Anti-VEGF therapy upregulates HA and sGAG to increase tumor stiffness and promote acquired resistance.

  • Major finding: Anti-VEGF therapy upregulates HA and sGAG to increase tumor stiffness and promote acquired resistance.

  • Concept: Anti-VEGF therapy induces hypoxia that drives extracellular matrix remodeling and reduces tumor perfusion.

  • Impact: Targeting ECM components may potentiate chemotherapy in patients receiving anti-VEGF therapy.

Antiangiogenic therapy with the VEGF antibody bevacizumab provides a modest survival benefit in combination with chemotherapy in patients with metastatic colorectal cancer, but the effectiveness is limited by the development of acquired resistance. Hypoxia resulting from antiangiogenic therapy has been shown to increase collagen expression in tumors, but the effect on other extracellular matrix (ECM) components such as hyaluronic acid (HA) and sulfated glycosaminoglycans (sGAG), compression-resistant molecules that could potentially contribute to solid stress–induced blood vessel collapse and reduced drug delivery to tumors, are not well understood. Rahbari and colleagues found that patients treated with bevacizumab and chemotherapy had elevated expression of HA in colorectal cancer liver metastases. Accordingly, in two syngeneic mouse models of metastatic colorectal cancer, treatment with a VEGF-blocking antibody increased the stiffness and solid stress of metastatic liver lesions and reduced the cell-to-matrix ratio, altogether indicating that antiangiogenic therapy induces desmoplasia to alter the mechanical properties of liver metastases. In mouse liver metastases, anti-VEGF therapy increased expression of the HA receptor CD44 in addition to HA, and also increased accumulation of sGAG, whereas collagen deposition was largely unchanged. Bevacizumab treatment also increased sGAG levels in patients with metastatic colorectal cancer. HA expression was localized to hypoxic regions, and culturing hepatic stellate cells (HSC) in hypoxic conditions increased HA synthesis, suggesting that hypoxia drives activated HSCs to produce HA after anti-VEGF therapy. Based on these findings, HA was targeted with polyethylene glycol–conjugated hyaluronidase (PEG-HAse) in mice with liver metastases treated with anti-VEGF therapy. PEG-HAse increased tumor perfusion and enhanced the efficacy of chemotherapy, resulting in prolonged survival. These findings suggest a mechanism by which anti-VEGF therapy remodels the ECM to reduce perfusion and induce acquired resistance, and indicate that targeting ECM components may enhance the effects of combined anti-VEGF therapy and chemotherapy in patients with metastatic colorectal cancer.

Rahbari NN, Kedrin D, Incio J, Liu H, Ho WW, Nia HT, et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci Transl Med 2016;8:360ra135.

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