| dc.description.abstract | Vascular endothelial cells (ECs) are specialized components in the tumor microenvironment (TME) that line the inner walls of blood vessels and serve as precursors for new blood vessel formation (angiogenesis). Compared to normal blood vessels, tumor blood vessels are abnormal with chaotic angiogenic sprouting which results in spontaneous hemorrhage and increased interstitial fluid pressure in the TME. These defects of intra-tumoral vessels lead to poor leukocyte trafficking and drug delivery. Although there is a solid published premise for tumor blood vessel normalization, mechanisms to improve tumor vessel quality are only beginning to be investigated. Because tumor ECs are fast growing, they require nutrients to generate biomass that support their proliferative program. Indeed, inhibition of glucose metabolism has been shown to normalize tumor vasculature and improve drug delivery. Glutamine metabolism is also essential for EC proliferation and angiogenic sprouting, but this pathway has not been previously studied in the context of the tumor. Using an inducible endothelial-specific glutaminase knockout (GLSECKO) mouse model, we found that there is a significant decrease in breast cancer tumor growth and lung metastasis in GLSECKO compared to WT animals. Loss of GLS decreased tumor microvascular density, increased perivascular support cell coverage, improved perfusion, and reduced hypoxia in mammary tumors. Importantly, chemotherapeutic drug delivery and therapeutic efficacy were improved in tumor-bearing GLSECKO hosts or in combination with GLS inhibitor, CB-839. Mechanistically, loss of GLS in tumor endothelium resulted in decreased leptin levels, and exogenous recombinant leptin rescued tumor growth defects in GLSECKO mice. Together, these data demonstrate that inhibition of endothelial glutamine metabolism normalizes tumor vessels, reducing tumor growth and metastatic spread, improving perfusion, and reducing hypoxia, and enhancing chemotherapeutic delivery. Thus, targeting glutamine metabolism in host vasculature may improve clinical outcome in patients with solid tumors. | |
