Abstract 1646: Combining molecular target drugs to inhibit cancer-stromal cell interaction in gastric cancer.

Abstract

Abstract Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone but also by various stromal cells. Many human tumors secrete platelet-derived growth factor (PDGF) ligands, and PDGF receptors (PDGF-Rs) are expressed by various stromal cell populations, including carcinoma-associated fibroblasts (CAFs). Tumor cells in surgical specimens and orthotopic tumors have been shown to express PDGF-B, whereas PDGF-Rβ has been shown to be expressed predominantly by stromal cells, including CAFs, pericytes, and lymphatic endothelial cells. mTOR (mammalian target of rapamycin) is a central regulatory kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. mTOR also increases the translation of hypoxia-inducible factor-1a (HIF-1a), which drives the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), resulting in new vasculature. In the present study, we examined the effects of PDGF-R tyrosine kinase inhibitors (imatinib, nilotinib) and mTOR inhibitor (everolimus) on tumor stroma in an orthotopic nude mouse model of human gastric cancer. Treatment with PDGF-R tyrosine kinase inhibitors did not inhibit tumor growth but did significantly decrease the stromal reaction, lymphatic invasion, lymphatic vessel area, and pericyte coverage of tumor microvessels. In contrast, treatment with mTOR inhibitor reduced tumor growth and microvessel density but did not decrease the stromal reaction. PDGF-R inhibitor and mTOR inhibitor used in combination reduced both the growth rate and stromal reaction. (control (5/5, 0.3±0.1g), nilotinib (6/6, 0.3±0.1g), everolimus (4/6, 0.08±0.02g: p<0.05), combination (1/6, 0.04g)) Target molecule-based inhibition of cancer-stromal cell interaction may hold promise as an effective anti-tumor therapy. Citation Format: Mieko Onoyama, Yasuhiko Kitadai, Kei Shinagawa, Ryo Yuge, Mayu Ohnishi, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Combining molecular target drugs to inhibit cancer-stromal cell interaction in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1646. doi:10.1158/1538-7445.AM2013-1646