CLINICAL AND PHARMACOLOGICAL IMPLICATIONS OF CANCER CELL-DIFFERENTIATION AND HETEROGENEITY

Various aspects and interrelationships of intra-neoplastic diversity have been investigated at two levels: (1) differences among multiple subpopulations of tumor cells at any point in time (heterogeneity) and (2) variations among these subpopulations as a result of their maturation with time (differentiation). The importance of tumor cell heterogeneity and differentiation in neoplasia has been studied using cancer cells obtained from murine mammary tumors and rhabdomyosarcoma, as well as from patients with carcinoma of the colon. Several cancer cell lines derived from these tumors have been cloned and characterized. Neoplastic cell differentiation has been induced using a polar solvent, N,N-dimethylformamide (DMF); the differentiation is evidenced by morphological maturation, conversion of tumor cell markers and cell culture characteristics to those consistent with a more benign phenotype, and loss of tumorigenicity. Striking morphological and biological heterogeneity has been observed in neoplastic subpopulations isolated from a single tumor, including marked variability in growth potential, surface antigens, and sensitivity to chemotherapeutic agents. The biological and pharmacological significance of these findings is discussed from the standpoint of their profound implications for clinical therapy. © 1979.