TRANSLATIONAL IMPACT

Abstract

In patients with locally advanced solid tumors, the first-line treatment is often neo-adjuvant or pre-operative chemotherapy, which helps shrink tumors before surgery, allowing for more conservative surgical approaches and reducing the potential for developing systemic disease. However, despite aggressive chemotherapy, long-term survival for many patients remains poor, in part owing to limitations with the targeting and accumulation of cytotoxic drugs in tumor tissue.The vasculature of solid tumors is abnormal, both in terms of vessel architecture and the dynamics of blood flow. Permeable heterogeneous vessel walls allow the leakage of proteins and fluid that, coupled with the inefficiency of lymphatic drainage, could be exploited to develop novel, enhanced drug delivery strategies that are therapeutically selective and improve clinical outcome.This work describes a previously unappreciated role for transforming growth factor beta (TGFβ) in regulating vascular stability and vessel permeability in solid tumors. Using mouse models, the authors demonstrate an endogenous pathway that regulates normal vascular permeability, which is controlled by perivascular collagen, the metalloproteinase enzyme MMP14, and TGFβ. In wild-type mice, inhibitors of either MMP14 or TGFβ signaling induce blood vessel permeability. Conversely, enhanced MMP14 or TGFβ activity in the mouse epidermis decreases leakage across cutaneous vessels. This pathway remains functional during tumor progression, as acute blockade of either MMP14 or TGFβ signaling transiently alters vessel stability, ‘opening’ vascular beds and promoting intravenous delivery of high molecular weight compounds to the tumor.The delivery of standard therapeutic agents or diagnostic molecular imaging agents to tumor tissue may be enhanced by transient blockade of the TGFβ pathway. If so, this could advance disease therapy and/or diagnostic imaging, not only in cancer medicine, but also in fibrotic disorders such as scleroderma and kidney failure.