Following up on our Jan. 22nd post, we see that researchers from University of Michigan and Stanford University reported in the January 16th issue of PNAS their findings of tumorigenic cancer stem cells in patients with head and neck squamous cell carcinoma (HNSCC). M. E. Prince et al. found a heterogenous population of cancer cells in HNSCC. Less than 10% of the cancer cells were CD44+. In immunodeficient mice, the CD44+ cells gave rise to new tumors whereas the CD44- cancer cells did not produce new tumors. Immunohistochemical analysis of the cells revealed the CD44+ cells had a primitive morphology and co-stain with the basal cell marker, Cytokeratin 5/14. On the other hand, CD44- cells in the tumor were found to be more differentiated squamous epithelial cells and express the surface marker, Involucrin. In the mouse model, the investigators reported that the CD44+ cells could be serially passaged and subsequently form a heterogenous population of cancer cells, similar in cellular composition to the original tumor. It was also noted that the CD44+ cancer cells differentially expressed high levels of the Bmi1 protein (Bmi1 is required for the maintenance of adult stem cells and their ability to self-renew. Bmi1 is a PCG repressors and it represses genes that induce cellular senescence and cell death. For a review on Bmi1 click herefor a review by I-K Park et al. in J. Clin. Invest. 113:174-179, 2004). The authors concluded that within HNSCC there is a subpopulation of CD44+ cancer stem cells which is tumorigenic and have the capability to self-renew.

In the January 18th issue of the New England Journal of Medicine, investigators from Stanford University reported the results of their study on the differential expression of genes between tumorigenic breast-cancer and normal breast epithelium cells. R. Liu et al. used cancer stem cells that were isolated by flow cytometry for cells sorted by their CD44+ and CD24-/low surface markers. Gene chip micro-arrays were also utilized to determine differentially expressed genes. The micro-arrays generated 186-gene "invasiveness" gene signature (IGS). These IGS genes were found in tumorigenic cells that tend to metastasize. The investigators subsequently evaluated the association of IGS with overall and metastasis-free survivals in patients with breast cancer as well as other forms of cancer. The results showed a statistically significant (p<0.001) association between IGS with respect to both overall and metastasis-free survival in breast cancer patients. When the patients were stratified into a subpopulation of patients high risk early breast cancer with poor or good prognosis according to their IGS, there was an 81% 10-year survival rate for patients with a good prognosis. Similarly, there was a 57% 10-year survival rate in patients with a poor prognosis. Statistical analysis also demonstrated that the association between the IGS and death or mestatasis was independent of a patient's age, estrogen receptor, and tumor differentiation. Additionally, it was important to note that following transcriptional profiling of serum-stimulated fibroblasts, the researchers identified 512-gene signatures associated with a wound response (WR). Both the IGS and WR signatures were synergistic in enhancing the prognostic accuracy for cancer patients. Since the tumorigenic cells behaved like stem cells, the authors concluded that tumors with a large number of cancer stem cells were more likely to metastasize than tumors with a small number of those cells. They also noted that IGS and WR gene signatures associated with clinical outcome is consistent with their model "in which self-renewing cancer stem cells represent the seeds of cancer and the tumor microenvironment the soil that promotes the growth of those seeds."

Scientists are now providing more experimental evidence linking cancer with stem cells, which as units of self renewal, may lead to many forms of cancers if not regulated. Researchers from the Universy of Southern California Norris Cancer Center reported in the December 31st online edition of Nature Genetics their findings on the epigenetic events in embryonic stem cells that may lead to cancer stem cells. M. Widschwendter et al. published the results of their study in which they found that out of 177 genes reversibly repressed by Polycomb group (PcG) protein complexes, 77 were found to be hypermethylated---epigenetic modifications normally associated with cancers. The investigators also noted that the PcG targets in embryonic stem cells are "12 times more likely to become abnormally methylated in cancer." The authors concluded that these epigenetic events permanently silence the embryonic stem cells, preventing them from differentiating and thus setting them up to become the "seeds of cancer later in life." The experimental results also point to epigenetic alterations that may precede cancer-causing genetic events. (The data provide more insight into the underlying mechanism that governs differentiation of stem cells and their dysregulation via epigenetic modifications. However, it is still unclear how these "cancer seeds" can remain dormant for such a long period of an organism's life and which mechanism(s) activate these pre-cancerous stem cells into the neoplastic state.)