[Hopeful]

Lani, thanks for this article. I went to the website for the National Cancer Advisory Board, where the minutes of their public meetings are available. This article was drawn from the minutes of the February, 2006 meeting, where there were two presentations on cancer stem cells. Following the second presentation, there was a Q&A. The following was contained in that Q&A session:



“Dr. Jones observed that the cancer stem cell discussions underscored the need for the cancer research community to understand them. He commented that one unexpected item of information from the recent think tank on this topic was that many of the pathways actually inactivated by epigenetic mechanisms. For example, Bmi-1, which was discussed by Dr. Wicha, is a chromatin-remodeling protein. Dr. Wicha commented further that Bmi-1 is thought to regulate the switch turning off p16 and that the epigenetic silencing of p16 has been shown in a number of tumors, as well as in early breast cancer. He expressed the view that the epigenetic changes that may lock these stems cells into a self-renewing configuration and expand them may be one of the earliest events in carcinogenesis. Dr. Armitage commented that the conclusions from stem cell research matches well with experience in treating hematologic malignancies in that acute myelocytic leukemia is presumably the most differentiated and the easiest to cure, whereas those malignancies thought to be injurious to primitive cells are not cured with drugs. He asked whether there are any circumstances where curing a patient with drugs was not merely the result of finding a way to kill a sufficient number of stem cells to make the tumor die but also could be an alteration of tumor microenvironment. Dr. Wicha agreed that the tumor microenvironment with its stromal-epithelial interaction is an important component of treatment. He pointed out that it is actually an interaction between the microenvironment and the stem cell. The area known as the niche is the surrounding environment, and it is thought that metastases are determined largely by the stem cell-niche interaction; therefore, some therapies may be working on the niche rather than the stem cell. As an interesting sideline, Dr. Wicha noted that, even though almost all patients with chronic mylegenous leukemia go into remission with Gleevec therapy, almost no one is cured and the cancer progresses if the Gleevec treatment is stopped. The progression occurs with a kinetics that is predicted by the stem cell model. He expressed the view that this is an indication that targeted therapies may improve the patient’s condition, buy a way must be found to target the stem cell.



Dr. Niedehuber asked whether it is possible that the supporting microenvironment cells should be thought of as changes in tissue stem cells as well. Dr. Wicha replied that current information on the crosstalk between tumor and stroma is indicating that the stroma is actually activated. Studies of the wounding profile show that the same kinds of genes expressed in a wound are expressed around a tumor, leading to the hypothesis that stem cell pathways are similar to tissue regeneration after an extreme injury. He expressed the view that probably the most important emphasis in the area of cancer stem cell research is how stem cells are controlled by the microenvironment. Dr. Freedman asked whether it is now possible to establish rules for isolating cancer stem cells from other cells in a tumor. Dr. Wicha replied that this is being done by means of functional assays. Dr. Franklyn Prendergast, Director, Mayo Clinic comprehensive Cancer Center, asked about the extent to which circulating tumor cells have the phenotypic characteristics of tumor stem cells. Dr. Wicha agreed that is an important question, and he cited studies in his institution looking at circulating breast cells as a possible marker of bad prognosis as well as studies by other groups to determine whether metastases are enriched for stem cells. He noted further that clinical literature in both breast and prostate cancer suggests that, at the time of diagnosis, about 30 percent of patients have micrometatases, but only one-half that number actually recur 10 years out. The hypothesis for those who recur is either their cells are not stem cells or the microenvironment of their stems cells is insufficient to allow them to self-renew. Dr. Prendergast asked about sentinel node tumor cells. Dr. Wicha replied that it is important to know whether cells in the sentinel node are stem cells and not just shed cells, which highlights the need for good stem cell markers. Currently, it is necessary to use a battery of markers to identify stem cells, but the goal is to use gene-expression profiling to obtain good markers of stem cells that could be used for immunohistochemistry. It would then be possible to examine a variety of completed clinical trails retrospectively and ask whether the micrometastases stem cell markers carry important prognostic implications.



Dr. deKernion asked how solid the evidence is that the pathway to malignancy in an organ almost always depends on change in the stem cell of that organ. Drs. Wicha noted that the change is believed to occur in the cells that have self-renewing potential, which is a characteristic of the stem cell, therefore, all that is needed is deregulation of an existing process. He pointed out that other cancers appear to arise from progenitor cells that have the potential to differentiate into several cell types and that it is important to make the distinction between the two concepts of self-renewal and division. It was noted that Dr. Von Hoff was one of the pioneers in stem cells, and that he and colleagues developed a functional test. The view was expressed that the underlying hypothesis of that test should be revisited and modern marker tests correlated with the ability of the putative stem cells to grow in agar.”



I think there is a typo in the second paragraph, concerning recurrence. From context, it seems that it should read that “the hypothesis for those who don’t recur is that either their cells are not stem cells or the microenvironment of their stem cells is insufficient to allow them to self-renew.”



Hopeful