The concept of the cancer stem cell (CSC) has taken off rapidly over the past 10 years. CSCs are cells with properties that are similar to those described for tissue stem cells: self-renewal and asymmetric division resulting in the generation of daughter cells destined to differentiate, enabling the regeneration of a tissue. Initial research into the properties of CSCs was based on identifying and verifying markers of this subset of cancer cells. However, most studies have now moved on to understanding the biology of CSCs and the cancers in which they maintain tumour growth, as well as how and why they are able to serially generate a tumour. It is thought that a key element regulating the biology of stem cells is their niche — cells and extracellular matrix that support self-renewal and survival. As we begin to understand the pathways that are crucial for the properties of CSCs, including signals provided by the niche, we will hopefully be able to effectively target this cell population. Linked to the identification of CSCs is the cell of origin. These are cells that when mutated are able to give rise to a tumour. Although these cells may share properties with CSCs, in most cases it is not yet clear whether these cells are one and the same. This poster highlights some of the recent findings regarding the biology of CSCs and the identification of cell types from which cancers can arise.
As regards to prostate cancer they state:
In the normal prostate, epithelial cells with tissue-regenerating capacity that are Sca1+, CD49fhi, TROP2hi, CD44+, CD133+ and CD117+ (mouse) or CD133+, CD44+, CD49fhi and TROP2+ (human) seem to reside in the basal layer of the prostate. However, studies in mice indicate the existence of luminal cells with progenitor characteristics that can regenerate the prostate after androgen withdrawal. As castration resistance is also a property of basal stem cells in the prostate, it suggests a complex cellular hierarchy. Studies in mice indicate that prostate tumours can arise after transformation of basal stem cells and luminal progenitor cells. A subset of cells that are CD133+, a2b1 + and CD44+ and have basal cell characteristics have been shown to be tumorigenic, but whether these cells can serially propagate tumours in mice has yet to be verified.
Again and interesting experiment can be performed:
1. Take biopsies from N men with HGPIN diagnosed on initial biopsies. Perform sampling from say 20 cores.
2. Wait 9 months, and rebiopsy, again with near saturation cores, 20+ .. There are three possible outcomes:
a. HGPIN remains
b. PCa has been determined
c. HGPIN regresses and only benign cells are left
3. The question is why did (c) above happen? What percent of the HGPIN have regressed? If the percent of HGPIN that have regressed equals the probability of having actually excised the cancer stem cell or cells, we can calculate this, then by chance we have removed the CSC from the HGPIN and this would affirm its existence by inference.
Now a similar article appears in Science which speaks to colon cancer and the cancer stem cell theory:
In normal colon tissue, intestinal stem cells (ISCs) that reside at the base of mucosal wells, named crypts, expand through mitosis and move upward toward the crypt tip. The cells then undergo cell cycle arrest and terminal differentiation, finally becoming the mucosal epithelium of the colon. In the recent study, the investigators identified in mouse ISCs a gene signature that was specifically marked by high expression of the ephrin type-B receptor 2 gene(Ephb2), which encodes a receptor tyrosine kinase, the leucine-rich repeat–containing G protein–coupled receptor 5 gene (Lgr5), which encodes a G-coupled protein receptor of unknown function, and ~50 other genes. This gene signature also defined a specific population of stem-like cells at the base of colorectal tumor structures in mice that were morphologically similar to normal mouse intestinal crypts. The authors then similarly inspected tumor samples from 340 colorectal patients and discovered a 10-fold increase in the relative risk of recurrence in patients whose tumors displayed high expression of the human counterparts of the mouse ISC genes, relative to patients whose tumors showed low expression of these genes.
To test whether the mouse colorectal tumor cells with the ISC gene signature were cancer stem cells, the investigators isolated the cells and introduced them into an immunodeficient mouse model. The stem-like cancer cells demonstrated both a tumor-initiating capacity and self-renewal capability in vivo. These findings pinpoint potential markers that may allow a clinician to predict a patient’s future with respect to recurrence. These differentially expressed genes also may give rise to therapeutic targets that quell cancer stem cells.
What is clear is that the CSC is becoming a viable model for understanding cancer at another level.
Posts
