Regulation of tumor cell invasion and metastasis by the type I insulin-like growth factor receptor (IGF-1R)

Invasion and metastasis largely determine the clinical course of cancer. A better understanding of the mechanisms required for metastases formation in secondary sites will lead to the development of new and more successful treatment strategies. The present work describes our results with a murine Lewis lung carcinoma model which consists of two cell lines, H-59 and M-27, with different patterns of metastasis in vivo. Using this model, a positive correlation was found between the expression of insulin-like growth factor I receptor (IGF-IR) and the ability of the tumor cells to metastasize to the liver. The highly invasive, highly metastatic, liver colonizing cell line H-59 expressed significantly higher levels (5-fold) of IGF-IR than the poorly invasive M-27 cells which metastasize to the lung only. When expression of IGF-IR in H-59 cells was suppressed by transfection with a plasmid vector expressing IGF-IR cDNA in an antisense orientation, the cells lost their proliferative response to IGF-I in vitro, their ability to migrate in response to IGF-I and their metastatic potential. To further study the role of IGF-IR in the process of liver metastasis, IGF-IR was overexpressed in the lung metastasizing M-27 cells by transfection with a plasmid vector expressing full length human IGF-IR cDNA. The stable transfectants had an enhanced proliferative response to IGF-I and hepatocyte conditioned medium (HCM) and acquired an invasive potential as demonstrated in the Matrigel invasion assay. When inoculated via the splenic/portal route in vivo, these cells but not the wild-type or mock-transfected cells gave rise to multiple liver nodules. To further investigate the link between IGF-IR and invasion, metalloproteinase 2 (MMP-2) expression in the tumor cells was investigated. It was found that the antisense transfected H-59 cells expressed significantly lower levels of MMP-2 as assessed by RT-PCR, Western blot analysis and gelatin zymography. M-27 cells overexpressing IGF-I