Saturday, August 30, 2008

Debate About the CSC Hypothesis

There continues to be some controversy about the possibility that the cells that have been identified as cancer stem cells may just have special abilities to grow in mice after transplantation. This possibility is mentioned in an article, A Tumor's Lifeblood, by Jessica Gorman (CR magazine, Summer 2006, page 2).

A comment in Science (Dec 14, 2007) about this controversy is freely accessible. (I've added some links to the references cited in the excerpts quoted below). The comment is:

Comment on "Tumor Growth Need Not Be Driven by Rare Cancer Stem Cells", by James A. Kennedy, Frédéric Barabé, Armando G. Poeppl, Jean C. Y. Wang, John E. Dick. Science 2007(Dec 14); 318(5857), 1722. Excerpts:
Kelly et al. (Brevia, 20 July 2007, p. 337) questioned xenotransplant experiments supporting the cancer stem cell (CSC) hypothesis because they found a high frequency of leukemia-initiating cells (L-IC) in some transgenic mouse models. However, the CSC hypothesis depends on prospective purification of cells with tumor-initiating capacity, irrespective of frequency. Moreover, we found similar L-IC frequencies in genetically comparable leukemias using syngeneic or xenogeneic models.

Kelly et al. (1) raise the important point that some experimental cancer models may not follow the CSC hypothesis. Accordingly, some human cancers may be found that also do not adhere to this model. However, it is important to consider that, similar to many cell lines that have lost the hierarchical structure of the primary leukemia from which they originated, some experimental mouse models may not accurately reflect spontaneously occurring human malignancies. For example, one could argue that some of the models used by Kelly et al. (i.e., the N-Ras lymphoma) have limited human antecedents.
The response is also freely accessible: Response to Comment on "Tumor Growth Need Not Be Driven by Rare Cancer Stem Cells", by Jerry M. Adams, Priscilla N. Kelly, Aleksandar Dakic, Stephen L. Nutt, Andreas Strasser. Science 2007(Dec 14); 318(5857), 1722. Excerpt:
We agree with Kennedy et al. (6) that tumors are likely to fall on a spectrum in which the tumor-propagating cells range from infrequent to the dominant population. However, the marked disparities between most transplant results with human and mouse leukemias suggests that current xenotransplantation systems seriously underestimate the frequency of cells that can maintain the growth of human tumors. Several mouse tumor models challenge the generality of the cancer stem cell hypothesis, and more compelling tests with human tumors presumably will require transfer into mice installed with all the requisite human support cells and support factors. Much of the excitement about the cancer stem cell hypothesis arises from the possibility that the putative stem cell population will prove to be uniquely responsible for the relapses that so frequently follow conventional therapy (1). On the available evidence, however, we suggest that curative therapy will require targeting all the tumor subpopulations.
From the editor: I'd welcome comments about this debate. To post a comment, it's currently necessary to register (to reduce spam posts). Comments will be moderated by the editor.

Thursday, August 28, 2008

Human Cancer Stem Cells: A Recent Review

Cancer stem cells: at the headwaters of tumor development,
Ward RJ, Dirks PB. Annu Rev Pathol. 2007;2:175-89. Abstract:
According to the cancer stem cell hypothesis, only a subpopulation of cells within a cancer has the capacity to sustain tumor growth. This subpopulation of cells is made up of cancer stem cells, which are defined simply as the population of cells within a tumor that can self-renew, differentiate, and regenerate a phenocopy of the cancer when injected in vivo. Cancer stem cells have now been prospectively isolated from human cancers of the blood, breast, and brain, and putative cancer stem cells have been identified from human skin, bone, and prostate tumors and from multiple established mammalian cancer cell lines. Furthermore, researchers are actively seeking cancer stem cells in every human cancer type. We present the current scientific evidence supporting the cancer stem cell hypothesis and discuss the experimental and therapeutic implications of the discovery of human cancer stem cells.

Cancer Stem Cell Consortium Launched

See: Sweeping Cancer Fight Launched by CIRM and Canada,
David Jensen, California Stem Cell Report, June 18, 2008. Excerpts:
SAN DIEGO -- Backed by $100 million in Canadian cash, the Canadian government and the California stem cell agency today announced a three-year effort to probe the role of cancer stem cells in developing the disease.

Canadian Minister of Health Tony Clement said his government will contribute more than $100 million to the Cancer Stem Cell Consortium, which will work with CIRM on the effort.