Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases

Abstract

The survival benefit of anti–vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition. The density of these matrix components correlated with increased tumor stiffness after anti-VEGF therapy. Treatment-induced tumor hypoxia appeared to be the driving force for the remodeling of the extracellular matrix. In preclinical models, we show that enzymatic depletion of HA partially rescued the compromised perfusion in liver mCRCs after anti-VEGF therapy and prolonged survival in combination with anti-VEGF therapy and chemotherapy. These findings suggest that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy.

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

“…The latter case explains one mechanism of anti-VEGF therapy resistance in patients, which is consistent with our observations in CRC models. Indeed, the therapeutic dose of bevacizumab currently used in the clinic is often considered as a high dose (69), which is comparable to the dose we used in our study (maximum effective dose). These findings imply that immune resistance may hinder responsiveness to anti-VEGF/ VEGFR therapy.…”

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

“…This is in line with its current use for the treatment of cerebral vasospasm after subarachnoid hemorrhage in Japan (87-89) while avoiding any long-term toxic effects that could arise from chronic treatment (36, 39). Therefore, targeting ECM-dependent and ECM-independent changes in cancer appears to be an important advantage of transient ROCK inhibition compared to chronic ECM targeting alone (39, 90, 91) and warrants further consideration with regard to repurposing the off-patent drugs in PC (92). …”

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…Experimental data indicate that VEGF and ANG2 might cooperate to induce tumour immunosuppression and that this effect might be dependent on the relative levels of these cytokines in the TME 35–37 . Importantly, however, preclinical evidence indicates that high-dose and/or long-term antiangiogenic therapy causes massive vessel pruning and increases immunosuppression in tumour models 37–40 , suggesting that an optimum level of VEGF and ANG2 blockade will be needed to alleviate immunosuppression in the TME.…”

“…Importantly, however, preclinical evidence indicates that high-dose and/or long-term antiangiogenic therapy causes massive vessel pruning and increases immunosuppression in tumour models 37–40 , suggesting that an optimum level of VEGF and ANG2 blockade will be needed to alleviate immunosuppression in the TME. Interestingly, emerging data suggest that immunosuppression, in turn, contributes to resistance to antiangiogenesis treatments 37–39,41 .…”