The type I insulin-like growth factor receptor regulates cancer metastasis independently of primary tumor growth by promoting invasion and survival.

The type I insulin-like growth factor receptor (IGF1R) regulates multiple aspects of malignancy and is the target of several drugs currently in clinical trials. Although the function of IGF1R in proliferation and survival is well studied, the regulation of metastasis by IGF1R is not as clearly delineated. Previous work showed that disruption of IGF1R signaling by overexpression of a dominant-negative IGF1R inhibited metastasis. To establish a clinically applicable approach to inhibition of metastasis by targeting IGF1R, we examined the effect of an inhibitory antibody against IGF1R, EM164 and its humanized version, AVE1642, on metastasis of cancer cells. EM164 and AVE1642 did not affect primary tumor growth of MDA-435A/LCC6 cells but inhibited metastasis of these cells. Consistent with this inhibition in the formation of metastatic nodules, disruption of IGF1R also resulted in a decreased number of circulating tumor cells in blood of tumor-bearing mice. Disruption of IGF1R with a dominant-negative construct or antibody inhibited invasion across Matrigel in vitro. When tumor cells were directly injected into the circulation through the lateral tail vein of mice, IGF1R disruption also resulted in significant reduction of pulmonary nodules, suggesting that regulation of invasion is not the only function of IGF1R signaling. Further, disruption of IGF1R rendered cells more susceptible to anoikis. Thus, IGF1R regulated metastasis independently of tumor growth. The multiple phenotypes regulated by IGF1R must be considered during development of this therapeutic strategy as inhibition of metastasis independent of inhibition of tumor growth is not easily assessed in phase II clinical trials.

Expression of Pla2g2a prevents carcinogenesis in Muc2-deficient mice.

Goblet cell depletion and down-regulation of MUC2 expression are observed in a significant percentage of human non-mucinous colorectal adenocarcinomas. Direct evidence for the role of MUC2 in gastrointestinal tumor formation was demonstrated by a knockout of Muc2 in mice that resulted in the development of adenocarcinomas in the small and large intestine. The secretory phospholipase Pla2g2a is a protein that confers resistance to Apc(Min/+)-induced intestinal tumorigenesis. Like Muc2, in the large intestine Pla2g2a is exclusively expressed by the goblet cells and Pla2g2a's tumor resistance is also strongest in the large intestine. Possible genetic interactions between Muc2 and Pla2g2a were examined by creating C57BL/6-Muc2(-/-)Pla2g2a transgenic mice. Expression of a Pla2g2a transgene reduced tumorigenesis in the large intestine by 90% in male Muc2(-/-) mice and by nearly 100% in female Muc2(-/-) mice. Expression of Pla2g2a also inhibited tumor progression. Microarray gene expression studies revealed Pla2g2a target genes that modulate intestinal energy metabolism, differentiation, inflammation, immune responses and proliferation. Overall, results of the present study demonstrate an Apc-independent role for Pla2g2a in tumor resistance and indicate that Pla2g2a plays an important role, along with Muc2, in protection of the intestinal mucosa.