The IGF axis regulates hepatic stellate cell recruitment and activation during colorectal carcinoma liver metastasis

FERNÁNDEZ, MA. CELIA; RONI RAYES; NI WANG; PNINA BRODT

Montreal

Conferencia; 25th Annual Fraser N. Gurd; 2014

Background: Previously in Dr. Brodtˈs lab it was found that in female mice with a chronic IGF-1 deficiency from birth (LID), liver metastasis of murine colon carcinoma MC-38 cells was not altered. In contrast, in mice with an acute IGF-1 depletion induced by a tamoxifen injection 3 weeks prior to tumor inoculation (iLID), metastasis was significantly reduced following intrasplenic inoculation of the cells. Objectives: The objective of this project is to characterize the stromal response of the liver to invading colon cancer cells and the role that IGF plays in regulating this response, with emphasis on the role of HSC recruitment and activation.Results: In vitro assay shows that Conditioned Medium from highly liver metastatic tumor cells line (MC38, H59 and M27IGF-IR+) can rapidly activate isolated HSC as evidenced by increased expression of SMA. In contrast to serum free medium or Conditioned Medium from either a no metastatic cell line (HEK293) or a lung carcinoma cell line that do not metastasize to the liver (M27) where the activation of HSC was significantly lower or even null. Also, stimulation with IGF-I can significantly activate HSC after 3 days of culture. In vivo, activation of HSC was significantly lower in LID mice intrasplenic inoculated with MC38 and iLID mice injected with tamoxifen 3 weeks prior to MC38 tumor inoculation compare to activated HSC in C57/Bl6 tumor bearing mice and iLID mice injected with tamoxifen 2 days prior to MC38 tumor inoculation. Interestingly, the number of HSC per tumor cells in the LID mice was not altered compared to the C57/Bl6 mice and only the iLID mice injected with tamoxifen 3 weeks prior to MC38 tumor inoculation have a significantly reduction of HSC recruitment into the tumors areas. Conclusion: The lack of IGF-I in the liver microenvironment for a long term period prevent the activation of HSC but it seems that other factors may be involved in the recruitment of this cells when liver metastasis are not altered.