Balancing angiogenic pathways in solid tumors

抄録

Intravital microscopy techniques have provided unprecedented insight into tumor angiogenesis, microcirculation and microenvironment. Tumor microvasculature has an abnormal organization, structure, and function. Tumor vessels are leaky. Blood flow is heterogeneous and often compromised. Lymphatic vessels are either defective or not functional inside tumors and together with leaky blood vessels elevate interstitial fluid pressure in solid tumors. All of these abnormalities hinder the delivery of therapeutic agents to tumors and also induce a hostile microenvironment characterized by hypoxia and acidosis. The abnormal microenvironment fuels malignancies of tumors and further lowers the effectiveness of anti-tumor treatments such as radiation therapy, chemotherapy and novel molecularly targeting therapies.
However, one can also exploit aberrant microenvironment in tumors for selective treatment of tumors. Enhanced permeability and retention effect of relatively large size particles in tumors is the major basis of nanomedicine. It not only increases therapeutic index but also allows delivering toxic agents and hydrophobic drugs to tumors otherwise prohibited for clinical use due to normal tissue toxicity. Unfortunately, crucial drawback of this approach is diffusion hindrance of the large nanoparticles. These nanotherapeutics cannot advance into tumor tissues after the extravasation from tumor vessels. To solve this dichotomy we proposed a multistage nanoparticle delivery system. We have developed a relatively large nanoparticle that can release small size nanoparticles upon exposure to enzymes uniquely present in tumor tissues and demonstrated superior intratumoral diffusion of these multistage nanoparticles.
Alternatively, one may try to tame abnormal tumor microenvironment. For example, host-tumor interactions regulate expression of pro- and anti-angiogenic factors. Imbalance of these factors results in above-mentioned pathophysiological features in the tumor. In a physiological setting, angiogenic vessels eventually become mature and stable vessels that represent long-lasting functional units. Restoring tissue balance of these factors in tumors may “normalize” tumor vasculature and thus, improve its function. Administration of cytotoxic therapy during the vascular normalization can enhance its efficacy. We have demonstrated a number of approaches to normalize tumor vasculature and microenvironment that improve a variety of anti-tumor therapies.