The type I insulin-like growth factor regulates the liver stromal response to metastatic colon carcinoma cells

MARÍA C. FERNÁNDEZ; RONI RAYES; BORAM HAM; NI WANG; FRANCE BOURDEAU; SIMON MILETTE; MARTIN ILLEMANN; NIGEL BIRD; ALI MAJEED; JUN XU; TATIANA KISSELOVA; PNINA BRODT

Oncotarget

Impact Journals, LLC

Año: 2016

Hepatic stellate cells (HSC) play a major role in initiating the liver fibrogenic(wounding) response of the liver and can also orchestrate a pro-metastaticmicroenvironment in the liver in response to invading cancer cells. Here we exploredthe role of the hepatic stellate cells in colon carcinoma liver metastasis with emphasison the contribution of the insulin-like growth factor (IGF) axis to their activation andfunction. To this end, we used mice with a Tamoxifen inducible liver IGF-I deficiency.We found that in mice with a sustained IGF-I deficiency, recruitment and activationof HSC into tumor-infiltrated areas of the liver were markedly diminished, resultingin decreased collagen deposition and reduced tumor expansion. In addition, IGF-Icould rescue HSC from apoptosis induced by pro-inflammatory factors such as TNF-`known to be upregulated in the early stages of liver metastasis. Moreover, in surgicalspecimens, activated IGF-IR was observed on HSC-like stromal cells surroundingcolorectal carcinoma liver metastases. Finally, IGF-targeting in vivo using an IGFTrapcaused a significant reduction in HSC activation in response to metastatic coloncancer cells. Therefore, our data identify IGF as a survival factor for HSC and thereby,a promoter of the pro-metastatic microenvironment in the liver. IGF-targeting couldtherefore provide a strategy for curtailing the pro-metastatic host response of theliver during the early stages of liver metastasis.