Abstract A66: Colonization of human ovarian cancer cells is promoted by cancer-fibroblast interaction via TGFα-EGFR signaling

Abstract

Abstract Tumor colonization involves reciprocal interactions between the metastatic cancer cells and various stromal cells in foreign microenvironment. Fibroblasts are the second most numerous cell types in omentum, which is the commonest site of ovarian cancer metastasis. However, the crosstalk between metastatic ovarian cancer cells and fibroblasts that involved in tumor colonization remains largely unknown. In this study, we used a three-dimensional (3D) co-culture model to study the role of normal fibroblasts on tumor colonization of ovarian cancer cells. Human ovarian cancer cell lines, which were established from peritoneal ascites, were seeded on normal fibroblasts embedded in extracellular matrix (Matrigel). Our results showed that ovarian cancer spheroids formed in Matrigel with fibroblasts were significantly larger and also more invasive than those formed in Matrigel without fibroblasts, suggesting the cancer-fibroblast interaction promotes the colonization of ovarian cancer cells. To search the signal, we compared the cytokine profile of the 3D co-culture with 3D monoculture of ovarian cancer cells/fibroblasts. De novo production of TGF-α was found in the fibroblasts of the co-culture. To determine whether TGF-α promotes the colonization of ovarian cancer cells, we treated the monoculture of ovarian cancer cells in Matrigel with recombinant human TGF-α (rhTGF-α). rhTGF-α significantly promoted the growth and invasion of ovarian cancer spheroids. Additionally, our qRT-PCR results demonstrated that EGFR, a receptor for TGF-α, was over-expressed in primary human ovarian cancer tissues when compared to non-malignant human ovarian tissues. To test whether fibroblast-derived TGF-α promotes tumor colonization of ovarian cancer cells through EGFR, we treated our in-vitro colonization assays with an EGFR inhibitor, AG1478. AG1478 significantly reduced the growth and invasion of rTGFα-induced ovarian cancer spheroids and the cancer spheroids formed in the co-culture, indicating the colonization of human ovarian cancer cells is promoted by cancer-fibroblast interaction via TGFα-EGFR signaling. We also found that Erlotinib and Gefitinb, two clinically approved EGFR-specific tyrosine kinase inhibitors, significantly reduced the growth and invasion of ovarian cancer spheroids in our in-vitro colonization assays. This result implicates the peritoneal metastasis of ovarian cancer can be potentially treated by EGFR-targeted therapy. (This project is supported by CUHK Research Committee Funding). Citation Format: Tat-San Lau, Tony Kwok-Hung Chung, Tak-Hong Cheung, So-Fan Yim, Chi-Hang Wong, Joseph Kwong. Colonization of human ovarian cancer cells is promoted by cancer-fibroblast interaction via TGFα-EGFR signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A66.