Cell Origin of Tumors and the Persistence of Cancer Propagating Cells in Tumor Lesions

ABSTRACT

Cells defined as “cancer stem cells” because of a postulated ability to self-renew in a stem cell-like fashion and regenerate a tumor analogous to that of provenience upon transplantation have been described in a range of myeloid leukemia, breast, prostate, brain, colon and ovarian cancers. However, the precise origin of these cells remains an enigma. Surgical pathologists have suspected for decades that connective tissue tumors could arise through the neoplastic transformation of an immature multipotent cell and that this cell persisted in the lesion in a transformed state. This hypothesis was later supported by some experimental data generated by hematologists who demonstrated the presence of stem/progenitor-type cells in different types of leukemia. In fact, increasing evidence now suggests that quiescent leukemic cells resembling normal hematopoietic stem cells and displaying a clonogenic self-renewal capacity are central in sustaining these pathologies. Although it remains technically challenging to verify the precise origin of a tumor, recent experimental findings in animal models incite a revisiting of the dogma that epithelial tumors may solely form as a consequence of a multistep “dedifferentiation process” of specialized epithelial cells. Moreover, despite the fact that progressive accumulation of genetic aberrations may remain the primary event leading to malignant transformation, some gastrointestinal tumors have been proposed to originate from stem cells residing within discrete niches of the intestinal crypta. Thus, the recent identification of discrete populations of tumor initiating cells in a number of carcinomas, melanomas and brain tumors, may be interpreted as to assign a more predominat role than previously thought to immature progenitor cells just as the ones specifically targeted by neoplastic transformation.