Anti-Angiogenic Therapy: Albumin-Binding Proteins Could Mediate Mechanisms Underlying the Accumulation of Small Molecule Receptor Tyrosine Kinase Inhibitors in Normal Tissues with Potential Harmful Effects on Health

SIMPLE SUMMARY: In the last five decades the tumor microvascular endothelium has been, and still remains, an object of sustained interest in biomedical research. This interest is undoubtedly connected with the importance of blood microvessels in cancer cell proliferation, tumor growth, and metastasis. Depriving a tumor of its oxygen and nutrients by preventing the formation of new vessels with anti-angiogenic drugs including small molecule receptor tyrosine kinase inhibitors (RTKIs) is a common treatment in oncology. However, resistance to treatment, insufficient efficacy, and high toxicity limit the success of this antivascular therapy. Cellular and molecular mechanisms mediated by several albumin-binding proteins (ABPs) expressed in normal tissues and organs seem to be responsible for the side effects and toxicity associated with this type of anti-angiogenic therapy. ABSTRACT: Anti-angiogenics currently used in cancer therapy target angiogenesis by two major mechanisms: (i) neutralizing angiogenic factors or their receptors by using macromolecule anti-angiogenic drugs (e.g., therapeutic antibodies), and (ii) blocking intracellularly the activity of receptor tyrosine kinases with small molecule (M(r) < 1 kDa) inhibitors. Anti-angiogenics halt the growth and spread of cancer, and significantly prolong the disease-free survival of the patients. However, resistance to treatment, insufficient efficacy, and toxicity limit the success of this antivascular therapy. Published evidence suggests that four albumin-binding proteins (ABPs) (gp18, gp30, gp60/albondin, and secreted protein acidic and cysteine-rich (SPARC)) could be responsible for the accumulation of small molecule receptor tyrosine kinase inhibitors (RTKIs) in normal organs and tissues and therefore responsible for the side effects and toxicity associated with this type of cancer therapy. Drawing attention to these studies, this review discusses the possible negative role of albumin as a drug carrier and the rationale for a new strategy for cancer therapy based on follicle-stimulating hormone receptor (FSHR) expressed on the luminal endothelial cell surface of peritumoral blood vessels associated with the major human cancers. This review should be relevant to the audience and the field of cancer therapeutics and angiogenesis/microvascular modulation-based interventions.