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Paracrine Growth Stimulation by Hepatocyte-derived Insulin-like Growth Factor-1: A Regulatory Mechanism for Carcinoma Cells Metastatic to the Liver¹

Departments of Surgery [L. L., J. N., P. B.] and Oncology [P. B.], McGill University and the Royal Victoria Hospital [P. B.], Montreal, Quebec H3A 1A4, Canada

Tumor H-59 is a subline of the Lewis lung carcinoma which is highly and preferentially metastatic to the liver. We used this carcinoma model to investigate the role of paracrine growth regulation by liver-derived factors in this organ-selective pattern of metastasis. We observed that serum-free medium conditioned by primary cultures of mouse hepatocytes was highly and specifically mitogenic for H-59 cells but had little effect on the proliferation of a second subline, i.e., carcinoma M-27, which is metastatic only to the lung. This mitogenic activity was hepatocytespecific and could be blocked or depleted by a monoclonal antibody to insulin-like growth factor 1 (IGF-1). IGF-1 could in turn be detected in hepatocyte conditioned medium by the Western blot assay, and when added to serum-deprived cells, IGF-1 could stimulate the proliferation of H-59 but not M-27 cells. Furthermore, when expression of the IGF-1 receptor was analyzed by the Northern blot assay, we found that H-59 cells expressed significantly higher levels of mRNA transcripts encoding IGF-1 receptor. A ligand binding assay revealed that the number of IGF-1 binding sites on H-59 cells was 3.4-fold higher than that on M-27 cells. The results identity IGF-1 as the growth factor mediating the proliferative effect of hepatocyte conditioned medium and suggest that paracrine growth stimulation by hepatocyte-derived IGF-1 is a potential mechanism of selection in the process of liver colonization by these carcinoma cells.

¹ This study was supported by a grant from the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at Department of Surgery, Division of Surgical Research, McGill University, Donner Bldg., 740 Dr. Penfield Ave., Montreal, Quebec H3A 1A4, Canada.

Received 3/ 3/94. Accepted 5/10/94.

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