Anti‐stromal therapy with imatinib inhibits growth and metastasis of gastric carcinoma in an orthotopic nude mouse model

Abstract

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 such a role in gastric carcinoma is undetermined. We examined whether inhibition of PDGF receptor (PDGF-R) tyrosine kinase signaling by imatinib affects tumor growth and metastasis in an orthotopic nude mouse model of human gastric carcinoma. TMK-1 human gastric carcinoma cells were injected into the gastric wall of nude mice. Groups of mice (n 5 10 each) received sterile water (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 (5 mg/kg/week) in combination for 28 days. Tumor growth and metastasis were assessed. Resected tumors were analyzed immunohistochemically. Carcinoma-associated fibroblasts, pericytes and lymphatic endothelial cells in stroma expressed high levels of PDGF-R; carcinoma cells did not. Treatment with imatinib alone did not inhibit tumor growth and metastasis; however, treatment with irinotecan alone or combined with imatinib significantly inhibited tumor growth. Only treatment with high-dose imatinib and irinotecan in combination inhibited lymph node and peritoneal metastases. Immunohistochemically, only imatinib alone or in combination with irinotecan was shown to significantly decrease the stromal reaction, microvessel area and pericyte coverage of tumor microvessels. These effects were marked with high-dose imatinib. In conclusion, administration of PDGF-R tyrosine kinase inhibitor in combination with irinotecan appears to impair the progressive growth of gastric carcinoma by blockade of PDGF-R signaling pathways in stromal cells.Recent studies in tumor biology have shown that tumor growth and metastasis are determined not only by cancer cells, but also by a variety of stromal cells. The stroma constitutes a large part of most solid tumors, and the cancer-stromal cell interaction contributes functionally to tumor growth and metastasis.

Real-time bioluminescence and tomographic imaging of gastric cancer in a novel orthotopic mouse model

“…In addition, the orthotopic cancer model reflects a relevant site to assess therapeutic outcomes, avoiding the false-positive drug responses caused by other cancer models (19). Although the orthotopic gastric cancer model has been employed in previous studies (20)(21)(22), little attention has been paid to its direct use for in vivo longitudinal monitoring and drug evaluation.…”

Clinical and Biological Implications of the Tumor Microenvironment

“…A different method using drugs which inhibit stromal mediators of tumor cell growth was successfully used by Sumida et al [80] to impair the growth of xenografted human gastric carcinoma by blockade of PDGF-R signaling. These investigators demonstrated that carcinoma-associated stromal fibroblasts, pericytes and lymphatic endothelial cells expressed high levels of PDGF-R whereas carcinoma cells did not and treatment with high-dose imatinib and irinotecan in combination inhibited tumor growth and lymph node and peritoneal metastases by disrupting stroma-tumor signaling via this natural mediator.…”

Human Mesenchymal Stem Cells Migrate toward Colon Cancer Partially Regulated by HMGB1

“…However, it is controversial whether systemically administrated MSCs can home to a target tissue and migrate into it. Some reports demonstrated that MSCs migrate towards inflammatory tissue [58] as well as cancerous tissue and may potentially be used for therapeutic purposes [49,59]; however, others showed that most of the cells were trapped in lymph nodes or the lungs and disappeared soon after injection [60]. This discrepancy could be partly explained by the difference of cell source such as bone-marrow or fat tissue and whether the cells were cultured or not cultured after isolation [61].…”