VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors

Abstract

The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes.

Periostin Limits Tumor Response to VEGFA Inhibition

“…For example, VEGFA inhibition in a mouse model of colorectal liver metastasis enhanced tumor deposition of hyaluronic acid and sulfated glycosaminoglycans, which in turn increased tumor stiffness and limited drug perfusion (Rahbari et al, 2016). Similarly, heightened deposition of fibrillar ECM proteins and elevated expression of lysyl oxydases, which have roles in collagen cross-linking, have been associated with impeded drug permeation and tumor refractoriness to anti-VEGFA therapy (Rö hrig et al, 2017).…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…They are essential for stabilization of collagen networks in a last extracellular maturation step. Thus, increased lysyl oxidase levels affect drug distribution in two ways: through better collagen stabilization toward degradation, they enhance collagen accumulation and the increasing quantity of cross-links turns the collagen network denser, further decreasing diffusivity (Rohrig et al, 2017;Rossow et al, 2018). Stromal fibroblasts contribute strongly to the elevated lysyl oxidase levels observed in many cancers (Peyrol et al, 1997).…”

“…Thus, the beneficial effect of antiangiogenic therapy on response to radiotherapy might not stem from reduced hypoxia but from increased sensitivity of the growth factor signaling-deprived endothelium. Moreover, antiangiogenic treatment leads, in most settings, not to improved supply but to increased hypoxia, both in murine models and in patients (Henke et al, 2007;Keunen et al, 2011;Van der Veldt et al, 2012;Miyazaki et al, 2014;Rohrig et al, 2017). Interestingly, Riesterer et al showed that fractionated radiation reversed the increased hypoxia after Vatalinib treatment (Riesterer et al, 2006).…”

Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer

“…In line with this, manipulation of the ECM in fibrosarcoma increased the permeability of the tumor vasculature and response to anti-VEGF agents. 69 In addition, Frentzas et al 70 reported interactions between the ECM and vasculature in liver metastases in human and in mice. Here, the authors demonstrated that metastatic emboli surrounded by a fibrotic capsule respond well to anti-angiogenic agents, whereas metastases progressing without a fibrotic tissue were resistant to these drugs.…”