Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms.
The insulin-like growth factor (IGF) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients.
Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source. Further, we provide functional evidence that stromal IGF2, via the paracrine IGF1R/insulin receptor axis, activated pro-survival AKT signaling in CRC cell lines. Concomitantly, high-level coexpression of IGF2 and TGFβ predict adverse outcome with higher accuracy than increased expression of the individual genes alone. Taken together this report in the journal Oncogene demonstrates that stroma-induced IGF2 promotes colon cancer progression in a paracrine and autocrine manner and propose IGF2 as potential target for tumor stroma cotargeting strategies.