Some but not all data suggest within a cancer not all cancer cells are the same, namely, there are diverse cell types. The stem cell theory of cancer proposes amongst all cancer cells a very few act as stem cells. These cells reproduce themselves and sustain the cancer much like normal stem cells renew and replenish organs and tissues like the haematopoietic system. There are important therapy implications if cancers are really driven by a few stem cells. For instance, many anti-cancer therapies are evaluated based on their ability to make a cancer smaller. This can happen without killing cancer stem cells. If so, the cancer is likely to recur, perhaps in a more dangerous form such as metastases. In fact, most people with cancer die from metastases, not the primary cancer. The analogy is selecting a more virulent microbe by indiscriminate use of antibiotics.
One component of the cancer stem cell theory concerns how cancers arise. Typically, for a cell to become cancerous it must accumulate substantial numbers of mutations. A leukaemia such as chronic myeloid leukaemia (CML) is an exception caused by 1 mutation (BCRABL1). Conventional cancer theory is that any cell has the potential to become a cancer. However, other data suggest only some cells, those with stem cell potential, can develop into a cancer. This may explain why some normal people can have cancer-related mutations without having cancer, for example normals with BCRABL1 or normals with t(14;18) without CML or without a lymphoma. The hypothesis is the cell(s) in which these mutations occur are not stem cells and therefore lack the potential to cause cancer. However, we must also consider the possibility some mutations can re-programme a cell without stem cell potentially to become a stem cell. An example of this are induced pluripotent stem cells iPSC) which are adult (non-stem) cells reverted to an embryonic stem cell state by introducing 4 genes. Another notion is only cells with stem cell like features survive sufficiently long to accumulate the typically large number of mutations required for cancer development. The theory, therefore, is cancer stem cells arise from normal stem cells or precursor cells produced by normal stem cells.
Another important implication of the cancer stem cell theory is cancer stem cells are closely related to normal stem cells and share many properties. Cancer cells produced by cancer stem cells should follow many of the rules observed by normal daughter cells. In this regard cancer cells can be considered a caricature of normal cells with similar but distorted features. If so, it may be possible to use knowledge about normal stem cells to identify and attack cancer stem cells.
Lastly, it may not be necessary to eradicate all cancer stem cells to cure a cancer. For example, in CML, therapy with tyrosine kinase-inhibitors (TKIs) markedly reduces numbers of mature leukaemia cells but not any and certainly not all CML stem cells. Regardless, in a substantial proportion of people with CML responding favorably to TKI-therapy it is possible to stop therapy without leukaemia returning. In sum, increasing knowledge of cancer stem cells should improve our understanding of and ability to treat diverse cancers.
Prof. Robert Peter Gale, Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, SW7 2AZ UK T:001-908-656-0484; E:robertpetergale@alumni.ucla.edu.
