Existing cancer treatments were mostly developed on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study.
The efficacy of cancer treatments are, in the initial stages of testing, often measured by the amount of tumour mass they kill off. As cancer stem cells would form a very small proportion of the tumour, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate new cells. A population of cancer stem cells, which gave rise to it, could remain untouched and cause a relapse of the disease.
The first conclusive evidence for cancer stem cells was published in 1997 in Nature Medicine. Bonnet and Dick isolated a subpopulation of leukaemic cells that express a specific surface marker CD34, but lacks the CD38 marker. The authors established that the CD34+/CD38- subpopulation is capable of initiating tumors in NOD/SCID mice that is histologically similar to the donor. (Matsui, 2004)
In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their ability to inhibit it. However, efficient tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this has been explained by poor methodology (i.e. the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the cancer stem cell paradigm argue that only a small fraction of the injected cells, the cancer stem cells, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000.
Further evidence comes from histology, the study of tissue structure of tumors. Many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types. In other words, it possessed multidifferentiative potential, a classical hallmark of stem cells.
The existence of leukaemic stem cells prompted further research into other types of cancer. Cancer stem cells have recently been identified in several solid tumours, including:
Some treatments with chemotherapy, such as paclitaxel in ovarian cancer (a cancer usually discovered in late stages), may actually serve to promote certain cancer growth (55-75% relapse <2 years). It potentially does this by destroying only the cancer cells susceptible to the drug (targeting those that are CD44-positive, a trait which has been associated with increased survival time in some ovarian cancers), and allowing the cells which are unaffected by paclitaxel (CD44-negative) to regrow, even after a reduction in over a third of the total tumor size. There are studies, though, which show how paclitaxel can be used in combination with other ligands to affect the CD44-positive cells. While paclitaxel alone, as of late, does not cure the cancer, it is effective at extending the survival time of the patients.
It is likely that in a tumour there are several lines of stem cells, with new ones being created and others dying off as a tumour grows and adapts to its surroundings. Hence, tumour stem cells can constitute a 'moving target', making them even harder to treat.
Normal somatic stem cells are naturally resistant to chemotherapeutic agents - they have various pumps (such as MDR) that pump out drugs, DNA repair proteins and they also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). Cancer stem cells, being the mutated counterparts of normal stem cells, may also have similar functions which allows them to survive therapy. These surviving cancer stem cells then repopulates the tumour, causing relapse. By selectively targeting cancer stem cells, it would be possible to treat patients with aggressive, non-resectable tumours, as well as preventing the tumour from metastasizing. The hypothesis implies that if the cancer stem cells are eliminated, the cancer would simply regress due to differentiation and cell death.
There has also been a lot of research into finding specific markers that may distinguish cancer stem cells from the bulk of the tumour (as well as from normal stem cells), with some success. Proteomic and genomic signatures of tumours are also being investigated. Success in these area would enable faster identification of tumour subtypes as well as personalized medicine in cancer treatments by using the right combination of drugs and/or treatments to efficiently eliminate the tumour.
Sonic hedgehog blockers are available, such as cyclopamine. There is also a new water soluble cyclopamine that may be more effective in cancer treatment. There is also DMAPT, a water soluble derivative of parthenolide that targets AML (leukemia) stem cells, and possibly other cancer stem cells as in myeloma or prostate cancer. A clinical trial of DMAPT is to start in England in late 2007 or 2008. Furthermore, GRN163L was recently started in trials to target myeloma stem cells. If it is possible to eliminate the cancer stem cell, than a potential cure may be achieved if there are no more cancer stem cells to repopulate a cancer.
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