The cancer stem cell hypothesis and the clonal evolution model

As we’ve already seen, cancer occurs due to mutations within oncogenes or tumour suppressor genes, resulting in increased proliferation and decreased cell death. However, one of the greatest puzzles for cancer researchers is why cancer cells differ so much. Cancer cells, even within the same tumour, differ, for instance, in size, as well as functionally by having different proliferation rates, ability to metastasize to other sites, and in their sensitivity to chemotherapy. Two popular concepts, the clonal evolution model and the cancer stem cell model, attempt to answer how cancer propagates. Even if these two approaches are not mutually exclusive, they’re fundamentally different. For scientists, it is important to determine which model is each cancer type following.

This is because cancers behave differently depending on the cell of origin. Therefore, identifying the cell of origin for a specific type of cancer will help in understanding each initiation, prevention, and treatment. Almost 40 years ago, Peter Nowell suggested the clonal evolution cancer model. It proposes that carcinogenesis is a multi-step process, and the transition from normal to a malignant phenotype requires the accumulation of a series of mutations. For instance, normal cell A divides into two cells, and one of them, cell B, gains a mutation that gives it a proliferative advantage. Cell B further divides, and one of its daughter cells, cell C, becomes pro-malignant by acquiring a mutation that enhances its survival.

Similarly, the daughter cell E can acquire a third mutation. The combination of these mutations leads ultimately to the acquisition of the hallmarks of cancer, and allows for tumour growth initiation. Adult stem cells sit at the top of the cell hierarchy. They are responsible for the production of every cell type within a particular niche through proliferation and differentiation. Stem cells are long lived, have high self renewal capacity, and low proliferation rates. In contrast, mature cells have a limited lifespan, almost no self renewal ability, and proliferate fast. The cancer stem cell model suggests that cancer is clonally derived by a single stem cell that has acquired a tumor-initiating mutation.

This malignant phenotype is supported by the inherent features of stem cells - self renewal, and clonal expansion. The first evidence in support of the cancer stem cell theory came from transplantation assays. Human leukemic cells were isolated from patients, separated into stem progenitor and mature cells, and transplanted into mice that were immunosuppressed The results of these experiments showed that the mice were developing leukaemia only when they were injected with leukemic stem cells, supporting the cancer stem notion. Taken together, the cancer stem cell model suggests that cancer initiates from stem cells that acquire tumour initiating mutations. Such mutations will pass through all the daughter cells, which will ultimately form the tumour. Currently, most anti-cancer treatments reduce tumour burden by targeting proliferating cells.

However, they fail to eliminate the cancer stem cells that will replenish the disease, therefore cancer researchers all over the world are working on ways of eliminating cancer stem cells in a targeted way to offer a cure for cancer.