Abstract B15: Invasive breast cancer amplifies lymphangiogenic signals in tumor microenvironment through integrin beta4 expressing cancer-associated fibroblasts

Abstract

Abstract Lymphangiogensis is widely acknowledged as a major route of breast cancer metastasis and a critical alteration of tumor microenvironment (TME) for tumor progression. But, most of it has remained still unknown. Previously, we found that invasive ductal carcinoma (IDC), not ductal carcinoma in situ (DCIS), upregulates integrin alpha6beta4 in the fibrosis adjacent to tumor burden, and that MDA-MB-231 induces integrin beta4 neoexpression in cancer-associated fibroblasts (CAFs) via cell-to-cell contract. Integrin (alpha6)beta4 overexpression is often detected in malignant tumors and negatively associated with patient survivor. In addition, integrin alpha6beta4 was reported to regulate eIF-4E activity leading to vascular endothelial growth factor (VEGF) translation in cancer cells. It is, therefore, plausible that invasive breast cancer cells increase lymphangiogenic signals in TME through driving integrin beta4 expression in CAFs. To verify our hypothesis, we induced integrin beta4 overexpression in CAFs using co-culture with MDA-MB-231 or transfection with pRK5_beta4 plasmid, and then observed tube formation of human dermal lymphatic endothelial cells (HDLEC) by integrin beta4-expressing CAFs in 3D co-culture model. VEGF-D, known as a major factor of lymphangiogenesis, was highly upregulated in integrin beta4-expressing CAFs, which promoted tube formation of HDLEC compared to normal CAFs and MDA-MB-231. Interestingly, the level of VEGF-D expression in MDA-MB-231 was much lower than that of integrin beta4-expressing CAFs before and after co-culture. Taken together, invasive breast cancer may amplify lymphangiogenic signals in TME by inducing integrin beta4-expressing CAFs, and integrin beta4 neoexpression in CAFs by breast cancer may be a pivotal process for lymphangiogensis. Citation Format: Baek Gil Kim, Yoon Pyo Choi, Suki Kang, Joo Hyun Lee, Nam Hoon Cho. Invasive breast cancer amplifies lymphangiogenic signals in tumor microenvironment through integrin beta4 expressing cancer-associated fibroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B15.