Perspectives on clonogenic tumor cells, stem cells, and oncogenes.

The last decade has seen major advances in both cellular and molecular aspects of cancer biology. Tissue culture methods that allow the recognition of clonogenic cells within human tu mors have been described (37, 64); on the basis of theoretical arguments and the application of these techniques, it has been proposed that neoplasms may be regarded as stem cell systems in which a minority of cells have the proliferative capacity to maintain the tumor whereas the majority of cells demonstrate differentiation features and have limited proliferative potential. This view has been summarized as a "stem cell" model of tumor growth (59) and is consistent with data concerning normal cell renewal (83) and with analysis of kinetics of survival of neoplastia cells following treatment (101). In parallel with these developments, investigations regarding the molecular biology of neoplasia have shown that aspects of the malignant character of human tumors are governed by the "activation" and/or the inappropriate expression of certain cellular genes that resemble retroviral transforming genes (oncogenes) (reviewed in Ref. 50). Some 20 such genes ("c-onc" genes) have been described; their relationship to carcinogenesis has been attributed to point mutations in a c-onc sequence creating an abnormal gene product or to loss of regulation of transcription of c-onc genes arising through processes such as gene amplifi cation or translocation to a transcriptionally active area of a chromosome. Recently, evidence of relationships between c-onc genes, endogenous peptide growth factors, and the control systems that regulate entry into cell cycle and subsequent pro liferative behavior has been presented. These two sources of information (tumor stem cell organization and oncogene activation) have not previously been integrated. We will first present our perspectives of the anticipated impact of research on clonogenic cells on tumor biology and clinical oncology. Subsequently, we will review certain key observations related to oncogenes and attempt to establish an integration between the concept of cell heterogeneity (imposed by viewing a tumor as a stem cell system) and results showing that c-onc gene transcription is related to cell differentiation and can be modulated by certain growth factors.