Tumor microenvironment abnormalities: Causes, consequences, and strategies to normalize

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Abstract
A solid tumor is an organ‐like entity comprised of neoplastic cells and non‐transformed host stromal cells embedded in an extracellular matrix. The expression of various genes is influenced by interactions among these cells, surrounding matrix, and their local physical and biochemical microenvironment. The products encoded by these genes, in turn, control the pathophysiological characteristics of the tumor, and give rise to the abnormal organization, structure, and function of tumor blood vessels. These abnormalities contribute to heterogeneous blood flow, vascular permeability, and microenvironment. Proliferating tumor cells produce solid stress which compresses blood and lymphatic vessels. As a result of vessel leakiness and lack of functional lymphatics, interstitial fluid pressure is significantly elevated in solid tumors. Each of these abnormalities forms a physiological barrier to the delivery of therapeutic agents to tumors. Furthermore, the metabolic microenvironment in tumors such as hypoxia and acidosis hinder the efficacy of anti‐tumor treatments such as radiation therapy and chemotherapy. A judicious application of anti‐angiogenic therapy has the potential to overcome these problems by normalizing the tumor vessels and making them more efficient for delivery of oxygen and drugs. Combined anti‐angiogenic and conventional therapies have shown promise in the clinic. J. Cell. Biochem. 101: 937–949, 2007.