Multi-imaging modality evaluation of prostate-specific membrane antigen (PSMA) as an enhancer of vascular endothelial growth factor (VEGF), a tumor-derived secreted factor (TDSF)

• Grant number: 15/11808-4
• Support Opportunities: Scholarships abroad - Research
• Start date: September 26, 2015
• End date: September 25, 2016
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Camila Maria Longo Machado
• Grantee: Camila Maria Longo Machado
• Host Investigator: Jan Grimm
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: Memorial Sloan-Kettering Cancer Center, United States

Abstract

Prostate-specific membrane antigen (PSMA) is a multifunction N-glycosylated protein with two well known enzymatic activities in cleaving N-acetylaspartyl glutamate (NAAG) (in N-acetylaspartate and glutamate) and also acting as a carboxypeptidase that cleaves gamma-glutamyl residues from folate. The detection of increased levels of PSMA in aggressive tumors may imply a role in transformation and/or invasiveness in prostatic, breast, bladder and glioma cancers. In these reported cases, the authors documented that PSMA is expressed in the primary tumor-associated vasculature as well as blood vessels inside organ metastasis. Recent and unpublished data from Dr. Grimm's group at MSKCC showed that PSMA inhibitors can abrogate the enzymatic function of PSMA with consequences in the normal neovasculature formation by a involvement of vascular endothelial growth factor (VEGF). VEGF is a well known tumor-derived secreted factor (TDSF) involved in angiogenesis of primary tumors, which is crucial to the development and growth of tumors. Importantly, TDSF can also support the formation of a pre-metastatic niche (PMN). It is as of yet unclear, which signals from tumors sustain or even increase the TDSFs (e.g. VEGF). Thus, based on current findings from Dr Grimm's group, the main aim objective of this project is the evaluation of PSMA as a VEGF enhancer in primary tumor sites or in PMN in mice models by using a multi-imaging modality approach. We will interrogate the role of enriched PSMA exossomes in the formation of tumor neovasculature and the PMN in tumor bearing mice xenografts by evaluating: (1) the level of VEGF and angiogenesis of tumor xenograft in mice; (2) the role of monocytes recruitment as bone marrow derived cells into primary tumors; (3) the role of VEGF on liver, spleen, bone marrow in order to promote organ tropism and; (4) the enhancement of myeloid compromised cells recruitment from bone marrow to distant tumor sites (e.g. PMN). This project is innovative as it assigns a new pathophysiological role of PSMA as an enhancer of VEGF in primary tumors or sites of the pre-metastatic niche. The information collected from this project will benefits cancer patients by better understanding the role of PSMA in tumor neovasculature with important implications for cancer therapy. (AU)