Effect of prolonged insulin treatment on carcinoma formation in mice.

Long-term insulin administration enhanced the incidence and development of chemically induced [3-methylcholanthrene (3-MCA)] squamous cell carcinomas in Swiss male mice. DNA radioactivity and light and electron microscopic autoradiography revealed that insulin administration significantly increased (2-fold) the [3H]thymidine incorporation and intracellular distribution in the neoplastic nuclei (38.50%) as compared to that of neoplastic nuclei treated with MCA alone (20%). Electron microscopic autoradiography showed a heavy [3H]thymidine distribution as developed grains over dense chromatin (heterochromatin) of neoplastic cell nuclei. Ultrastructural and cytological studies of insulin-treated carcinomas revealed the predominance of less differentiated squamous cell carcinomas with numerous vacuoles, polysomes, laminated concentric myelin figures, and phagolysosomes as compared to well differentiated squamous neoplastic cells treated with MCA only. Scanning electron microscopic observations revealed in the insulin + MCA-treated tumors the predominance of rounded cells covered with several elongated microvilli and blebs as compared to polygonal cells covered with sparse and thin microvilli, horny pearls with concentric keratinized layers after MCA treatment. An intense stromal tumor reaction can be also seen following insulin and MCA treatment. These findings demonstrate that insulin in pharmacological doses stimulates the carcinoma formation, increases DNA synthesis, and affects the squamous neoplastic cell differentiation.