Paracrine growth stimulation by hepatocyte-derived insulin-like growth factor-1: a regulatory mechanism for carcinoma cells metastatic to the liver.
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 hepatocyte-specific 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 identify 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.
Long
L
L
Department of Surgery, McGill University, Montreal, Quebec, Canada.
Nip
J
J
Brodt
P
P
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D017077:Culture Media, Conditioned; D005260:Female; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008099:Liver / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D017526:Receptor, IGF Type 1 / Q000032:analysis; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1