Differentiation and cancer: The conditional autonomy of phenotype

摘要

The role of differentiation in the neoplas-tic process has been an issue of interest ever since pathologists began to examine tumors with the microscope. The cytolog-ical and histological mimicry of normal tissue development exhibited by neoplasms is a common occurrence, but the extent to which individual tumors appear to recapitulate the ontogeny of their tissue of origin varies considerably. Probably the most conspicuous display of differentiation in neoplasms is the progression in some tumors from cells that are clearly proliferating to cells incapable of proliferation because they no longer contain a nucleus. For example, certain skin cancers characteristically show zones of mitotically active cells with cytologic features that mimic the basal generative layer of skin, and whose progeny become large polygonal cells with desmosomes and abundant keratin that mimic cells of the stratum spinosum of skin. With further maturation, the malignant keratinocytes undergo nuclear dissolution, the cell borders become obscure, and foci reminiscent of the stratum corneum of the skin develop in the tumor. An analogous process occurs in chronic granulocytic leukemia where some clonal members differentiate to postmitotic polymorphonuclear leukocytes and in erythroid leukemia where some cells differentiate to enucleated erythrocytes. In the examples cited, differentiation of tumor cells to a cell incapable of further division is not accompanied by depletion of the tumor stem cell pool, and therefore, the tumor continues to proliferate. Were it possible to deplete tumor stem cells by therapeutically induced tumor cell differentiation, further growth of the tumor would cease. Interestingly, there are documented instances in which the malignant neuroblasts in childhood neuroblastoma spontaneously differentiate to postmitotic sympathetic ganglion cells accompanied by depletion of the tumor stem cell pool (1). While this is a very rare event, when it does occur, it results in cessation of tumor growth, spontaneous cure of the malignant process, and a residual mass that is clinically insignificant.