Editors' ChoiceCancer

New connections: VEGF beyond the vasculature

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Science Signaling  16 Oct 2018:
Vol. 11, Issue 552, eaav7125
DOI: 10.1126/scisignal.aav7125

The growth factor VEGF promotes cancer-associated stem cell biology and pain, as well as angiogenesis.

Vascular endothelial growth factor (VEGF) is essential to both the growth of new blood vessels (angiogenesis) and the maintenance of vessel integrity. Tumor cells need an abundant supply of nutrients and oxygen, and they secrete VEGF; hence, the vasculature-associated roles of VEGF signaling are well known to support cancer progression. However, studies are emerging that show nonvascular roles for VEGF in cancer. In this issue of Science Signaling, Yang et al. showed that VEGF directly promoted cancer-associated pain. A rat model of bone metastatic breast cancer revealed that secreted VEGF activated a calcium-mediated, negative feedback pathway in sensory neurons through which the expression of the potassium channel TRESK was repressed. Loss of potassium current through TRESK increased the excitability of the neurons and made the rats more sensitive to heat and touch on the foot of the leg bearing the bone lesion. Blocking this pathway restored channel activity and alleviated pain in the rats. These findings suggest that VEGF inhibitors may lessen pain and improve quality of life in patients with bone metastasis, which is a very painful condition.

Because of its role in angiogenesis, not surprisingly, VEGF is associated with poor prognosis in cancer patients. However, in the Science Signaling Archives, Elaimy et al. (see also the Review by Elaimy and Mercurio) showed that tumor-intrinsic effects may additionally contribute to this association. Using various breast cancer cell lines, the authors found that VEGF promoted the development and proliferation of cancer stem-like cells (CSCs). Exogenous and tumor-secreted VEGF bound to its noncanonical receptor NRP2 on tumor cells and subsequently activated the migration-associated kinase FAK and the GTPase Rac1. This activated the Hippo pathway transcription cofactor TAZ, which, like VEGF, is associated with poor prognosis in various cancers. TAZ repressed the expression of β2-chimaerin, an enzyme that effectively shuts off Rac1. Thus, loss of β2-chimaerin promoted sustained Rac1 activity in a self-perpetuating loop. Through this mechanism, VEGF promoted CSC-like behavior in the breast cancer cells and correlated with stem-like and metastatic markers in patient tumors. CSCs promote drug resistance and progression in some tumors.

This VEGF-CSC link in breast cancer is potentially supported by another study in the Science Signaling Archives: Thomas et al. uncovered an interesting mechanism in which signaling by the kinase PI3K promoted stem-like traits in basal-like breast tumors. Notably, PI3K is activated by VEGF signaling. These findings suggest that VEGF inhibitors, by repressing CSCs, may potentially enhance the efficacy of various anticancer therapies in patients. It will be interesting to further investigate that potential and to see whether this pathway is active in other CSC-associated tumor types. Together, these reports (and potentially many others, as our knowledge of pathway cross-talk evolves) broaden the landscape of VEGF signaling and encourage a rather holistic, systems-level analysis of VEGF biology and therapeutic applications in cancer.

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