Abstract LB-267: Role of VEGFR-1 signaling in obesity-induced tumor progression

Abstract

Abstract Background: Obesity associates with angiogenesis and increased macrophage infiltration in adipose tissues during weight gain. Whether these effects also occur in cancer to promote tumor progression in obese condition remains unclear. We have shown that the vascular endothelial growth factor receptor-1 (VEGFR-1) pathway can modulate tumor angiogenesis and recruitment of tumor-associated macrophages (TAMs). Here, we tested the emerging hypothesis that obesity enhances tumor progression and metastasis by augmenting angiogenesis and TAM recruitment via activation of the VEGFR-1 pathway. Methods: We used a high-fat diet-induced obesity model in either wild type (WT) or VEGFR-1 tyrosine kinase null (Flt1TK-/-) C57BL/6 mice. Then, we implanted orthotopically syngeneic pancreatic (PAN02) or breast (E0771) carcinomas. We evaluated the role of VEGFR-1 activity on systemic metabolism, tumor angiogenesis and immune environment, and tumor growth and metastasis. Results: Obesity increased p38-MAPK activation and TAM infiltration, tumor growth (p = 0.001) and metastasis (p = 0.035) in PAN02 tumors. VEGFR-1 inhibition reduced tumor growth (p = 0.007) and metastasis (p = 0.017) in obese but not lean mice. This was associated with a decreased p38-MAPK activity and a shift in TAM polarization towards the M1 phenotype with reduced secretion of pro-tumor cytokines, but no change in vascular density or number of TAMs. In the E0771 model, VEGFR-1 inhibition reduced MMP-9 expression and decreased lung metastatic burden (p = 0.026) in obese mice. In addition to these tumor effects, VEGFR-1 inhibition reduced weight gain, but caused metabolic disorder-hyperinsulinemia-during obesity. Combining metformin with VEGFR-1 inhibition not only prevented this metabolic alteration, but also by recruiting cytotoxic cells further decreased tumor growth in the PAN02 model (p = 0.047). Conclusion: Inactivation of VEGFR-1 signaling prevents weight gain and obesity-induced acceleration of tumor progression in pancreatic and breast cancer models. Targeting VEGFR-1 signaling axis in combination with an anti-diabetic drug such as metformin might be a considerable cancer therapeutic option in the obese setting. Note: This abstract was not presented at the meeting. Citation Format: Joao Incio, Joshua Tam, Nuh Rahbari, Priya Suboj, Daniel McManus, Shan Chin, Trupti Vardan-Kaur, Ana Batista, Suboj Babycutty, Keehoon Jung, Anna Khachatryan, Masabumi Shibuya, Raquel Soares, Dan Duda, Rakesh K. Jain, Dai Fukumura. Role of VEGFR-1 signaling in obesity-induced tumor progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-267. doi:10.1158/1538-7445.AM2015-LB-267