Wang and Shen have written a quite useful review of the cancer stem cell thesis for prostate cancer. There is no definitive conclusion but the review covers a wide path through what has been accomplished to date.
Recall as we have written before the cancer stem cell (CSC) model, and it is a model, hypothesizes that there are certain core cells which control the malignant growth of other cells and that the other cancerous type cells do not in and of themselves have the ability to continue to grow. In fact it could be concluded, although not part of the current theory, that removal of a CSC from a tumor, say the only CSC, would result in the apoptosis of the remaining cells. Namely a remission.
In contrast to the CSC model we have the clonal model which says that the cells have progressed through a set of pathway modifications that have resulted in a single cell which takes off and multiples and that the progeny have identical genetic makeup or further genetically modified makeup but all and equally malignant.
These are two fundamentally different views of cancer. One could also state that recent work with melanoma as we have discussed also posit that the CSC “communicates” to progeny to have them multiply and that arguably the loss of the CSC
There is a great deal of difficulty in identifying the CSC, usually attempting to do so via surface markers such as CD44 and the like.
Wang and Shen then discuss the controversy regarding the CSC concept. They state:
Much of the confusion in the literature arises through inconsistencies in nomenclature within the field. In particular, due to the wide use of xenotransplantation as a functional assay for CSCs, transformed cells that can initiate tumor formation in this assay are often referred to as CSCs in the literature. However, a tumor initiating cell (TIC) represents a different concept from that of a CSC, as TICs unquestionably exist within tumors and their identification does not by itself imply a hierarchical organization of a tumor.
Indeed, the majority of cells within a tumor could potentially possess TIC properties and nonetheless follow a clonal evolution model. Consequently, it is important to distinguish CSCs that have been strictly defined by their position and function within a lineage hierarchy in vivo from CSCs that have been identified as rare TICs in transplantation studies.
A similar confusion arises with respect to the cell of origin for cancer, which corresponds to a normal tissue cell that is the target for the initiating events of tumorigenesis. In principle, a normal adult stem cell could be a logical cell of origin for cancer, as it would retain the ability to self-renew and generate a hierarchy of differentiated lineages within a tumor. However, it is also possible that a cell of origin could correspond to a downstream progenitor cell or conceivably even a terminally differentiated cell that acquires stem cell properties during oncogenic transformation.
Our argument has been that the CSC may most likely exist and that it has undergone certain pathway changes and that as a result it may influence the growth of not identically genetically changed cells to multiply but not in and of themselves have the potential to multiply.
Wang and Shen continue:
The identification of normal cells that can serve as a cell of origin for prostate cancer is highly relevant for understanding the applicability of a CSC model, and is currently under intense investigation. The cell of origin may also have clinical significance, as in the case of breast cancer, distinct tumor subtypes have been proposed to originate through transformation of different progenitors within the mammary epithelial lineage. Thus, it is conceivable that there may be distinct cells of origin for other epithelial cancers, and different cells of origin may give rise to clinically relevant subtypes that differ in their prognosis and treatment outcome.
Thus there are either basal cells or luminal cells as the cell of origin. Goldstein et al in Witte’s lab had developed a murine model demonstrating the basal cell as the cell of origin. However there may be strong issue regarding this model as applied to human prostate cancer. It represents a viable pathway but not necessarily the only. The issue is one of pathways as well as one of intercellular communications with debilitated pathways.
Now to follow the Wang and Shen model we have the following. Fist we show a normal prostate gland with basal and luminal cells.
Then we show their view of a Tumor Initiating Cell in either the basal or luminal layer. The Goldstein et al murine model argue for the basal layer and there are others arguing for the luminal.
The Wang and Shen model is as follows.
1. A normal prostate cell has both luminal and basal cells.
2. TICs may be formed in either basal or luminal cells.
3. Neoplasia starts with intro acinar proliferation.
4. Carcinoma starts when it expands beyond the gland and starts up its own quasi-glandular structures.
Now what causes this? Genetic changes result in pathway changes. We show two pathways below. We lose PTEN and we may activate myc and other parts of the pathway control mechanism.
and the following pathway:
We now make a different argument. If there exists a true PCa CSC then perhaps one may putatively validate it as follows. The logic then is:
1. Assume a PCa CSC exists.
2. Assume that the PCa CSC replicates its CSC self at a low rate and is initially confined to the prostate gland.
3. Assume that the PCa CSC can influence the growth of TIC which themselves cannot sustain a malignancy. Specifically we assume that the TICs require the CSC for continued growth and further the CSC does so via cell growth as well as intercellular communications.
4. Now let us assume we have performed an 18 core biopsy on a 60 cc prostate gland and find histologically extensive high grade focal prostatic intraepithelial neoplasia. According to Wang and Shen they are most likely TICs and furthermore there may be a CSC somewhere so that eventually we see a PCa. There may be one or a few CSC in one or all of the glands yet we have no definitive marker to indicate as such.
5. Now assume we perform a second multi core biopsy on the gland and say do 22 cores in a 60 cc gland. This is the same gland but say 9 months later. We would arguably expect one ot two possible outcomes. First that the HGPIN remains in place and possibly has expanded. Second that there was a CSC and the HGPIN had become classic PCa with say Gleason 2 or 3 at a minimum about the HGPIN clusters.
6. If however, we examine the cores and find no evidence of any neoplasia or PCa, namely the gland has totally reverted to benign histology, we may have a reasonable argument that perhaps the CSC was present initially, and it was somehow removed along with the HGPIN in the initial biopsy leaving the TIC alone behind. Thus the TICs requiring a CSC to survive go into an apoptotic state and are removed from the prostate. Perhaps.
We have seen that specific situation occur and one could then argue that the Wang and Shen model for CSCs may be a viable model and further if such can be shown more extensively than we may have a basis for PCa progression.
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