesenchymal cell in an autocrine fashion [35].

There are also changes in matrix metalloproteinase (MMP) expression, especially MMP-2. These zinc containing endopeptidases are activated in situ and degrade the extra-cellular matrix, facilitating cell migration and invasion. Increased MMP-2 expression has been reported in primary prostate cancer and associated with an increasing Gleason score and pathological stage [33, 50, 51].

Not all cancer cells that actively migrate to the blood show EMT characteristics, centrosome amplification has been reported to induce cancer invasion [52]. In these cells cellular adhesion is reported to be decreased downstream of Rac-1 by an increased Arp2/3 dependent actin polymerization [52].

Survival in the circulation and implantation in distant tissues

In order to implant at distant sites, CPCs must survive in the circulation, it has been suggested that only 0. 01% of CTCs can produce a single bony metastasis [53, 54], and injected CPCs obtained from men with castrate resistant prostate cancer may fail to produce metastasis when injected in immune compromised mice [55]. Sheer stresses found in the blood decrease the number of CTCs, however it has been reported that cells that have undergone EMT are more resistant than epithelial cells [56]. They resist anchorage dependent cell death, anoikis, which may be due to over-expression of anti-apototic proteins such as Bcl-2 [57] or suppression of caspase associated death via the activation of tropomyosin related kinase B [58].

Escape from the immune system may be direct, increased CD47 expression, an anti-phagocytic signal expressed on cancer cells prevents macrophage and dendritic cell attachment and the expression of pro-phagocytic calreticulin is decreased [59]. Furthermore, myeloid derived suppressor cells facilitate cancer cell survival by adhering to the CPCs [60]. In addition, CPCs become coated by platelets, transferring MHC class I antigens to the tumor cell surface. This coating of phenotypic normality disrupts the normal recognition of tumor cells by NK and T cell mediated immunity and as such improves tumor cell survival [61]. This platelet coating also enhances binding of the tumor cell to the endothelial lining of vessels at distant sites, enhancing invasion [62].

The pre-micrometastatic niche and CTC homing

In 1889 Paget reported that the process of metastasis did not appear to occur by chance and suggested the “seed and soil” hypothesis [63]. Thus the seed (CTC) arising from a specific tumor shows a strong preference for the soil of specific metastatic sites, in the case of prostate cancer cells bone [64, 65]. Tumor cells may express parathyroid hormone related peptide (PTHrP) [66], chemokine CXCL 12 receptors, such as CXC chemokine receptor type 7 [67] or type 4 [68]. CXCL 12 is produced predominately by a diversity of bone marrow stromal cells, the cancer cells homing into the bone marrow by a CXL 12 gradient. In the bone marrow microenvironment there is a dynamic balance between stem cells, progenitor cells, mature immune cells and supporting stromal cells, this has been termed the metastatic niche [69, 70]. It is thought that there are two primary niches; the osteoblastic niche comprised of hematopoietic stem cells and the perivascular niche comprised of mesenchymal stem cells [70, 71]. In addition trophic factors, cytokines and chemokines act as bone marrow stromal mediators in the bone marrow niche. CXCL 12, integrins, osteopontin, vascular cell adhesion molecule-1 (VCAM-1), transforming growth factor beta (TGF-beta) and the receptor activator of nuclear factor kappa-b ligand (RANKL) are have been reported to influence the metastatic niche specificity for tumor type [69, 72]. Cell to cell adhesion is crucial for the initial seeding to the bone marrow niche. The expression on the surface of CTCs of integrin αvβ3 promotes the adherence to the extracellular matrix, via osteopontin, fibronectin, vitronectin and thrombospondin [73]. CTCs have also been shown to express α4β1 integrin which binds to the intercellular adhesion molecule-1 (ICAM-1) and VCAM-1 expressed by bone marrow and vascular cells [73]. Annexin II a protein that mediates the adhesion of hematopoietic stems to osteoblasts has also been reported in prostate cancer seeding to bone marrow [74]. Recent studies report that CTCs locate to the perivascular niche where endothelial cells, CXCL 12 abundant reticular (CAR) cells and mesenchymal stem cells regulate the implanting tumor cells [75]. Inversely there is a subpopulation of mesenchymal stem cells which carry endothelial and pericyte markers which suppress the homing of CTCs to bone marrow [76]. CPCs home in the niche via a SDF-1 cytokine gradient, SDF-1 is expressed in vascular “hot-spots” corresponding to regions in the bone that attract circulating tumor cells. The SDF-1/CXCR-4 interaction is pivotal for the recognition and binding to permissive vasculature [77]. The role of tumor suppression genes/proteins is also involved, CD82 expression on CPCs, the product of the tumor suppressor gene KAI1, impedes adhesion of the tumor cell to endothelial cells by inhibiting crosstalk with the Duffy antigen receptor [78]. The presence of CPCs that express CD82 is associated with low grade prostate cancer and the absence of bone marrow micrometastasis [79].

Cancer cell implantation and survival

Although mechanical entrapment may be one mechanism by which CTCs lodge in distant sites it is insufficient [80], tumor cells must adhere to the vascular endothelium and extravasation by an active process. The initial attachment is via selectins, the presentation of selectin ligands is thought to be crucial to extravasation, especially E-selectin [81]. This results in morphological changes in the tumor cells, reorganization of the cytoskeleton and tyrosine phosphorylation [82]. This suggests that downstream signaling effects occur as a result of cellular adhesion. The expression of selectin ligands varies with tissue type and thus may influence the site of cancer cell colonization and explain in part organotropism [83]. This initial adhesion via selectins is reinforced by other adhesion molecules, the expression of immunoglobulin cell adhesion molecules ICAM and VCAM have been implicated in this role [84].

Once implanted, the biochemical signature of the niche will determine the fate of the cancer cell and it is thought to be the rate limiting step of metastasis [85]. In order to implant it is postulated that the tumor cells undergo a process opposite to the initial EMT, that of the mesenchyme epithelial transition (MET). It is suggested that there is re-expression of epithelial markers and down regulation of mesenchyme markers, which permits tumor cell adhesion and colonization in the new environment. The evidence for MET is more limited that EMT; it has been shown that E-cadherin expression is increased with respect to the primary tumor [86] and its re-expression may allow the cancer cell to survive in the target tissue [87]. The expression of E-cadherin in metastatic tissues may be found in patients with E-cadherin negative primary tumors [86]. Down regulation of E-cadherin in invasive cancer is due to promoter methylation and transcriptional repression and regulated by epigenetic mechanisms [88]. Re-expression of E-cadherin is not a random process; studies using breast cancer cell metastatic models in liver suggest that E-cadherin is directly regulated by the hepatocytes [89]. The methylation of a CpG island proximal to the E-cadherin transcription start site is inversely related to E-cadherin expression [90]. This is not the result of global hypo-methylation but specifically at the E-cadherin promoter site [89]. Re-expression secondary to hypo-methylation in prostate cancer cell models has also been shown to be driven by lung parenchymal cells [91]. Thus regulation of E-cadherin expression is not a result of gene loss or mutation, this epigenetic regulation allows for an increased phenotypic plasticity and influenced by factors in the microenvironment. Inhibition of Epithelial Growth Factor receptor signaling causes re-expression of E-cadherin in cultured prostate cancer cells [92] via the transcription factors Snail [93] and/or Slug [94] is one described mechanism, the second being by direct interaction at the promoter site or via the transcriptional factors Snail, Slug and Twist [95]. While Laminin-1, a component of the extra-cellular matrix, induces E-cadherin expression in 3 dimensional cultured breast cancer cells by inhibiting DNA methyltransferase 1 and reversing promoter methylation status [96].

However the MET is only partial, re-expression of E-Cadherin does not completely suppress the expression of the mesenchymal markers Vimentin and FSP1 [97], thus retain abilities for trans-endothelial migration [84].

Tumor-stromal cell interactions are important; in occupying the hematopoietic stem cell (HSC) niche tumor cells interact with bone marrow osteoblasts. The binding of tumor cells to bone marrow osteoblasts induces TANK binding kinase 1 (TBK1) expression that leads to inhibition of mTOR signaling and cell cycle arrest. Various cytokines and chemokines produced by osteoblasts determine the proliferative activity of the implanted tumor cell.

Growth arrest specific gene 6 (GAS6) is a growth factor that regulates cell cycling of HSCs and is expressed by osteoblasts, it acts as a ligand for the AXL, TYRO3 and MERTK family of tyrosine kinase receptors [98] inhibiting tumor cell proliferation through G1 cell cycle arrest and S cell cycle phase delay [99]. GAS6 overexpression activates MERTK via phosphorylation leading to a decreased p-ERK/p-p38 and increased cell cycle inhibitors/dormancy associated transcription factors p27, NR2F1, SOX2 and NANOG [100]. In the presence of GAS6 there is an increased AXL/TYRO3 receptor ratio that increases growth arrest, changes in this ratio of receptor expression changes the cells ability to enter or exit dormant or proliferative states [101]. GAS6 binds to the TAM receptor Axl on prostate cancer tumor cells which in turn induces expression of TGF-β1 and β2, this stimulates paracrine secretion (from osteoblasts) and autocrine secretion (from tumor cells) and leads to tumor cell dormancy through up-regulation of p27 an ubiquitous cell cycle inhibitor [102].

Thus GAS 6 appears to be important in tumor cells remaining dormant in the bone marrow niche and thus viable for extended periods. There is also evidence that GAS6 increases the number of prostate cancer cells with a stem cell phenotype, which is CD133 positive/CD44 positive, within the bone marrow [103]. Cancer stem cells (CSCs) are proposed to be stem like cells found in tumors and possess the capability to self-renew and differentiate into new diverse tumor cells. They represent a subpopulation of tumor cells that express specific surface antigens and possess mesenchymal phenotypes. The hematopoietic niche has the molecular mechanisms to regulate stem cell quiescence and self-renewal. Using murine models of human metastasis, it has been shown that of prostate cancer tumor cells recovered from bone marrow was significantly enriched for CSCs [104]. The expression of CD133 and CD44 was used to identify CSCs, increases in cytokine levels in bone marrow after intra-cardiac injection of tumor cells quickly returns to basal levels, using BrdU labeling CSCs had a lower proliferation rate compared with non-stem cell tumor cells, nor was there evidence that there was selective homing of CSCs or increased survival in the circulation [104]. It was further shown that direct cell-to-cell contact of prostate cancer cells and osteoblasts causes a significant shift from non-CSCs to CSCs [104]. GAS6 regulates part of the conversion of tumor cells into stem cells via its receptor Mer that activates the mTOR signaling pathway following cell to cell contact [104]. Furthermore, GAS6 inhibits the cleavage of caspase-3 and PARP to prevent apoptosis of the tumor cell [99]. When tumor cells are cultured with GAS6-null osteoblasts the conversion to CSCs is significantly diminished, and in mice models CSCs are found in much higher numbers in endothelial bone surfaces expressing GAS6 [104]. These changes to form CSCs are seen only in bone marrow and not in lung or spleen [104] and as such the bone marrow plays an important role in the accumulation of self-renewing, slowly proliferating CSCs. The growth of CSCs in the bone marrow depends on the GAS6 pathway, not only its expression in osteoblasts but also in prostate cells [101]. Consistently when prostate cancer cells reach the bone marrow Axl expression in prostate cells and GAS6 expression in osteoblasts both increase simultaneously [105]. The implication is that stromal cell-tumor cell contact converts the implanted tumor cells into cancer stem cells, which have the capability to self-renew and are resistant to chemo and radiotherapy.

It has also been reported that the microenvironment also decreases the expression of matrix metalloproteinase-2 (MMP-2). CPCs have been shown to express membrane MMP-2; tumor cells detected in bone marrow aspirates may also express MMP-2; however, on implanting in bone marrow the micrometastasis from low grade tumors and surrounding stromal cells are negative for MMP-2 expression, while in higher-grade cancers the micrometastasis retain MMP-2 expression [106, 107]. MMP-2 is important in the ability of cells to disseminate and in the activation of MMP-9 which leads to neovascularization [106]. The authors suggested that stromal Tissue Inhibitor of Metalloproteinase-2 might be responsible for this finding. Decreased MMP-2 expression together with increased epithelial cell marker expression by tumor cells decreases their ability to further disseminate.

In order to grow, the tumor cells need space within the micrometastatic niche. The Receptor Activator of Nuclear Factor Kappa B-Ligand (RANKL) is expressed by osteoblasts and stromal cells within the bone marrow. RANKL activates osteoclastogenesis that leads to bone reabsorption and creates space for the tumor cells. Osteoclastogenesis causes demineralization and the release of tumor growth stimulating factors from the extracellular matrix [108]. RANKL released from local osteoblasts stimulates the expression of interleukin 6 (IL-6) in the tumor cells. IL-6 activates three major signaling pathways, the Janus tyrosine family kinase (JAK) signal transducer and activator of transcription (STAT) pathway, the ERK1/2 and MAPK pathway and the PI3-K pathway. These signaling pathways regulate apoptosis and thus cell survival and cellular proliferation and play a key role in bone metastasis [109]. The secretion of IL-6 from tumor cells induces bone turnover and enhances osteoclastogenesis and osteoblast differentiation [110] which in turn leads to production of IL-6 by osteoblasts and further stimulates tumor cell proliferation in a paracrine fashion [111]. The IL-6 expressed by tumor cells stimulates the expression of RANKL and increases tumor cell sensitivity to its effects [112]. The inhibition of IL-6 production with tocilizumab decreases skeletal tumor growth, serum RANKL levels and RANK expression in animal models [112].

Escaping from dormancy

Little is known on how cells escape from dormancy, many hypotheses have been proposed on how tumor cells are maintained in a dormant or indolent state before the emergence of overt metastasis. The lack of angiogenesis, immune surveillance by T-cells, balanced proliferation and apoptosis have all been proposed [113]. The majority of patients have tumor cells negative for Ki-67, a marker for cellular proliferation [114], although the fraction of Ki-67 positive cells in higher in more aggressive cancers [115]. More recently there is experimental evidence using mouse models that aberrant unregulated expression of the vascular cell adhesion molecule-1 (VCAM-1) is involved in the progression from indolent to overt metastasis [116]. It is thought to recruit pre-osteoclasts to the bone marrow micrometastasis and promotes signal flow through the P13K-Akt pathway and possibly dependent on an intact NFκB pathway [117]. More recently the identification of microRNAs (miRs) as regulators of the transcriptome are involved in this process. Sixteen miRs were found to be highly expressed in dormant tumors, down-regulation of these dormancy associated miRs was correlated to the switch to a fast growing angiogenic phenotype [117]. miR-580 and miR-190 expression was shown to be inversely reverted to disease stage. It is thought that loss of dormancy associated miRs switches tumor cells to a stage of exponential growth [117]. Two important targets of miR-580 and miR-190 are the EphA5 and Angiomotin genes, both are expressed in dormant tumors, are inversely related to tumor stage and down regulated during the angiogenic switch [118]. The circulating protein products of these two genes, EphA5 and angiostatin, respectively, are correlated with the tumor dormancy phase [118].

Once free from dormancy, there is tumor growth and the appearance of clinical and radiological evidence of metastasis.

Changing the soil selects the seed—Paget revisited

Micrometastatic growth is seen in clinical practice as an increase in serum PSA after curative therapy and before any imaging studies show evidence of metastatic disease and is defined as biochemical failure.

First line treatment is with androgen deprivation therapy (ADT) which can be achieved by bilateral orchiectomy (surgical castration) or more frequently a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist (medical castration) which appear to be equally effective [119]. Treatment success is reflected in a decreasing serum PSA, but after a variable time period the serum PSA increases although the serum testosterone remains at castrate levels (< 50 ng/dl) and defined as castrate resistant prostate cancer.

A fundamental question is whether the ADT resistant tumor cells are a result of clonal selection or clonal evolution as a result of genetic instability or both. In the case of clonal selection, the phenotypic and genotypic characteristics should be present in at least a subgroup of tumor cells in the primary tumor: The use of ADT gives this cells a selective advantage permitting them to proliferate and form metastasis. With clonal evolution the tumor cells may not be present in the primary tumor, but with time the genotype has evolved to an ADT resistant phenotype. There are few clinical reports of sequential changes with time, the majority are in animal models, or comparing ADT sensitive and resistant tumors after ADT.

In animal models ADT causes EMT with increases in the expression of N-cadherin, Zeb1, Twist 1 and Slug and decreases in E-cadherin. Although the tumors diminished in size, the surviving tumor cells had increased “stemness” and activated TGF-beta both at mRNA and protein expression levels, as well as N-cadherin and vimentin and decreased E-cadherin [120]. These changes have been observed in human prostate cancer tissue [121]. Zeb 1 appears to mediate androgen deprivation induced EMT via a bidirectional negative feedback loop with ADT and its inhibitor miR-200b decreases [120]. Over expression of Zeb 1 is sufficient to switch cells from a non-cancer stem cell to a cancer stem cell status and required for maintaining tumor cells in a stem cell state [122]. These cancer stem cells express the CD133 membrane protein as well as CD44. As to the question of the origin of these cells, it has been reported that the basal cells of prostate contain a subpopulation of androgen independent epithelial stems cells [123], furthermore it has been reported that prostate cancers contain both androgen dependent and independent tumor cells. The selective pressure of ADT causes clonal expansion of the androgen insensitive cells altering their relative frequency and leads to the development of castrate resistance [124]. Hormone free cell cultures obtained from early stage prostate cancer specimens showed that colonies of androgen independent cells grow in 70% of cases, supporting the hypothesis that clonal selection may be a key mechanism in castrate resistant prostate cancer [125].

In the clinical, the expression of HER-2 has been associated with resistance to ADT. Prostate cancer and bone marrow micrometastasis contained both HER-2 positive and negative cells, that the risk of treatment failure was similar in patients with HER-2 positive and negative micrometastasis. However, after starting ADT there was selection of HER-2 expressing cells, HER-2 negative cells being eradicated and these men had a higher risk of progressing to castrate resistant prostate cancer and a shorter time to treatment failure with ADT [126, 127].

Mechanisms of androgen resistance

Patients treated with androgen/androgen receptor (AR) directed therapies, including abiraterone and enzalutamide have tumor cells with a molecular signature consistent with continued “addiction” to AR. These cells acquire or possessed molecular alterations in the AR axis. The AR gene is frequently amplified or mutated (62%) and less frequently there is amplification of the androgen receptor (< 1%). In primary prostate cancer specimens there are numerous reports of recurrent somatic mutations, copy number alterations and oncogenic structural DNA arrangements [128130]. These include point mutations in SPOP, FOXA1, TP53, copy number alterations involving Myc, PTEN, CHD1 and transformation specific (ETS) fusions of which some have prognostic significance [131]. The combination of Myc activation and PTEN loss are sufficient to create genomic instability and lethal metastatic prostate cancer [132]. In men with castrate resistant prostate cancer genomic studies showed a high frequency of AR pathway alterations; this suggests that the tumor cells remain dependent of AR signaling for viability. In metastatic castrate resistant prostate cancer there is frequently over-expression of both full length AR (AR-FL) and AR variants (AR-V). AR-Vs are alternatively spliced isoforms of the AR mRNA, and lack the ligand binding domain, which is the intended target of all existing androgen/AR directed therapies. AR-Vs can activate AR signaling in the absence of androgens or the AR-FL. The levels of expression of AR-Vs are increased in castrate resistant prostate cancer, in response to AR blockade and associated with disease progression [133]. AR-V7 is the more frequently found variant and often co-expressed with AR-FL, the levels of nuclear AR-Vs required to drive an androgen-independent transciptome remains unclear. The levels of AR-V mRNA and protein expression relative to AR-FL varies within normal and malignant prostate tissues [133], CPCs [134] and prostate cancer cell lines [133]. The mechanism to achieve AR-V is unknown, rearrangements of the AR gene and/or changes in splicing dynamics have been suggested. AR-Vs not only activate transcription of AR regulated target genes such as PSA, HK2, TMPRSS2 and NK-X3-I [135] but also genes associated with the regulation of the cell cycle [136]. Over-expression of AR-V7 has been shown to be associated with higher levels of SNAIL, TWIST, N-cadherin and ZEB1 without affecting E-cadherin expression, with the suggestion that over-expression of AR-V s produces a partial EMT [137]. Similarly, the expression of AR-V3 was higher in Gleason 7–9 primary tumors, was shown to involved in inducing stem cell markers such as Nanog and Lin28B and EMT markers, and finally the use of enzalutamide led to increased AR-V3 expression [137].

As such it would seem that in the primary tumor cancer stem cells are present and disseminate, whether there is clonal selection or clonal evolution or both, and the relative importance of either remains unknown.

Circulating tumor cell and micrometastasis detection

The first reports of bone marrow micrometastasis in men with prostate cancer used bone marrow aspiration samples, differential gel centrifugation to enrich tumor cells and immunocytochemistry with anti-cytokeratin antibodies to detect tumor cells [138]. The frequency of tumor cell detection depends on the method used, immunocytochemistry or RT-PCR and the marker, PSA, PMSA or cytokeratins. Detection of PSA mRNA using RT-PCR was not associated with the results of immunocytochemistry [139], is limited by the illegitimate transcription of tumor associated or epithelial specific genes in hematopoietic cells and the deficient expression of the marker gene in tumor cells [140]. Both immunocytochemistry and RT-PCR have similar specificities (PSA mRNA versus anti-PSA) but RT-PCR has a tenfold increased sensitivity at detecting micrometastasis [141].

It has been suggested that cells detected in bone marrow aspirates may not represent true “micrometastasis” but rather are prostate cells circulating in the bone marrow compartment, explaining the expression of similar phenotypic markers, as CPCs. “True” micrometastasis were those detected in biopsy specimens. The low concordance between prostate cells detected in bone marrow aspirates with those detected in biopsies for patients with Gleason 5, 6 and 7 suggests there is a difference in their physiological/oncological role. In high grade Gleason 8 and 9 there is good concordance between the results of the two methods of sampling. There are no studies of in vivo tumor cell rheology in the bone marrow. However, there are in vivo optical imaging studies in laboratory animals demonstrating the mechanisms of tumor cell attachment to the endostium that are similar to stem cell engraftment [142, 143]. Topological and chronological patterns of stem cell seeding have shown that most cells drift within the bone marrow space and then are gradually found close to the endosteal surface. The center of the bone marrow space seems to be the site of proliferation of the transplanted cells and not at the endosteal surface [144]. Further data has shown that the adherent cells are viable, whereas cells in transit contain a percentage of dead or dying cells [145]. Thus cells anchored to the endothelial surface may not be detected in bone marrow aspirates and thus explain partially why aspirate negative patients may relapse in the bone, or inversely why bone marrow aspirate negative patients go on to development bony metastasis. In high grade cancer the interchange between attached and in transit may be sufficiently high so as the results of aspirate and biopsy are concordant [106].

There are a number of techniques that have been developed for the detection of circulating tumor cells, which has hindered the comparison of different studies and the consensus of defining these cells. Each method has differing advantages and disadvantages and has been extensively reviewed [118, 146]. In summary because of the rarity of these cells, enrichment methods are used to concentrate CPCs. Density gradient centrifugation separates a layer of mononuclear blood cells and CPCs from other blood cells, it is a simple fast process but tumor cells may be lost during the process, as they sediment to the granulocyte fraction or when present as clusters sediment to the bottom of the tube. Due to the size differences between CPCs and normal blood cells filtration has been used as a method to enrich CPCs from whole blood. The OncoQuick® system uses a porous barrier above the density gradient while the Screencell® cyto, ISET® and Metacell® are three commercially available filtration systems. CPCs are isolated on the filter and then subsequently stained. The filter based systems do not detect CPCs smaller than 8 µm, and the filter may become clogged during the process [118, 147]. Leukapheresis of large blood volumes has been reported to detect CTCs in up to 90% of non-metastatic breast cancer patients, the authors also reported that in healthy controls there was a high background of cytokeratin positive CD45 positive cells due to false positive staining of leukocytes [148]. The FDA approved CellSearch® system uses immunomagnetic selection of CTCs with anti-EpCAM (positive selection) while there are methods using depletion of CD45 positive (leukocytes) (negative selection). In high risk prostate cancer patients CPCs were detected in 37% of patients using CellSearch®, 55% with Cellcollector®, and 59% with Epispot® [149]. The use of specific antibodies such as EpCAM to enrich CPCs results in the loss of CPCs which have undergone EMT.

Clinical evidence and possible uses

Studies reported that the presence of micrometastasis was associated with tumor stage and Gleason score [150152], however other reports did not confirm this finding [139, 153, 154]. Furthermore samples taken after radical prostatectomy or radiotherapy had a lower frequency of micrometastatic detection [153, 155, 156] and that these cells were cytogenetically aberrant [157]. The inference of these findings is either local removal of the primary tumor decreases or eliminates micrometastatic disease, that is to say that the micrometastasis is dependent on a factor produced by the primary tumor in order to survive or the method of detection in some way is deficient or the interpretation of what the test is detecting. Using bone marrow aspirate and biopsy samples it was shown that there was no difference in the frequency of micrometastasis detected pre-treatment but there was a significant difference post-treatment, there was a significant reduction in “micrometastasis” detected in bone marrow aspirates [158]. Phenotypic classification of circulating prostate cells, and cells detected in bone marrow aspirates were similar but differed from the phenotypic characteristics of prostate cells detected in bone marrow biopsies with respect to CD82 and MMP-2 [106].

The detection of prostate cells in bone marrow aspirate samples as a prognostic marker has given conflicting results; this may be in part due to a short follow up time. Some studies have reported no association with biochemical failure [159, 160], whereas others have reported a higher rate of failure when detected in post-treatment samples [156, 161].

There is more evidence for the prognostic role of secondary circulating prostate cells that is those detected after curative therapy. In patients with non-metastatic disease the presence of secondary CPCs is associated with early relapse [162165]. Their presence was associated with a shorter PSA doubling time and shorter time to treatment failure [166]. EpCAM based detection systems failed to show an association with prognosis [167, 168] in men with localized prostate cancer. In contrast using telomerase based technology [169] or RT-PCR [170] an association as an independent prognostic factor was reported.

More recently, it has been reported that men CPC positive have a higher risk of early treatment failure, whereas those with only bone marrow micrometastasis have an identical failure rate to men negative for CPCs and micrometastasis up to 5 years of follow-up, after this time there is increasing failure in this group. This suggests that there are two types of minimal residual disease, one associated with a more aggressive outcome, that is CPC positive, and one showing features of dormancy and later treatment failure [171].

As a guide to treatment options

Standard recommendations include the following; in men with positive surgical margins radiotherapy is suggested as adjuvant therapy to eradicate local foci of tumor left behind at surgery. At the time of biochemical failure, salvage radiotherapy or androgen deprivation therapies are alternatives. The use of PSA kinetics, time to relapse, PSA doubling time and Gleason score have all been proposed to define local or systemic failure. However, in this group of patients 67% were found to have bone marrow micrometastasis. In comparison with the anterior parameters, there was no association with micrometastatic disease. The detection of bone marrow micrometastasis implies the presence of systemic relapse and such systemic treatment [172]. First line ADT treatment is with a LHRH agonist or antogonist, there is normally a decrease in the serum PSA for a period of 3–5 years. Thereafter resistance to ADT develops with an increasing PSA and testosterone levels < 50 ng/dl, second line hormonal therapy using newer agents such as aberiterone or enzulatamide are used, and finally if failure continues the use of taxanes. This may be accompanied by the appearance of bone metastasis in imaging studies.

It has been shown that ADT can eliminate bone marrow micrometastasis in approximately 80% of patients [173, 174]. Further studies reported that micrometastatic cells expressing HER-2 were resistant to ADT and were selected in an androgen-deprived environment [125]. Thus although serum PSA decreased with ADT, a population of resistant cells were selected which later produced PSA failure. In contrast treatment with diethylstilbestrol eliminated both positive and negative expressing HER-2 cells, possibly by stimulating beta estrogen receptor and blocking HER-2 stimulation of the androgen receptor (AR) downstream [125]. The AR antagonist bicalutamide is effective in treating prostate cancer, irrespective of HER-2 expression levels [175]. The expression of HER-2 was similar in CPCs and bone marrow micrometastasis [125]. Thus the expression of HER-2 could be used to select the better treatment option. Continued AR activity in resistant cancer has been linked to the expression of a number of truncated but constitutively active AR isoforms. One such variant is AR-v7; classifying patients as CPC negative, and CPC positive AR-v7 negative and positive it was possible to determine three prognostic subgroups, CPC negative having the best prognosis, CPC positive AR-v7 positive the worst [176]. The frequency of CPCs expressing mRNA for AR-v7 increases with successive endocrine therapies [177], overall survival was superior with the use of taxanes in these positive patients. The expression of AR-v7 in CPCs is associated with resistance to abiraterone and enzalutamide but not resistance to cabazitaxal [178]. Using single cell immunofluorescence analysis, CPCs were predominately AR-on (AR activity positive) pre ADT, first line ADT produced a switch from AR-on to AR-off (AR activity negative) CPCs, whereas variable expression was seen after second line ADT. The presence of AR-mixed or increasing AR-on expressing CPCs while being treated with abiraterone was associated with a decreased survival [179]. Thus the possibility of determining the best treatment options using CPC phenotypic expression seems possible, as well as detecting resistance to treatment before detectable disease progression.

What is important is that CPC detection is method dependent, and as such there is no consensus on the best approach for their detection. Those methods relying on specific markers will not detect CPCs lacking the determined marker and this may be stage dependent and on the presence of EMT and MET.

Conclusions

with advancing technology and single cell gene analysis the use of liquid biopsies of CPCs may be useful in the classification of patients, assess the risk of treatment failure in specific patients and which treatments may be more appropriate. In combination with the analysis of micrometastatic cells found in bone marrow, it may be possible to tailor treatment to eliminate these residual cells or maintain this cell population in a dormant state on an individual patient basis.

Declarations

Authors’ contributions

NPM wrote the manuscript. The author read and approved the final manuscript.

Acknowledgements

Special thanks to Mrs. Ana Maria Palazuelos for her help in the writing of the manuscript.

Competing interests

Dr. Murray has received consultancy fees from Viatar CTC Solutions, Boston, USA.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Ethics approval and consent to participate

All articles reviewed in this paper had been approved by the relevant local ethics committees. No patients participated in this review article and given that this was a systematic review which utilizes published data, ethical approval was not required.

Funding

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Circulating Tumor Cell Unit, Faculty of Medicine, University Finis Terrae, Av Pedro de Valdivia 1509, Providencia, Santiago, Chile

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86. https://doi.org/10.1016/S1470-2045(14)71123-4 (Epub 2014 Nov 26).PubMedView ArticleGoogle Scholar
  2. Han M, Partin AW, Chan DY, Walsh PC. An evaluation of the decreasing incidence of positive surgical margins in a large retropubic prostatectomy series. J Urol. 1996;156:137–43. https://doi.org/10.1097/01.ju.0000098604.09395.27.View ArticleGoogle Scholar
  3. Freedland SJ, Partin AW, Epstein JI, Walsh PC. Biochemical failure after radical prostectomy in men with pathologic organ confined disease: pT2a versus pT2b. Cancer. 2004;100:1646–9. https://doi.org/10.1002/cncr.20145.PubMedView ArticleGoogle Scholar
  4. Pinto F, Prayer-Galetti T, Gardiman M, Sacco E, Ciaccia M, Fracalanza S, et al. Clinical and pathological characteristics of patients presenting with biochemical progression after radical retro-pubic prostatectomy for pathologically organ-confined prostate cancer. Urol Int. 2006;76:202–8. https://doi.org/10.1159/000091619.PubMedView ArticleGoogle Scholar
  5. Chun FK, Graefen M, Zacharias M, Haese A, Steuber T, Schlomm T, et al. Anatomic radical retro-pubic prostatectomy: long term recurrence free survival rates for localized prostate cancer. World J Urol. 2006;24:273–80. https://doi.org/10.1007/s00345-006-0058-2.PubMedView ArticleGoogle Scholar
  6. Amling CL, Blute ML, Bergstralh EJ, Seay TM, Slezak J, Zincke H. Long term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol. 2000;164:101–5.PubMedView ArticleGoogle Scholar
  7. Loeb S, Feng Z, Ross A, Trock BJ, Humphreys EB, Walsh PC. Can we stop PSA testing 10 years after radical prostatectomy? J Urol. 2011;186:500–5. https://doi.org/10.1016/j.juro.2011.03.116.PubMedPubMed CentralView ArticleGoogle Scholar
  8. Kane CJ, Amling CL, Johnstone PA, Pak N, Lance RS, Thrasher JB, et al. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology. 2003;61:607–11.PubMedView ArticleGoogle Scholar
  9. Moreira DM, Cooperberg MR, Howard LE, Aronsen WJ, Kane CJ, Terris MK, et al. Predicting bone scan positivity after biochemical recurrence following radical prostatectomy in both hormone naïve men and patients receiving androgen deprivation therapy: results from the SEARCH database. Prostate Cancer Prostatic Dis. 2014;17:91–6. https://doi.org/10.1038/pcan.2013.59.PubMedPubMed CentralView ArticleGoogle Scholar
  10. Lenzo NP, Meyrick D, Turner JH. Review of Gallium-68 PSMA PET/CT imaging in the management of prostate cancer. Diagnostics. 2018;8:16. https://doi.org/10.3390/diagnostics8010016.PubMed CentralView ArticleGoogle Scholar
  11. van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B, et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int. 2016;117:732–9. https://doi.org/10.1111/bju.13397.PubMedView ArticleGoogle Scholar
  12. Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, et al. Senstivity, specificity and predictors of positive 68Ga-PSMA PET/CT in advanced prostate cancer: A systemic review and meta-analysis. Eur Urol. 2016;70:926–37. https://doi.org/10.1016/j.eururo.2016.06.021.PubMedView ArticleGoogle Scholar
  13. Rauscher I, Duwel C, Haller B, Rischpler C, Heck MM, Gschwend JE, et al. Efficacy, predictive factors and predictive nomograms for 68Ga labeled PSMA PET/CT in early biochemical recurrent prostate cancer after radical prostatectomy. Eur Urol. 2018;73:656–61. https://doi.org/10.1016/j.eururo.2018.01.006.PubMedView ArticleGoogle Scholar
  14. Eissa A, El Sherbiny A, Coelho RF, Rasseiler J, Davis JW, Porpiglia F, et al. The role of 68 Ga-PSMA PET/CT scan in biochemical recurrence after primary treatment for prostate cancer: a systemic review of literature. Minerva Urol Nefrol. 2018. https://doi.org/10.23736/SO393-2249.18.03081-3.View ArticlePubMedGoogle Scholar
  15. Noto B, Auf der Springe K, Huss S, Allkemper T, Stegger L. PSMA negative metastases-a potential pitfall in PSMA PET. Clin Nucl Med. 2018;43:186–8. https://doi.org/10.1097/RLU002073.View ArticleGoogle Scholar
  16. Afshar-Oromieh A, Sattler LP, Steiger K, Holland-Letz T, da Cunha ML, Mier W, et al. Tracer uptake in mediastinal and paraaortal thoracic lymph nodes as a potential pitfall in image interpretation of PMSA ligand PET/CT. Eur J Nucl Med Mol Imaging. 2018;45:1179–87. https://doi.org/10.1007/s00259-018-3965-8.PubMedView ArticleGoogle Scholar
  17. Rischpler C, Beck TI, Okamoto S, Schlitter AM, Knorr K, Schwaiger M, et al. 68Ga-PSMA_HBED_CC uptake in cervical, coeliac and sacral ganglia as an important pitfall in prostate cancer PET imaging. J Nucl Med. 2018. https://doi.org/10.2967/jnumed.117.204677.PubMedView ArticleGoogle Scholar
  18. Muller V, Alix-Panabieres C, Pantel K. Insights into minimal residual disease in cáncer patients:implications for anti-cancer therapies. Eur J Cancer. 2010;46:1189–97. https://doi.org/10.1016/j.ejca.2010.02.038.PubMedView ArticleGoogle Scholar
  19. Ignatiadis M, Reinholz M. Minimal residual disease and circulating tumor cells in breast cancer. Breast Cancer Res. 2011;13:222. https://doi.org/10.1186/bcr2906.PubMedPubMed CentralView ArticleGoogle Scholar
  20. Bork U, Grutzmann R, Rahbari NN, Scholch S, Distler M, Reissfelder C, et al. Prognostic relevance of minimal residual disease in colorectal cancer. World J Gastroenterol. 2014;20:10296–304. https://doi.org/10.3748/wjg.v20.i30.10296.PubMedPubMed CentralView ArticleGoogle Scholar
  21. Mordant P, Loriot Y, Lahon B, Castier Y, Leseche G, Soria JC, et al. Minimal residual disease in solid neoplasia: New frontier or red-herring? Cancer Treat Rev. 2012;38:101–10. https://doi.org/10.1016/j.ctrv.2011.04.014.PubMedView ArticleGoogle Scholar
  22. Ashworth TR. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Med J Aust. 1869;14:146–9.Google Scholar
  23. Joose SA, Gorges TM, Pantel K. Biology, detection and clinical implications of circulating tumor cells. EMBO Mol Med. 2015;7:1–11. https://doi.org/10.15252/emmm.201303698.View ArticleGoogle Scholar
  24. McDonald DM, Baluk P. Significance of blood vessel leakiness in cancer. Can Res. 2002;62:5381–5.Google Scholar
  25. Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000;156:1363–80. https://doi.org/10.1016/S0002-9440(10)65006-7.PubMedPubMed CentralView ArticleGoogle Scholar
  26. Granger DN, Grisham MB, Kvierys PR. Mechanisms of microvascular injury. In: Johnson LR, editor. Physiology of the gastrointestinal tract. New York: Raven Press; 1994. p. 1693–722.Google Scholar
  27. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7. https://doi.org/10.1038/nature01322.PubMedPubMed CentralView ArticleGoogle Scholar
  28. Pantel K, Deneve E, Nocca D, Coffy A, Vendrell JP, Maudelonde T, et al. Circulating epitelial cells in patients with benign colon diseases. Clin Chem. 2012;58:936–40. https://doi.org/10.1373/clinchem.2011.175570.PubMedView ArticleGoogle Scholar
  29. Murray NP, Reyes E, Badínez L, Orellana N, Fuentealba C, Olivares R, et al. Circulating prostate cells found in men with benign prostate disease are P504S negative: clinical implications. J Oncol. 2013;2013:165014. https://doi.org/10.1155/2013/165014.PubMedPubMed CentralView ArticleGoogle Scholar
  30. Eschwege P, Dumas F, Blanchet P, Le Maire V, Benoit G, Jardin A, et al. Haematogenous dissemination of prostatic epithelial cells during radical prostatectomy. Lancet. 1995;346:1528–30.PubMedView ArticleGoogle Scholar
  31. Oefelein MG, Kaul K, Herz B, Blum MD, Holland JM, Keeler TC, et al. Molecular detection of prostate epithelial cells from surgical field and peripheral circulation during radical prostatectomy. J Urol. 1996;155:238–42.PubMedView ArticleGoogle Scholar
  32. Tsumura H, Satoh T, Ishiyama H, Tabata KI, Takenaka K, Sekiguchi A, et al. Perioperative search for circulatingtumor cells in patients undergoing prostate brachytherapia for clinicaqlly nonmetastatic prostate cancer. Int J Mol Sci. 2017;18:E128. https://doi.org/10.3390/ijms18010128.PubMedView ArticleGoogle Scholar
  33. Murray NP, Reyes E, Orellana N, Fuentealba C, Dueñas R, Jacob O. Expression of P504S and matrix metalloproteinase-2 in circulating prostate cells disseminated as a result of transrectal ultrasound guided biopsy as determined by immunocytochemistry: clinical implications. Arch Esp Urol. 2015;68:474–81.PubMedGoogle Scholar
  34. Friedl P, Wolf K. Proteolytic interstitial cell migration: a five step process. Cancer Metastasis Rev. 2009;28:129–35. https://doi.org/10.1007/s10555-008-9174-3.PubMedView ArticleGoogle Scholar
  35. Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19:1438–49. https://doi.org/10.1038/nm.3336.PubMedPubMed CentralView ArticleGoogle Scholar
  36. Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:12348–50. https://doi.org/10.1126/science.1234850.View ArticleGoogle Scholar
  37. Jaggi M, Johansson SL, Baker JJ, Smith LM, Galich A, Balaji KC. Aberrant expression of E-cadherin and beta-catenin in human prostate cancer. Urol Oncol. 2005;23:402–6. https://doi.org/10.1016/j.urolonc.2005.03.024.PubMedView ArticleGoogle Scholar
  38. Umbas R, Schalken JA, Aalders TW, Carter BS, Karthaus MF, Schaafsma HE, et al. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res. 1992;52:5104–9.PubMedGoogle Scholar
  39. Pontes J Jr, Srougi M, Borra PM, Dall`Oglio MF, Ribeiro-Filho LA, Leite KR, et al. E-cadherin and beta-catenin loss of expression related to bone metastasis in prostate cancer. Appl Immunohistochem Mol Morphol. 2010;18:179–84. https://doi.org/10.1097/PAI.0b013e3181640bca.PubMedView ArticleGoogle Scholar
  40. Murant SJ, Handley J, Stower M, Reid N, Cussenot O, Maitland NJ. Co-ordinated changes in expression of cell adhesion molecules in prostate cancer. Eur J Cancer. 1997;33:263–71.PubMedView ArticleGoogle Scholar
  41. Alberti I, Barboro P, Barbesino M, Sanna P, Pisciotta L, Parodi S, et al. Changes in the expression of cytokeratins and nuclear matrix proteins are correlated with the level of differentiation in human prostate cancer. J Cell Biochem. 2000;79:471–85.PubMedView ArticleGoogle Scholar
  42. Friedlander TW, Ngo VT, Dong H, Premasekharan G, Weinberg V, Doty S, et al. Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration-resistant prostate cancer. Int J Cancer. 2014;134:2284–93. https://doi.org/10.1002/ijc.28561.PubMedView ArticleGoogle Scholar
  43. Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, et al. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res. 2011;9:997–1007. https://doi.org/10.1158/1541-7786.MCR-10-0490.PubMedPubMed CentralView ArticleGoogle Scholar
  44. Chen CL, Mahalingam D, Osmulski P, Jadhav RR, Wang CM, Leach RJ, et al. Single-cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT-related genes in metastatic prostate cancer. Prostate. 2013;73:813–26. https://doi.org/10.1002/pros.22625.PubMedView ArticleGoogle Scholar
  45. Kuphal F, Behrens J. E-cadherin modulates Wnt dependent transcription in colorectal cancer cells but does not alter Wnt independent gene expression in fibroblasts. Exp Cell Res. 2006;312:457–67. https://doi.org/10.1016/j.yexcr.2005.11.007.PubMedView ArticleGoogle Scholar
  46. Asnaghi L, Vass WC, Quadri R, Day PM, Quian X, Braverman R, et al. E-cadherin negatively regulates neoplastic growth in non-small cell lung cancer: role of Rho GTPases. Oncogene. 2010;29:2760–71. https://doi.org/10.1038/onc.2010.39.PubMedPubMed CentralView ArticleGoogle Scholar
  47. Mao Z, Ma X, Rong Y, Cui L, Wang X, Wu W, et al. Connective tissue growth factor enhances the migration of gastric cancer through down-regulation of E-cadherin via the NF-kappaB pathway. Cancer Sci. 2011;102:104–10. https://doi.org/10.1111/j.1349-7006.2010.01746.x.PubMedView ArticleGoogle Scholar
  48. Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, et al. Ex vivo culture of circulating breast tumor cells for individual testing of drug susceptibility. Science. 2014;345:216–20. https://doi.org/10.1126/science.1253533.PubMedPubMed CentralView ArticleGoogle Scholar
  49. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90. https://doi.org/10.1016/j.cell.2009.11.007.PubMedView ArticleGoogle Scholar
  50. Ross JS, Kaur P, Sheehan CE, Fisher HA, Kaufman RA Jr, Kallakury BV. Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer. Mod Pathol. 2003;16:198–205. https://doi.org/10.1097/01.MP.0000056984.62360.6C.PubMedView ArticleGoogle Scholar
  51. Trudel D, Fradet Y, Meyer F, Harel F, Tetu B. Significance of MMP-2 expression in prostate cancer: an immunohistochemical study. Cancer Res. 2003;63:8511–5.PubMedGoogle Scholar
  52. Godhinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, et al. Oncogene like induction of cellular invasión from centrosome amplification. Nature. 2014;510:167–71. https://doi.org/10.1038/nature13277.View ArticleGoogle Scholar
  53. Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labelled with 125 I-5-yodo-2′-deoxyuridine. J Natl Cancer Inst. 1970;45:773–82.PubMedGoogle Scholar
  54. Liotta LA, Saidel MG, Klienerman J. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res. 1976;36:889–94.PubMedGoogle Scholar
  55. Carvalho FL, Simons BW, Antonarakis ES, Rasheed Z, Douglas N, Villegas D, et al. Tumorigenic potential of circulating prostate tumor cells. Oncotarget. 2013;4:413–21. https://doi.org/10.18632/oncotarget.895.PubMedPubMed CentralView ArticleGoogle Scholar
  56. Mitchell MJ, King MR. Computational and experimental models of cancer cell response to fluid shear stress. Front Oncol. 2013;3:44. https://doi.org/10.3389/fonc.2013.00044.PubMedPubMed CentralView ArticleGoogle Scholar
  57. Smerage JB, Budd GT, Doyle GV, Brown M, Paoletti C, Muniz M, et al. Monitoring apoptosis and Bcl-2 on circulating tumor cells in patients with metastatic breast cancer. Mol Oncol. 2013;7:680–92. https://doi.org/10.1016/j.molonc.2013.02.013.PubMedPubMed CentralView ArticleGoogle Scholar
  58. Douma S, van Laar T, Zevenhoven J, Meuwissen R, van Garderen E, Peepr DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 2004;430:1034–9. https://doi.org/10.1038/nature02765.PubMedView ArticleGoogle Scholar
  59. Steinert G, Scholch S, Niemietz T, Iwata N, Garcia SA, Behrens B, et al. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 2014;74:1694–704. https://doi.org/10.1158/0008-5472.CAN-13-1885.PubMedView ArticleGoogle Scholar
  60. Liu Q, Liao Q, Zhao Y. Myeloid derived suppressor cells (MDSC) facilitate distant metastasis of malignancies by shielding circulating tumor cells (CTCs) d from immune surveillance. Med Hypothesis. 2016;87:34–9. https://doi.org/10.1016/j.mehy.2015.12.007.View ArticleGoogle Scholar
  61. Placke T, Orgel M, Schaller M, Jung G, Rammensee HG, Kopp HG, et al. Platelet derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 2012;72:440–8. https://doi.org/10.1158/0008-5472.CAN-11-1872.PubMedView ArticleGoogle Scholar
  62. Uppal A, Wightman SC, Ganai S, Weichselbaum RR, An G. Investigation of the essential role of platelet-tumor cell interactions in metastasis progression using an agent based model. Theor Biol Med. 2014;11:17. https://doi.org/10.1186/1742-4682-11-17.View ArticleGoogle Scholar
  63. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;133:571–3.View ArticleGoogle Scholar
  64. Fidler IJ, Poste G. The, “seed and soil” hypothesis revisted. Lancet Oncol. 2008;9:8. https://doi.org/10.1016/S1470-2045(08)70201-8.View ArticleGoogle Scholar
  65. Ribatti D, Mangialardi G, Vacca A. Stephen Paget and the “seed and soil” theory of metastatic dissemination. Clin Exp Med. 2006;6:145–9. https://doi.org/10.1007/s10238-006-0117-4.PubMedView ArticleGoogle Scholar
  66. Mundy GR. Metastasis to bone, causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584–93. https://doi.org/10.1038/nrc867.PubMedView ArticleGoogle Scholar
  67. Cawthorn TR, Amir E, Broom R, Freedman O, Gianfelice D, Barth D, et al. Mechanisms and pathways of bone metastasis: challenges and pitfalls of performing molecular research on patient samples. Clin Exp Metastasis. 2009. https://doi.org/10.1007/s10585-009-9284-5.PubMedView ArticleGoogle Scholar
  68. Dupont VN, Gentien D, Oberkampf M, De Rycke Y, Blin N. A gene expression signature associated with metastatic cells in effusions of breast carcinoma patients. Int J Cancer. 2007;121:1036–46. https://doi.org/10.1002/ijc.22775.PubMedView ArticleGoogle Scholar
  69. Shen Y, Nilsson SK. Bone, microenvironment and hematopoiesis. Curr Opin Hematol. 2012;19:250–5. https://doi.org/10.1097/MOH.0b013e328353c714.PubMedView ArticleGoogle Scholar
  70. Frenette PS, Pinho S, Lucas D, Scheiermann C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping stone for regenerative medicine. Annu Rev Immunol. 2013;31:285–316. https://doi.org/10.1146/annurev-immunol-032712-095919.PubMedView ArticleGoogle Scholar
  71. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Mac Arthur BD, Lira SA, et al. Mesenchymal and hematopoetic stem cells form a unique bone marrow niche. Nature. 2010;466:829–34. https://doi.org/10.1038/nature09262.PubMedPubMed CentralView ArticleGoogle Scholar
  72. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9:285–93. https://doi.org/10.1038/nrc2621.PubMedPubMed CentralView ArticleGoogle Scholar
  73. Schneider JG, Amend SR, Weilbaecher KN. Integrins and bone metastasis: integrating tumor cell and stromal cell interactions. Bone. 2011;48:54–65. https://doi.org/10.1016/j.bone.2010.09.016.PubMedView ArticleGoogle Scholar
  74. Shiozawa Y, Havens AM, Jung Y, Ziegler AM, Pedersen EA, Wang J, et al. Annexin II/annexin II receptor axis regulates adhesion, migration, homing and growth of prostate cancer. J Cell Biochem. 2008;105:370–80. https://doi.org/10.1002/jcb.21835.PubMedPubMed CentralView ArticleGoogle Scholar
  75. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain hematopoietic stem cells. Nature. 2012;481:457–62. https://doi.org/10.1038/nature10783.PubMedPubMed CentralView ArticleGoogle Scholar
  76. Rossnagi S, Ghura H, Groth C, Altrock E, Jakob F, Schott S, et al. A subpopulation of stromal cells controls cancer cell homing to the bone marrow. Cancer Res. 2018;78:129–42. https://doi.org/10.1158/0008-5472.CAN-16-3507.View ArticleGoogle Scholar
  77. Sipkins DA, Wei X, Juwell WW, Runnels JM, Cote D, Means TK, et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumor engraftment. Nature. 2005;435:969–73. https://doi.org/10.1038/nature03703.PubMedPubMed CentralView ArticleGoogle Scholar
  78. Bandyopadhyay S, Zhan R, Chaudburi A, Watabe M, Pai SK, Hirota S, et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelial leads to metastasis suppressor. Nat Med. 2009;12:933–8. https://doi.org/10.1038/nm1444.View ArticleGoogle Scholar
  79. Murray NP, Badinez L, Badinez O. Expresión del supresor tumoral CD82 en células prostáticas primarias y secundarias en la circulación sanguínea (CPCs) de pacientes con cáncer prostático. Rev Mex Urol. 2010;70:92–6.Google Scholar
  80. Glinskii OV, Huxley VH, Glinsky GV, Pienta KJ, Raz A, Glinsky VV. Mechanical entrapment is insufficient and intercellular adhesion is essential for metastatic cell arrest in distant organs. Neoplasia. 2005;7:522–7.PubMedPubMed CentralView ArticleGoogle Scholar
  81. Brodt P, Fallavollita L, Bresaleir RS, Meterissian S, Norton CR, Wolitzky BA. Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis. Int J Cancer. 1997;71:612–9.PubMedView ArticleGoogle Scholar
  82. Di Bella MA, Flugy AM, Russo D, D`Amato M, De Leo G, Alessandro R. Different phenotypes of colon carcinoma cells interacting with endothelial cells: role of E-selectin and ultrastructural data. Cell Tissue Res. 2003;312:55–64. https://doi.org/10.1007/s00441-003-0704-6.PubMedView ArticleGoogle Scholar
  83. Gout S, Temblay PL, Huot J. Selectins and selectin ligands in extrasation of cancer cells and organ selectivity of metastasis. Clin Exp Metastasis. 2008;25:335–44. https://doi.org/10.1007/s10585-007-9096-4.PubMedView ArticleGoogle Scholar
  84. Schmidmaier R, Baumann P. Anti-adhesion evolves to a promising therapeutic concept in oncology. Curr Med Chem. 2008;15:978–90.PubMedView ArticleGoogle Scholar
  85. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastasis. Am J Pathol. 1998;153:865–73. https://doi.org/10.1016/S0002-9440(10)65628-3.PubMedPubMed CentralView ArticleGoogle Scholar
  86. Kowalski PJ, Rubin MA, Kleer CG. E-cadherin expression in primary carcinomas of breast and its distant metastasis. Breast Cancer Res. 2003;5:R217–22. https://doi.org/10.1186/bcr651.PubMedPubMed CentralView ArticleGoogle Scholar
  87. Wells A, Yates C, Shepard CR. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis. 2008;25:621–8. https://doi.org/10.1007/s10585-008-9167-1.PubMedPubMed CentralView ArticleGoogle Scholar
  88. Graff JR, Gabrielson E, Fujii H, Baylin SB, Herman JG. Methylation patterns of the E-cadherin 5′CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem. 2000;275:2727–32.PubMedView ArticleGoogle Scholar
  89. Chao YL, Shepard CR, Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer. 2010;9:179–98. https://doi.org/10.1186/1476-4598-9-179.PubMedPubMed CentralView ArticleGoogle Scholar
  90. Corn PG, Smith BD, Ruckdeschel ES, Douglas D, Baylin SB, Herman JG. E-cadherin expression is silenced by 5´CpG island methylation in acute leukemia. Clin Cancer Res. 2000;6:4243–8.PubMedGoogle Scholar
  91. Kallakury BV, Sheehan CE, Winn-Deen E, Oliver J, Fisher HA, Kaufman RP Jr, et al. Decreased expression of catenins (alpha and beta), p120 CTN and E-cadherin cell adhesion proteins and E-cadherin gene promoter methylation in prostatic adenocarcinomas. Cancer. 2001;92:2786–95.PubMedView ArticleGoogle Scholar
  92. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, et al. E-cadherin is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 1995;55:5195–9.PubMedGoogle Scholar
  93. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor Snail controls EMT by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83. https://doi.org/10.1038/35000025.PubMedView ArticleGoogle Scholar
  94. Hajra KM, Chen DY, Fearon ER. The SLUG zinc finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62:1613–8.PubMedGoogle Scholar
  95. Nam JS, Ino Y, Kanai Y, Sakamoto M, Hirohashi S. 5-aza-2´-deoxycytidine restores the E-cadherin system in E-cadherin silenced cancer cells and reduces cancer metastasis. Clin Exp Metastasis. 2004;21:49–56.PubMedView ArticleGoogle Scholar
  96. Benton G, Crooke E, George J. Laminin-1 induces E-cadherin expression in 3 dimensional cultured breast cancer cells by inhibiting DNA methyltransferase 1 and reversing promoter methylation status. FASEB J. 2009;23:3884–95. https://doi.org/10.1096/fj.08-128702.PubMedView ArticleGoogle Scholar
  97. Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A. Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron. 2012;5:19–28. https://doi.org/10.1007/s12307-011-0085-4.PubMedView ArticleGoogle Scholar
  98. Dormandy SP, Zhang XM, Basch RS. Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest specific gene 6 (GAS6). Proc Nat Acad Sci USA. 2000;97:12260–5. https://doi.org/10.1073/pnas.97.22.12260.View ArticleGoogle Scholar
  99. Lee E, Decker AM, Cackowski FC, Kana LA, Yumoto K, Jung Y, et al. GAS6 promotes prostate cancer survival by G1 arrest/S phase delay and inhibition of apoptotic pathway during chemotherapy in bone marrow. J Cell Biochem. 2016;117:2815–24. https://doi.org/10.1002/jcb.25582.PubMedPubMed CentralView ArticleGoogle Scholar
  100. Cackowski F, Eber MR, Rhee J, Decker A, Yumoto K, Berry JE, et al. Mer tyrosine kinase regulates disseminated prostate cancer cellular dormancy. J Cell Biochem. 2017;118:891–902. https://doi.org/10.1002/jcb.25768.PubMedView ArticleGoogle Scholar
  101. Taichman RS, Patel LR, Bedenis R, Wang J, Weidner S, Schumann T, et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS ONE. 2013;8:e61873. https://doi.org/10.1371/journal.pone.0061873.PubMedPubMed CentralView ArticleGoogle Scholar
  102. Yumoto K, Eber M, Wang J, Cackowski F, Decker A, Lee E, et al. Axl is required for TGF-β2 induced dormancy of prostate cancer cells in the bone marrow. Sci Rep. 2016;6:36520. https://doi.org/10.1038/srep36520.PubMedPubMed CentralView ArticleGoogle Scholar
  103. Jung Y, Decker AM, Wang J, Lee E, Kana LA, Yumoto K, et al. Endogenous GAS6 and Mer receptor signaling regulate prostate cancer stem cells in bone marrow. OncoTarget. 2016;7:25698–711. https://doi.org/10.1002/jcb.25582.PubMedPubMed CentralView ArticleGoogle Scholar
  104. Shiozawa Y, Berry JE, Eber MR, Jung Y, Yumoto K, Cackowski FC, et al. The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget. 2016;7:41217–32. https://doi.org/10.18632/oncotarget.9251.PubMedPubMed CentralView ArticleGoogle Scholar
  105. Shiozawa Y, Pedersen EA, Patel LR, Ziegler AM, Havens AM, Jung Y, et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation and survival in bone marrow niche. Neoplasia. 2010;12:116–27.PubMedPubMed CentralView ArticleGoogle Scholar
  106. Murray NP, Reyes E, Tapia P, Badinez L, Orellana N, Fuentealba, et al. Redefining micrometastasis in prostate cancer- a comparison of circulating prostate cells, bone marrow disseminated tumor cells and micrometastasis: implications in determining local or systemic treatment for biochemical failure after radical prostatectomy. Int J Mol Med. 2012;30:896–904. https://doi.org/10.3892/ijmm.2012.1071.PubMedView ArticleGoogle Scholar
  107. Murray NP, Reyes E, Tapia P, Badinez L, Orellana N. Differential expression of MMP-2 expression in disseminated tumor cells and micrometastasis in bone marrow of patients with non-metastatic and metastatic prostate cancer: theoretical considerations and clinical implications-an immunocytochemical study. Bone Marrow Res. 2012. https://doi.org/10.1155/2012/259351.PubMedPubMed CentralView ArticleGoogle Scholar
  108. Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80:1546–56.PubMedView ArticleGoogle Scholar
  109. Heinrich PC, Behrmann I, Serge H, Hermanns HM, Muller-Newen G, Schaper F. Principles of Interleukin (IL) 6 type cytokine signaling and its regulation. Biochem J. 2003;374:1–20.PubMedPubMed CentralView ArticleGoogle Scholar
  110. Taichman RS, Loberg RD, Mehra R, Pienta KJ. The evolving biology and treatment of prostate cancer. J Clin Invest. 2007;117:2351–61. https://doi.org/10.1172/JCI31791.PubMedPubMed CentralView ArticleGoogle Scholar
  111. Nguyen DP, Li J, Tewari AK. Inflammation and prostate cancer: the role of interleukin 6. BJU Int. 2014;113:986–92. https://doi.org/10.1111/bju.12452.PubMedView ArticleGoogle Scholar
  112. Zheng Y, Basel D, Chow SO, Fong-Lee C, Kim S, Buttgereit F, et al. Targetting IL-6 and RANKL signaling inhibits prostate cancer growth in bone. Clin Exp Metastasis. 2014;31:921–33. https://doi.org/10.1007/s10585-014-9680-3.PubMedView ArticleGoogle Scholar
  113. Uhr JW, Pantel K. Controversies in clinical cancer dormancy. Proc Natl Acad Sci USA. 2011;108:12396–400. https://doi.org/10.1073/pnas.1106613108.PubMedView ArticleGoogle Scholar
  114. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nature Rev Cancer. 2004;4:448–56. https://doi.org/10.1038/nrc1370.View ArticleGoogle Scholar
  115. Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small cell lung cancer. J Clin Oncol. 2012;30:525–32. https://doi.org/10.1200/JCO.2010.33.3716.PubMedView ArticleGoogle Scholar
  116. Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell. 2011;20:701–14. https://doi.org/10.1016/j.ccr.2011.11.002.PubMedPubMed CentralView ArticleGoogle Scholar
  117. Almog N, Ma L, Raychowdbury R, Schwager C, Erber R, et al. Transcriptional switch of dormant tumors to fast growing angiogenic phenotype. Cancer Res. 2009;69:836–44. https://doi.org/10.1158/0008-5472.CAN-08-2590.PubMedView ArticleGoogle Scholar
  118. van der Toom EE, Verdone JE, Gorin MA, Pienta KJ. Technical challenges in the isolation and analysis of circulating tumor cells. Oncotarget. 2016;7:62754–66. https://doi.org/10.18632/oncotarget.11191.PubMedPubMed CentralView ArticleGoogle Scholar
  119. Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D, et al. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol. 2002;167:1670–4.PubMedView ArticleGoogle Scholar
  120. Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S, et al. Androgen deprivation causes EMT in the prostate: implications for ADT. Cancer Res. 2011;72:527–36. https://doi.org/10.1158/0008-5472.CAN-11-3004.PubMedView ArticleGoogle Scholar
  121. Best CJ, Gillespie JW, Yi Y, Chandramoull GV, Perlmutter MA, Gathright Y, et al. Molecular alterations in primary prostate cancer after androgen ablation therapy. Clin Cancer Res. 2005;11:6823–34.PubMedPubMed CentralView ArticleGoogle Scholar
  122. Chaffer CI, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, et al. Poised chromatin at the Zeb 1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013;154:61–74.PubMedPubMed CentralView ArticleGoogle Scholar
  123. Denmeade SR, Lin XS, Isaacs JT. Role of programmed (apoptotic) cell death during progression and therapy for prostate cancer. Prostate. 1996;28:251–65.PubMedView ArticleGoogle Scholar
  124. Craft N, Chhor C, Tran C, Belldegrun A, DeKemion J, Whitte ON, et al. Evidence for clonal outgrowth of androgen independent prostate cancer cells from androgen dependent tumors through a twostep process. Cancer Res. 1999;59:5030–6.PubMedGoogle Scholar
  125. Finones RR, Yeargin J, Lee M, Kaur AP, Cheng C, Sun P, et al. Early human prostate adenocarcinomas harbor androgen-independent cancer cells. PLoS ONE. 2013;8:e74438. https://doi.org/10.1371/journal.pone.0074438.PubMedPubMed CentralView ArticleGoogle Scholar
  126. Murray NP, Badinez L, Duenas R, Orellana N, Tapia P. Positive HER-2 protein expression in circulating prostate cells and micrometastasis, resistant to androgen blockade but not diethylstilbestrol. Ind J Urol. 2011;27:200–7. https://doi.org/10.4103/0970-1591.82838.View ArticleGoogle Scholar
  127. Murray NP, Reyes E, Fuentealba C, Jacob O, Orellana N. Possible Role of HER-2 in the Progression of Prostate Cancer from Primary Tumor to Androgen Independence. Asian Pac J Cancer Prev. 2015;16:6615–9.PubMedView ArticleGoogle Scholar
  128. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–77. https://doi.org/10.1016/j.cell.2013.03.021.PubMedPubMed CentralView ArticleGoogle Scholar
  129. Cooper CS, Eeles R, Wedge DC, Van Loo P, Gundem G, Alexandrov LB, et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat Genet. 2015;47:367–72. https://doi.org/10.1038/ng.3221.PubMedPubMed CentralView ArticleGoogle Scholar
  130. Wanjala J, Taylor BS, Chapinski C, Hieronymus H, Wongvipat J, Chen Y, et al. Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling. Mol Cancer Ther. 2015;14:278–88. https://doi.org/10.1158/1535-7163.PubMedView ArticleGoogle Scholar
  131. Lalonde E, Ishkanian AS, Sykes J, Fraser M, Ross-Adams H, Erno N, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5 year biochemical recuurance of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014;15:1521–32. https://doi.org/10.1016/S1470-2045.PubMedView ArticleGoogle Scholar
  132. Hubbard GK, Mutton LN, Khalili M, McMullin RP, Hicks JL, Bianchi-Frias D, et al. Combined Myc activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res. 2016;76:283–92. https://doi.org/10.1158/0008-5472.CAN-143280.PubMedView ArticleGoogle Scholar
  133. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand independent androgen receptor variants derived from splicing of cryptic exons signify hormone refractory prostate cancer. Can Res. 2009;69:16–22.View ArticleGoogle Scholar
  134. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–38.PubMedPubMed CentralView ArticleGoogle Scholar
  135. Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008;68:5469–77.PubMedPubMed CentralView ArticleGoogle Scholar
  136. Krause WC, Shafi AA, Nakka M, Weigel NL. Androgen receptor and its splice variant AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells. Int J Biochem Cell Biol. 2014;54:49–59.PubMedPubMed CentralView ArticleGoogle Scholar
  137. Kong D, Sethi S, Li Y, Chen W, Sakr WA, Heath E, et al. Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate. 2015;75:161–74.PubMedView ArticleGoogle Scholar
  138. Pantel K, Schlimok G, Angstwurm M, Weckermann D, Schmaus W, Gath H, et al. Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother. 1994;3:165–73. https://doi.org/10.1089/scd.1.1994.3.165.PubMedView ArticleGoogle Scholar
  139. Albers P, Ko Y, Wardelmann E, Schmidt D, Adam M, Vetter H, et al. Limitations of detection of bone marrow micrometastasis in prostate carcinoma patients by CK18/PSA immunocytochemistry and PSA RT-PCR. Anticancer Res. 2000;20:2107–11.PubMedGoogle Scholar
  140. Zippelius A, Kufer P, Honold G, Kollermann MW, Oberneder R, Schlimok G, et al. Limitations of RT-PCR analysis for detection of micrometastatic epithelial cancer cells in bone marrow. J Clin Oncol. 1997;15:2701–8.PubMedView ArticleGoogle Scholar
  141. Wood DP Jr, Banks ER, Humphreys S, Rangnekar VM. Sensitivity of immunohistochemistry and polymerase chain reaction in detecting prostate cancer cells in bone marrow. J Histochem Cytochem. 1994;42:505–11.PubMedView ArticleGoogle Scholar
  142. Quesenberry PJ, Becker PS. Stem cell homing: rolling, crawling and nesting. Proc Natl Acad Sci USA. 1998;95:15155–7.PubMedView ArticleGoogle Scholar
  143. Askenasy N, Farkas DL. Optical imaging of PKH labeled hematopoietic cells in recipient bone marrow in vivo. Stem Cells. 2002;20:501–13. https://doi.org/10.1634/stemcells.20-6-501.PubMedView ArticleGoogle Scholar
  144. Christensen JL, Wright DE, Wagers AJ, Weissman IL. Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol. 2004;2:E75. https://doi.org/10.1371/journal.pbio.0020075.PubMedPubMed CentralView ArticleGoogle Scholar
  145. Mazo IB, von Andrian UH. Adhesion and homing of blood borne cells in bone marrow microvessels. J Leukoc Biol. 1999;66:25–32.PubMedView ArticleGoogle Scholar
  146. Panteleakou Z, Lembessis P, Sourla A, Pissimissis N, Polyzos A, Deliveliotis C, et al. Detection of circulating tumor cells in prostate cancer patients: methodological pitfalls and clinical relevance. Mol Med. 2009;15:101–14. https://doi.org/10.2119/molmed.2008.00116.PubMedView ArticleGoogle Scholar
  147. Dolfus C, Piton N, Toure E, Sabourin JC. CTC isolation: the assets of filtration methods with polycarbonate track etched filters. Chin J Cancer Res. 2015;27:479–87. https://doi.org/10.3978/j.issn.1000-9604.2015.09.01.PubMedPubMed CentralView ArticleGoogle Scholar
  148. Fischer JC, Niederacher D, Topp SA, Honisch E, Schumacher S, Schmitz N, et al. Diagnostic leukapherasis enables reliable detection of CTCs of nonmetastatic cancer patients. Proc Nat Acad Sci USA. 2013;110:16580–5. https://doi.org/10.1073/pnas.1313594110.PubMedView ArticleGoogle Scholar
  149. Kuske A, Gorges TM, Tennstedt P, Tiebel AK, Pompe R, Preiber F, et al. Improved detection of CTCs in non-metastatic high-risk prostate cancer patients. Sci Rep. 2016;6:39736. https://doi.org/10.1038/srep39736.PubMedPubMed CentralView ArticleGoogle Scholar
  150. Bretton PR, Melamed MR, Fair WR, Cote RJ. Detection of occult micrometastasis in the bone marrow of patients with prostate carcinoma. Prostate. 1994;25:108–14.PubMedView ArticleGoogle Scholar
  151. Melchior SW, Corey E, Ellis WJ, Ross AA, Layton TJ, Oswin MM, et al. Early tumor cell dissemination in patients with clinically localized carcinoma of the prostate. Clin Cancer Res. 1997;3:249–56.PubMedGoogle Scholar
  152. Berg A, Berner A, Lilleby W, Bruland OS, Fossa SD, Nesland JM, et al. Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy. Int J Cancer. 2007;120:1603–9. https://doi.org/10.1002/ijc.22488.PubMedView ArticleGoogle Scholar
  153. Morgan TM, Lange PH, Porter MP, Lin DW, Ellis WJ, Gallaher IS, et al. Disseminated tumor cells in prostate cancer patients after radical prostatectomy and without evidence of disease predicts biochemical recurrence. Clin Cancer Res. 2009;15:677–83. https://doi.org/10.1158/1078-0432.CCR-08-1754.PubMedPubMed CentralView ArticleGoogle Scholar
  154. Pantel K, Aignherr C, Kollermann J, Caprano J, Reithmuller G, Kollermann W. Immunocytochemical detection of isolated tumor cells in bone marrow of patients with untreated stage C prostate cancer. Eur J Cancer. 1995;31A:1627–32.PubMedView ArticleGoogle Scholar
  155. Ellis WJ, Pfitzenmaier J, Colli J, Arfman E, Lange PH, Vessella RL. Detection and isolation of prostate cancer cells from peripheral blood and bone marrow. Urology. 2003;61:277–81.PubMedView ArticleGoogle Scholar
  156. Lilleby W, Nesland JM, Fossa SD, Torlakovic G, Waehre H, Kvalheim G. The prognostic impact of cytokeratin positive cells in bone marrow of patients with localized prostate cancer. Int J Cancer. 2003;103:91–6. https://doi.org/10.1002/ijc.1078.PubMedView ArticleGoogle Scholar
  157. Mueller P, Carroll P, Bowers E, Moore D 2nd, Cher M, Presti J, et al. Low frequency epithelial cells in bone marrow aspirates from prostate carcinoma patients are cytogenetically aberrant. Cancer. 1998;83:538–46.PubMedView ArticleGoogle Scholar
  158. Murray NP, Calaf GM, Badinez L. Presence of prostate cells in bone marrow biopsies as a sign of micrometastasis in cancer patients. Oncol Rep. 2009;21:571–5.PubMedGoogle Scholar
  159. Kollermann J, Heseding B, Helapa B, Kollermann MW, Pantel K. Comparative immunocytochemical assessment of isolated carcinoma cells in lymph nodes and bone marrow of patients with clinically localized prostate cancer. Int J Cancer. 1999;84:145–9.PubMedView ArticleGoogle Scholar
  160. Weckermann D, Wawroschek F, Krawczak G, Haude KH, Harzmann R. Does the immunocytochemical detection of epithelial cells in bone marrow (micrometastasis) influence the time to biochemical relapse after radical prostatectomy. Urol Res. 1999;27:285–90.View ArticlePubMedGoogle Scholar
  161. Wood DP Jr, Banerjee M. Presence of circulating prostate cells in bone marrow of patients undergoing radical prostatectomy is predictive of disease free survival. J Clin Oncol. 1997;15:3451–7.PubMedView ArticleGoogle Scholar
  162. Ma X, Xiao Z, Li X, Wang F, Zhang J, Zhou R, et al. Prognostic role of circulating and disseminated tumor cells in patients with prostate cancer: a systemic review and meta-analysis. Tumour Biol. 2014;35:5551–60. https://doi.org/10.1007/s13277-014-1731-5.PubMedView ArticleGoogle Scholar
  163. Murray NP, Aedo S, Reyes E, Orellana N, Fuentealba C, Jacob O. Prediction model for early biochemical recurrence after radical prostatectomy based on the Cancer of the Prostate Risk Assessment score and the presence of secondary circulating prostate cells. BJU Int. 2016;118:556–62. https://doi.org/10.1111/bju.13367.PubMedView ArticleGoogle Scholar
  164. Murray NP, Reyes E, Orellana N, Fuentealba C, Jacob O. Comparison of the Walz nomogram and presence of secondary circulating prostate cells for predicting early biochemical failure after radical prostatectomy for prostate cancer in Chilean men. Asian Pac J Cancer Prev. 2015;16:7123–7.PubMedView ArticleGoogle Scholar
  165. Murray NP, Reyes E, Orellana N, Fuentealba C, Badinez L, Olivares R, et al. Secondary circulating prostate cells predict biochemical failure in prostate cancer patients after radical prostatectomy and without evidence of disease. Sci World J. 2013. https://doi.org/10.1155/2013/762064.View ArticleGoogle Scholar
  166. Tombal B, Van Cangh PJ, Loric S, Gala JL. Prognostic value of circulating prostate cells in patients with a rising PSA after radical prostatectomy. Prostate. 2003;56:163–70. https://doi.org/10.1002/pros.10237.PubMedView ArticleGoogle Scholar
  167. Davis JW, Nakanishi H, Kumar VS, Bhadkamkar VA, McCormick R, et al. Circulating tumor cells in peripheral blood samples from patients with increased serum PSA: initial results in early prostate cancer. J Urol. 2008;179:2187–91. https://doi.org/10.1016/j.juro.2008.01.102.PubMedView ArticleGoogle Scholar
  168. Eschwège P, Moutereau S, Droupy S, Douard R, Gala JL, Benoit G, Conti M, et al. Prognostic value of prostate circulating cells detec-tion in prostate cancer patients: a prospective study. Br J Cancer. 2009;100:608–10. https://doi.org/10.1038/sj.bjc.6604912.PubMedPubMed CentralView ArticleGoogle Scholar
  169. Fizazi K, Morat L, Chauveinc L, Prapotnich D, De Crevoisier R, Escudier B, et al. High detection rate of circulating tumor cells in blood of patients with prostate cancer using telomerase activity. Ann Oncol. 2007;18:518–21. https://doi.org/10.1093/annonc/mdl419.PubMedView ArticleGoogle Scholar
  170. Joung JY, Cho KS, Kim JE, Seo HK, Chung J, et al. Prostate stem cell antigen mRNA in peripheral blood as a potential predictor of biochemical recurrence in high risk prostate cancer. J Surg Oncol. 2010;101:145–8. https://doi.org/10.1002/jso.21445.PubMedView ArticleGoogle Scholar
  171. Murray NP, Aedo S, Fuentealba C, Reyes E, Salazar A. Minimal residual disease in patients post radical prostatectomy for prostate cancer: theoretical considerations, clinical implications and treatment outcome. Asian Pac J Cancer Prev. 2018;19:229–36. https://doi.org/10.22034/APJCP.2018.19.1.229.PubMedPubMed CentralView ArticleGoogle Scholar
  172. Murray NP, Reyes E, Fuentealba C, Orellana N, Jacob O. Comparison between use of PSA kinetics and bone marrow micrometastasis to define local or systemic relapse in men with biochemical failure after radical prostatectomy for prostate cancer. Asian Pac J Cancer Prev. 2015;16:8387–90.PubMedView ArticleGoogle Scholar
  173. Kollermann J, Weikert S, Schostak M, Kempkensteffen C, Kleinschmidt K, Rau T, et al. Prognostic significance of disseminated tumor cells in the bone marrow of prostate cancer patients treated with neoadjuvant hormone treatment. J Clin Oncol. 2008;26:4928–33. https://doi.org/10.1200/JCO.2007.15.0441.PubMedView ArticleGoogle Scholar
  174. Pantel K, Enzmann T, Kollermann J, Caprano J, Reithmuller G, Kollerman MW. Immunocytochemical monitoring of micrometastatic disease reduction of prostate cancer cells in bone marrow by androgen deprivation. Int J Cancer. 1997;71:521–5.PubMedView ArticleGoogle Scholar
  175. Gravina GL, Festuccia C, Millimaggi D, Tombolini V, Dolo V, Vicentini C, et al. Bicalutamide demonstrates biologic effectiveness in prostate cancer cell lines and tumor primary cultures irrespective of HER-2/neu expression levels. Urology. 2009;74:452–7. https://doi.org/10.1016/j.urology.2009.01.018.PubMedView ArticleGoogle Scholar
  176. Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Zhu Y, et al. Clinical significance of AR-v7 mRNA detection in circulatingtumor cells of men with metastatic castration resistant prostate cancer treated with first and second line abiraterone and enzalutamide. J Clin Oncol. 2017;35:2149–56. https://doi.org/10.1200/JCO.2016.70.1961.PubMedPubMed CentralView ArticleGoogle Scholar
  177. Scher HI, Lu D, Schreiber NA, Louw J, Graf RP, Vargas HA, et al. Association of AR-v7 on circulating tumor cells as a treatment specific biomarker with outcomes and survival in castration resistant prostate cancer. JAMA Oncol. 2016;2:1441–9. https://doi.org/10.1001/jamaoncol.2016.1828.PubMedPubMed CentralView ArticleGoogle Scholar
  178. Onstenk W, Sieuwerts AM, Kraan J, Van Nieuweboer MAJ, Mathijssen RH, et al. Efficacy of cabazitaxal in castration resistant prostate cancer is independent of the presence of AR-v7 in circulating tumor cells. Eur Urol. 2015;68:939–45. https://doi.org/10.1016/j.eururo.2015.07.007.PubMedView ArticleGoogle Scholar
  179. Miyamoto DT, Lee RJ, Stott SL, Ting DT, Wittner BS, Ulman M, et al. AR signaling in CTCs as a marker of hormonally responsive prostate cancer. Cancer Discov. 2012;2:995–1003. https://doi.org/10.1158/2159-8290.CD-12-0222.PubMedPubMed CentralView ArticleGoogle Scholar

Copyright

Advertisement