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.
• Thus far, eight antiangiogenic agents have been approved for patients with certain types of cancer. Based on these successes, antiangiogenic therapy is expected to make a difference in many other tumor types. Two main hurdles to further development of antiangiogenic agents are the better understanding of the mechanisms of action of these agents and the development of biomarkers to select patients for these drugs and to predict and monitor their effects.
A Conglomerates of genetically mutated cancer cells
B Conglomerates of genetically mutated cancer cells and stromal cells recruited from blood circulation
C Organ-like structures composed of extracellular matrices containing genetically mutated cancer cells, host-derived stromal cells recruited from surrounding tissues and from blood circulation and extracellular matrices
2. Vascular compression in tumors limits perfusion and is caused by
A Interstitial hypertension associated with fluid retained in tumors
B Solid stress produced from cancer and stromal cells as they proliferate
3. Plasma soluble VEGFR1 is an endogenous vascular endothelial growth factor (VEGF) inhibitor and is currently explored in trials of antiangiogenic agents as a
4. Interstitial hypertension is a hallmark of solid tumors and results from
1. Answer: C. Malignant tumors are organ-like structures composed of malignant cells and host-derived stromal cells (recruited from surrounding tissue and from blood circulation) in variable proportions depending on tumor type, stage, and site
2. Answer: E. Solid components of tumors, including cancer cells, stromal cells, and matrix molecules, lead to elevated mechanical solid stress. These solid tissue forces can greatly exceed the microvascular pressure, and thus solid components of tumors compress blood vessels. Interstitial hypertension is caused by the leakiness of tumor blood vessels, as in physiological edema during inflammation. Thus interstitial fluid pressure (fluid stress) in tumors cannot exceed the microvascular pressure and these fluid pressures completely oppose each other, such that interstitial hypertension cannot lead to vascular compression.
3. Answer: C. sVEGFR1/sFLT1 is an endogenous blocker of VEGF and placental-derived growth factor and has been proposed as a predictive biomarker of intrinsic resistance to anti-VEGF therapy. Our group reported that patients with locally advanced rectal carcinoma who had high plasma sVEGFR1 levels prior to treatment were less likely to benefit—or experience toxicities—from bevacizumab therapy combined with chemoradiation. We later found the same association for newly diagnosed patients with glioblastoma multiforme, triple-negative breast cancer, hepatocellular carcinoma, and metastatic colorectal carcinoma who were treated with anti-VEGF agents.
4. Answer: D. The blood vasculature of malignant tumors is abnormal and hyperpermeable, and the lymphatic (drainage) system is disrupted within tumors. Along with the pressure created by proliferating cancer cells, these factors results to an increase in interstitial fluid pressure from approximately 0 mm Hg (normal) levels that can reach 94 mm Hg.
5. Answer: E. Reduced perfusion, caused by vascular compression and interstitial hypertension, limits the supply of oxygen and drugs to tumors. This limitation promotes hypoxia and inadequate drug delivery in tumors, both leading to drug resistance. Higher perfusion correlates with lengthened survival in patients, and agents in preclinical development that improve perfusion lead to enhanced therapeutic outcomes. Metastasis thus far is not affected by agents that increase perfusion.
