Cancer Stem Cells and Novel Cancer Therapies
In the past few years evidence has increased that "cancer stem cells" play a fundamental role in cancer. Typically comprising about 1% or less of a total tumor mass, these cancer stem cells appear to have unlimited proliferation potential, and the capacity to drive cancer growth. In addition, cancer stem cells have been implicated in metastasis. Cancer stem cells have already been found in the leukemias, lung, colon, prostate, breast, skin, ovarian, and neural cancers. They may be present in all cancers. Their discovery may be the most important discovery in cancer biology in the past half century. Cancer stem cells are likely to afford entirely new cancer therapies in the modestly near future.
Given cancer stem cells, it becomes obvious that merely reducing the mass of a tumor without eliminating the cancer stem cells will almost surely lead to a recurrence of the disease. Thus, increasing numbers of investigators, including myself, are now focusing effort in three related directions: 1) Find means to selectively kill cancer stem cells. 2) Find means to stop cancer stem cells from proliferating. 3) Find means to induce cancer stem cells to differentiate—or change cell type—to non-malignant cell types.
While it is simply foolish to think cancer is simple, I believe it is a realistic hope that work on cancer stem cell therapy has a strong chance to dramatically improve cancer therapy within the next few decades. There are a number of approaches to this attempt. Among them, it is now possible using a new discovery, siRNA, to "turn off" the translation of the messenger RNA of any specific gene into its protein product. In addition, using other molecular biology techniques it is possible to over express any gene. These molecular techniques mean that investigators can now try to perturb the activities of specific genes that control cancer stem cell behavior in an attempt to attain the three aims above.
Further, high throughput screening via robotics now allow small molecule and other chemical libraries of high diversity to be screened to search for molecular perturbations which, if applied to cancer stem cells, achieves selective killing, cessation of proliferation, or differentiation to benign cell types. Our own laboratory and an increasing number of other laboratories are undertaking this work.
Differentiation therapy is already clinically effective in the case of treatment of acute myelogenous leukemia, AML, with vitamin A. The cancer cells differentiate into normal blood cells that do not proliferate. In addition, a research group recently screened a mere 1700 chemicals and found eight that caused AML cells to differentiate to or towards normal non-proliferating blood cells. Thus it is not improbable that by screening chemical libraries with thousands to hundreds of thousands of distinct compounds, molecules capable of selectively killing, shutting down proliferation, or inducing differentiation of cancer stem cells will be found in the modestly near future.
These approaches, however, must, as ever, be viewed with cautious optimism. For example, it may be the case that other cancer cells in a tumor can differentiate back into cancer stem cells. If so, they would require treatment, perhaps making cancer a chronic disease. The "same" cancer from diverse patients may typically have accumulated different subsets of gene mutations, rendering the hope of finding a single magic bullet good for all cases of that cancer moot. Conversely, vitamin A is widely useful in AML, raising the hope that a modest number of compounds might treat most cases of the "same" cancer in diverse patients. Further, the relation between cancer stem cells and normal adult stem cells remains to be clarified. A treatment that eliminated both cancer stem cells and normal stem cells of a given tissue could have untoward effects. Elimination of leukemic cancer stem cells might eliminate normal blood (hematopoetic) stem cells and affect the normal processes of these normal stem cells in blood formation. Conversely, one can hope that techniques will be found that can sustain the patient during therapy and regenerate normal, here blood, stem cells from other stem cells in a patient, transplant them into the patient after cancer therapy, and overcome the normal stem cell loss induced by therapy. And for some tissues, prostate, ovaries, uterus, loss of normal stem cells may not be grave.
The potential implications of cancer stem cell therapy are enormous. And the world scientific community is rapidly grasping the potential significance. It is important to stress that this effort will be "big biology", for techniques such as high throughput screening and tests of patterns of gene activities using genetic microarrays are very expensive. Adequate funding will be required. Overall, I am deeply optimistic as a doctor and biological scientist that we will, at last, find subtle ways to treat cancer either as stand alone therapies, or in conjunction with familiar surgery, radiation and chemotherapy.