Modulation Of Stromal Reaction By Pdgf-R Tyrosine Kinase Inhibitor In An Orthotopic Mice Model Of Gastric Carcinoma

Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone but also by a variety of 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). We reported recently that, in a mice model of colon cancer, bone marrow-derived mesenchymal stem cells (MSCs) traveled to tumor stroma, where they differentiated into CAF-like cells. In the present study, we examined PDGF-B and PDGF-Rβ expression in relation to clinicopathologic features of human gastric carcinomas. We also examined the effects of PDGF-R tyrosine kinase inhibitors (imatinib, nilotinib) on tumor stroma in an orthotopic nude mouse model of human gastric carcinoma. Five gastric carcinoma cell lines and 38 surgical specimens of gastric carcinoma were used. Under culture conditions, gastric cancer cell lines expressed PDGF-B at various levels but not PDGFR-β. When cells from these lines were implanted orthotopically into the gastric wall of nude mice, cells with high PDGF-B expression resulted in tumors with abundant stroma. In contrast, cells with low PDGF-B expression resulted in medullary tumors with little stromal reaction. In surgical specimens, we found PDGF-B expression to be associated with stromal reaction. PDGF-B and PDGF-Rβ mRNA expression was significantly higher in patients with lymph node metastasis than in those without and also significantly higher in diffuse-type carcinoma than in intestinal-type carcinoma. In surgical specimens and orthotopic tumors, tumor cells expressed PDGF-B, but PDGF-Rβ was expressed predominantly by stromal cells, including CAFs, pericytes, and lymphatic endothelial cells. 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 addition, tumor tropism of MSCs was also inhibited by treatment with PDGF-R inhibitors in vivo and in vitro. The PDGF/PDGF-R signaling pathway appears to regulate cancer-stromal cell interaction, and target molecule-based inhibition of the stromal reaction may hold promise as an effective anti-tumor therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1509. doi:1538-7445.AM2012-1509