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Cancer is a leading cause of morbidity and mortality worldwide. In 2007 cancer accounted for 7.9 million (13%) of all deaths.1 Each year 10.9 million people are diagnosed with cancer worldwide.2 Cancer hence represents a major burden of disease and public health problem.
Carcinogenesis, literally meaning the generation of cancer, is the process whereby normal cells are transformed into malignant cells. Two models on the mechanism of development of cancer currently exist. The classic genetic model, postulated by Nowell and Vogelstein, describes the formation of a tumor by the sequential accumulation of mutations in oncogenes and tumor suppressor genes.3 Oncogenes promote cell growth while tumor suppressor genes code for anti-proliferative signals and proteins that suppress mitosis and cell growth. Activation of oncogenes and silencing of tumor suppressor genes upsets the normal balance between cell proliferation and death resulting in uncontrolled cell division and generation of a tumor. This model proposes that all tumor cells can form new tumors and are therefore equally tumorigenic.
In contrast, the new cancer model proposes another layer of complexity in the malignant transformation. It reports that only a minority of cells can form new tumors. Disruption in the regulatory mechanism in the stem cell renewal pathways results in unregulated cell growth. The model classifies cancer as a stem cell disorder rather than a proliferative disease. The cancer stem cell hypothesis supports and adds on to this new model.
CANCER STEM CELL HYPOTHESIS
The concept that cancers arise from stem cells was first proposed about 150 years ago but recent advances in research have produced novel insights. The cancer stem cell hypothesis postulates that malignant tumors are initiated and maintained by a single, abnormal population of adult stem cell. Stem cells are defined as cells that have the ability to perpetuate themselves through self renewal and to generate mature cells of a particular tissue through differentiation.4
The exact origin of the cancer stem cell (CSC), however, has not be defined and it was initially thought that CSCs originated from multi-potential stem cells, tissue-specific stem cells, progenitor cells and cancer cells which had undergone genetic changes in self renewal and proliferative pathways. However, present knowledge highlights only self renewing stem cells which have lost the ability to regulate proliferation and progenitor cells which have acquired self renewal capabilities as the source of CSCs.5 Signaling pathways which regulate normal stem cells, including WNT, Notch, Hedgehog, PTEN, TGF-β, β-catenin and Bmi-I6-9 were found to be mutated in human cancers.
Figure 1: A simplified model of suggested hypothesis about origin of cancer stems cells5
EVALUATION: Cancer stem cells- the key to carcinogenesis?
The stem cell hypothesis stemmed from the observation that not all the cells within a tumor could maintain tumor growth and that large numbers of tumor cells were needed to transplant a tumor, even in an autologous context.10 In the late 1980's and early 1990's novel techniques in stem cell biology allowed researchers to identify and isolate specific populations of self renewing cells and prospectively transplant these cells into animal models. Cancer stem cells were discovered in acute myeloid leukemia cells (AML) and the first conclusive evidence for CSCs was published in 1997 in Nature Medicine. John Dick and colleagues demonstrated a small subset of human AML cells were phenotypically similar to normal hematopoietic stem cells and had the ability to transfer AML when transplanted into immunodeficient mice.11 Using fluorescence-activated cell sorting (FASC) to evaluate CD 34+ AMLS, they showed that the CD34+CD38- fraction was highly enriched for leukemia-initiating activity in transplanted recipients, while both the CD34+CD38+ and CD34- fractions did not initiate leukemia. In addition, the engrafted leukemia could be serially transplanted into secondary recipients, strong evidence of self renewing capacity. These findings excluded the possibility that all AML has a similar clonogenic capacity and showed that indeed a small, predictable subset was consistently enriched for the ability to proliferate and transfer disease.4
Furthermore, similar experiments involving solid tumors were subsequently performed and proved that findings were not just confined to leukemia. The first such study was reported by Al-Hajj et al12 who isolated tumorigenic CD44+CD24- cells from breast carcinoma using FACS and transplanted them into immunodeficient mice. Only the CD44+CD24- fraction contained tumor-initiating activity, whereas 100-fold more cells from the CD44+CD24+ or CD44- fractions did not form tumors. The engrafted tumor could also be transplanted to secondary recipients. The existence of CSC has also been shown in brain, lung, prostrate, testis, ovary, stomach, colon, skin, liver, and pancreas carcinomas.13-17 Three studies have independently demonstrated the existence of a cancer stem cell compartment in human brain tumors. These cancer stem cells were able to form neurospheres in vitro and express the neural stem cell markers CD133 and nestin. Furthermore, as few as 100 of these cells were able to transfer the tumors when injected intracranially into immunosuppressed mice.14,18
The results of these as well as numerous similar studies involving a variety of malignancies lend convincing support of the CSC paradigm. The hypothesis suggests that cancer develops from a small subset of cells, CSC, which the above studies were able to identify and demonstrate using purified samples. Utilising the cell theory which states that all cells arise from pre-existing cells, the cancer cells had to originate from the CD34+CD38- and CD44+CD24- cells in the leukemia and breast carcinoma respectively.
Additionally evidence of stem cell involvement in carcinogenesis also arise from observing the striking parallels that exist between normal stem cells and cancer cells. These include the capacity for self-renewal, the ability to differentiate, active telomerase expression, activation of anti-apoptotic pathways, increased membrane transporter activity and the ability to migrate and metastasize.4 19 Another viable argument is the longevity of stem cells make them susceptible to the accumulation of multiple mutations that are required for carcinogenesis.19 An average of six successive mutations are necessary to transform a normal cell to a malignant one. A study conducted by Little found that women exposed to radiation during late adolescents, the period when the mammary glands are thought to have the highest number of stem cells, had the highest susceptibility to breast cancer development.20 It has also been recognised that small numbers of disseminated cancer cells were detected at sites distant from the primary tumors in patients that never manifest metastatic disease.21,22 This supports the possibility that most cancer cells lack the ability to form a new tumor and only dissemination of rare cancer stem cells can lead to metastases. Also analyses of the doses required to control tumors with radiation therapy, using information about the measured radiation sensitivity of tumor cells, suggests that not every cell in a tumor needs to be killed in order to cure the tumor. A study by Hill and Milas23 using various spontaneous
rodent tumors, particularly mammary tumors, found that the radiation dose required to cure early generation transplants of these tumors (TCD50 value) was inversely proportional to the number of cells required to transplant the tumors (the TD50 value).
Despite this mount of persuasive evidence supporting the existence of cancer stem cells, the theory does not go unopposed and is still considered to be very much in its early stages. Critics have highlighted a number of viable theoretical and methodological points that questions the validity of the CSC hypothesis. Firstly the cancer stem cell model is based on the idea that stemness and maturation/differentiation are mutually exclusive and neglects the idea that stemness can vary with time.24 Secondly, the genome of cancer cells are also highly unstable and hence the relationship between stemness and differentiation can change over time in the tumor cells, adding another complexity to the research forum.
In vivo transplantation is the recognised gold standard for demonstrating normal and malignant stem cell behaviors but there are many limitations to this technique. Xenotransplantation assays may introduce a selection bias as engraftment may depend on other properties of cancer cells including homing, evasion of host immune response and proliferative capacity.25 In addition, these xenograft experiments may not adequately model the interaction between tumor cells and the tumor microenvironment that occurs in humans, as highly purified, FACS-isolated tumor cells were used for transplantation. Mice only partially recapitulate the biology of human cells. Interactions between cells and the extracellular matrix play a major role in controlling their behaviour and indeed may dictate whether or not a tumor develops from a genetically damaged cell.26 Bissell and colleagues showed that an aberrant extracellular matrix may promote cancer development.27
These limitations to the CSC paradigm do not completely dismiss the idea but simply raise questions that need to be answer in order to holistically accept the hypothesis and a fact.
In conclusion, the cancer stem cell hypothesis has started a new era in cancer research propelled by advances in cancer stem cell biotechnologies. There is a growing body of evidence that supports the idea that malignant tumors are initiated and maintained by a population of tumor cells that share similar biologic properties to normal adult stem cells. It provides an attractive explanation for the understanding of the biology of carcinogenesis but the current limitations that exist must be resolved before the hypothesis can be fully accepted. If proven to be true, it can have profound implications for revolutionizing current treatment and possibly a cure to one of the world's most dreaded disease.