Tumors direct vessels to feed growth

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Sci. Signal.  07 Feb 2017:
Vol. 10, Issue 465, eaam9091
DOI: 10.1126/scisignal.aam9091

Blood vessels go from blocking growth factor signaling with IGFBP7 to sending the growth factor IGF1 in response to tumor-released FGF4.

Tumors and cells of the tumor microenvironment reciprocally secrete signaling molecules that promote tumor progression. For example, tumors stimulate angiogenesis in the adjacent vasculature that promote tumor growth by delivering oxygen and nutrients and enable metastasis by providing an escape route from the primary site. Despite this clear tumor-promoting role, therapies aimed at limiting blood vessel growth have had limited success in patients. Cao et al. found an alternate way to inhibit protumorigenic communication between the tumor and vasculature. Insulin-like growth factor (IGF) signaling promotes cell survival and proliferation and is increased in many types of tumors. Various assays using cocultures and transgenic mouse models of multiple tumor types revealed that endothelial cells normally secrete IGFBP7, an inhibitor of the IGF1 receptor. In response to secretion of fibroblast growth factor 4 (FGF4) from tumor cells, which was stimulated by various chemotherapies, endothelial cells decreased the production of IGFBP7 and instead increased their production of IGF1. The switch promoted proliferation and chemoresistance in IGF1 receptor–positive tumor cells. Knocking down the FGF4 receptor or the transcription factor ETS2 in endothelial cells prevented this switch and the associated phenotypes. The findings reveal an intercellular cross-talk between the FGF and IGF signaling pathways in the tumor microenvironment and suggest that inhibiting the subversive FGF4 signal or restoring IGFBP7 to the tumor microenvironment might slow tumor growth and improve the efficacy of chemotherapy in patients.

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