Abstract
Cancer-stem-cell theory states that most, if not all, cancers arise from a stem/uncommitted cell. This theory revolutionised our view to reflect that cancer consists of a hierarchy of cells that mimic normal cell development. Elegant studies of twins who both developed acute lymphoblastic leukaemia in childhood revealed that at least two genomic insults are required for cancer to develop. These ‘hits’ do not appear to confer a growth advantage to cancer cells, nor do cancer cells appear to be better equipped to survive than normal cells. Cancer cells created by investigators by introducing specific genomic insults generally belong to one cell lineage. For example, transgenic mice in which the LIM-only 2 (LMO2, associated with human acute T-lymphoblastic leukaemia) and BCR-ABLp210 (associated with human chronic myeloid leukaemia) oncogenes were active solely within the haematopoietic stem-cell compartment developed T-lymphocyte and neutrophil lineage-restricted leukaemia, respectively. This recapitulated the human form of these diseases. This ‘hardwiring’ of lineage affiliation, either throughout leukaemic stem cell development or at a particular stage, is different to the behaviour of normal haematopoietic stem cells. While normal cells directly commit to a developmental pathway, they also remain versatile and can develop into a terminally differentiated cell that is not part of the initial lineage. Many cancer stem cells do not have this versatility, and this is an essential difference between normal and cancer stem cells. In this report, we review findings that support this notion.
Highlights
The precise cellular origin of a cancer, and the ability of the underlying cell to differentiate dictate the course of overt disease
In transgenic mice in which the expression of BCR-ABLp190, LMO2, and BCR-ABLp210 was restricted to haematopoietic stem cell (HSC) via the Sca-1 promotor, carcinogenesis was initiated by the oncogenes, and the resultant cancer recapitulated lineage-restricted human disease [27,28,29]
leukaemic stem cell (LSC)/CSCs and their progeny lack the versatility of HSCs/HPCs, which is an essential difference between normal and cancer stem cells
Summary
The precise cellular origin of a cancer, and the ability of the underlying cell to differentiate dictate the course of overt disease. In the late 1990s, John Dick and his colleagues proposed cancer-stem-cell theory on the basis of evidence from studies of acute myeloid leukaemia (AML). They stated that most, if not all, cancers arise from genetic lesions involving a tissue-specific stem cell [1]. Investigators identified further lesions in the 1950s and 1960s, leading to the view that the underlying driver of the development of cancer was an insult to the genome Around this time, cancer modelling began to include the concept of cancer initiation (preneoplasia) in addition to overt disease (malignancy). A further ‘hit’ converts this cell into a leukaemic stem cell (LSC) that gives rise to and sustains the disease
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