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Murray Primary circulating prostate cells

Methods of enrichment and detection of these cells are such as E-cadherin [25-27] and beta-catenin [25,27] and a
considered in how the method may affect what is being loss of cytokeratins 8, 18, and 19, which increases
detected or not. Finally, we consider the clinical utility of tumor cell plasticity. [28,29] These changes occur in a
these tests and how in day-to-day clinical practice they coordinated fashion; they are higher in higher grade
[28]
may help in decisions to proceed to prostate biopsy and less differentiated tumors. There is increased
and treatment decisions of detected cancer. expression of matrix metalloproteinases; these zinc-
containing endopeptidasesare activated in situ from
A search for articles between the years 2000 and 2016, their latent form and degrade the extracellular matrix.
evaluating the detection of circulating tumor cells and As such, they permit the cancers to disseminate to
CPCs was carried out using PubMed, Web of Science, the circulation, implant, and form metastases. [29,30]
and Cochrane Library. Case reports, review articles, Increased expression of metalloproteinase-2 (MMP-
non human models, and series involving fewer than 10 2) has been demonstrated [31-33] and is associated with
patients were excluded. increasing Gleason score, pathological stage, and as
a prognostic factor. [33,34] Primary CPCs detected before
THE DISSEMINATION OF CANCER CELLS prostate biopsy express MMP-2, whereas one hour
FROM THE PRIMARY TUMOR post-biopsy there are a mixture of MMP-2 positive and
negative CPCs, inferring that MMP-2 is important in
The metastatic process by which tumor cells leave CPC dissemination from the primary tumor. [35]
the primary tumor and implant, survive, and growth
in distant sites is multistage and complex. Several Epithelial to mesenchymal transition plays an
steps are needed for the cancer cells to escape important role in cancer dissemination. There is a
change in the phenotypic expression of epithelial and
from the primary tumor and intra-vasation, towards mesenchymal markers, with increased expression of
extravagation and successful implantation in distant mesenchymal markers such as vimentin, N-cadherin,
tissues. With the advent of prostate cancer screening or O-cadherin. [36,37] These patterns of expression are
and the use of total serum PSA, there has been a shift heterogeneous with a global decrease in epithelial cell
towards a diagnosis of localized cancers. However, marker expression. However, CPCs that express
[19]
[38]
despite being considered as localized by currently only mesenchymal markers be may easily able to
accepted staging methods, approximately 20-30% of escape from the primary tumor, but for the same
patients suffer primary treatment failure, suggesting reason they have limited ability to implant in distant
[20]
that cancer cells have disseminated prior to treatment. tissues. [39-42] Intermediate states have been reported,
Using polymerase chain reaction amplification of PSA with circulating tumor cells expressing both epithelial
mRNA, it has been reported that prostate cancer cells and mesenchymal markers. This increased state of
disseminate early in the metastatic process into the cell plasticity may be advantageoust0 implantation at
circulation. These have been defined as primary distant sites and the future formation of metastasis.
[21]
circulating tumor cells, those detected before initial This plasticity is the hallmark of cancer stem cells, [43-47]
curative therapy. and CPCs from prostate cancer patients have been
reported to express CD133 or ALDH1 both
[48]
[49]
Tumor cells may enter the circulation actively or markers of cell stem-ness.
passively; passive entry into the circulation is a
[22]
result of vessel leakage by the growing tumor and One important epithelial marker that has relevance in
external forces such as surgical manipulation at the the detection of CPCs is the epithelial cell adhesion
time of biopsy; in these cases the circulating tumor molecule (EpCAM) (CD326). This is a 40 kD
[23]
cells do not require specific phenotypic characteristics. glycoprotein that was originally identified as a marker
Active entry of tumor cells requires specific abilities for carcinoma, with an increased expression being
which permit the cell to detach from the surrounding identified in rapidly proliferating epithelial tumors.
cells, survive free of them, and migrate towards blood
vessels where they cross the capillary endothelium, EpCAM was initially thought to be important in cellular
enter the circulation, and disseminate. Thus, primary adhesion. However, more recent reports indicate that
CPCs consist of a heterogeneous population ranging it plays a role in cell to cell signaling, in migration
from metastatic initiating cells with specific cell and proliferation of cancer cells, and possibly in the
properties to non-aggressive cells without any prevention of cell-cell adhesion. In normal cells there
[24]
specific survival ability. is a variable expression of EpCAM, but it is reported to
be lower than that found in primary tumors. [50]
In order to escape from the primary tumor, cancer cells
exhibit a decreased expression in anchor proteins Thus, the specific phenotypic characteristics of
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 16, 2016 455