Vascular and Interstitial Biology of Tumors
Summary of Key Points
• A solid tumor is an organ composed of neoplastic cells and stromal cells nourished by a vasculature made of endothelial cells—all embedded in an extracellular matrix. The interactions among these cells and between these cells, their surrounding matrix, and their local microenvironment control the expression of various genes. The products encoded by these genes, in turn, control the pathophysiological characteristics of the tumor. Tumor pathophysiology governs not only tumor growth, invasion, and metastasis but also the response to various therapies.
• Tumor vasculature is made of host vessels co-opted by cancer cells and by new vessels formed by the processes of vasculogenesis and angiogenesis. A constellation of positive and negative regulators of angiogenesis governs the process of neovascularization.
• Tumor vessels are abnormal in terms of their organization, structure, and function. These abnormalities contribute to heterogeneity in vascular permeability, blood flow, and the microenvironment.
• Tumor interstitial matrix is formed of proteins secreted by stromal and cancer cells and by those leaked from the nascent blood vessels.
• Tumor interstitium is heterogeneous, with some regions fairly permeable and others difficult to penetrate. Modification of collagen and hyaluronan in the matrix can improve penetration of large-molecular-weight therapeutics.
• Solid components of tumors—cancer cells, stromal cells, and matrix molecules—mechanically compress blood and lymphatic vessels, resulting in reduced perfusion that limits oxygen and drug supply. Depleting these constituents decompresses blood vessels to enhance perfusion and drug delivery.
• Interstitial hypertension is a hallmark of solid tumors and results from vessel leakiness, lack of functional lymphatics, and compression of vessels. This elevated fluid pressure contributes to blood flow heterogeneity and directly hinders the penetration of large-molecular-weight therapeutics. Alleviating interstitial hypertension improves oxygen and drug delivery to tumors.
• Judicious application of angiogenic therapy can normalize the tumor vessels and make them more efficient for delivery of oxygen (a known radiosensitizer) and drugs. Antiangiogenic agents can prune tumor vessels, induce cancer cell apoptosis, and lower interstitial hypertension in tumors.
