Abstract 1420: Inhibition of platelet-derived growth factor receptor tyrosine kinase reduces tumor growth and metastasis in an orthotopic nude mice model of human gastric cancer

Background: Recent studies have revealed that platelet-derived growth factor (PDGF) plays a role in promoting progressive tumor growth in several organs; however, whether PDGF plays a role in gastric cancer is undetermined. We examined whether inhibition of PDGF receptor (PDGF-R) tyrosine kinase signaling by imatinib affects tumor growth and metastasis of human gastric cancer cells in an orthotopic nude mouse model. Methods: TMK1 human gastric cancer cells were injected into the gastric wall of nude mice. Groups of mice (n=10 each) received saline (control), low-dose imatinib (50 mg/kg/day), high-dose imatinib (200 mg/kg/day), cancer chemotherapeutic agent irinotecan (5 mg/kg/week), or imatinib (50 mg/kg/day or 200 mg/kg/day) and irinotecan in combination for 28 days. Tumor growth and metastasis were assessed. Resected tumors were analyzed immunohistochemically. Results: Carcinoma-associated fibroblasts (CAFs) within gastric tumors expressed high levels of PDGF-R; cancer cells did not. Treatment with imatinib alone did not inhibit tumor growth and metastasis; however, treatment with irinotecan alone or combined with imatinib (single-agent therapy or relative control) significantly inhibited tumor growth. Only treatment with high-dose imatinib and irinotecan in combination inhibited lymph node and peritoneal metastasis. Immunohistochemically, only imatinib alone or in combination with irinotecan significantly decreased the stromal reaction, pericyte coverage of tumor microvessels, and microvessel area. These effects were marked in the high-dose imatinib group. Conclusion: Administration of PDGF-R tyrosine kinase inhibitor in combination with irinotecan appears to impair the progressive growth of gastric cancer cells by blockade of PDGF-R signaling pathways in CAFs and pericytes on the tumor vasculature. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1420.