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Treatment with both PKI166 and irinotecan also produced significant increase in apoptosis of tumor associated endothelial cells. In SW620CE2 nontargeting shRNA tumors, the median number of apoptotic endothelial cells in control tumors was 0. Treatment with PKI166 alone significantly checkpoint inhibitors increased the number of apoptotic endothelial cells also did the combination of PKI166 and irinotecan. In SW620CE2 TGF shRNA tumors from mice treated with saline, the median number of apoptotic endothelial cells was 0. Treatment with irinotecan alone, PKI166 alone, or the combination of PKI166 and irinotecan did not produce a significant increase in apoptosis of tumor associated endothelial cells. We here present compelling evidence to support the important role of paracrine activation of EGFR in tumor associated endothelial cells in the colon for mediating response to EGFR kinase inhibitors. In the current study, we report that the systemic administration of the EGFR TKI PKI166 to nude mice bearing the human SW620CE2 colon cancer leads to significant inhibition of Plastid cecal tumor growth and lymph node metastasis. The SW620CE2 cells do not express EGFR, HER2, or VEGFR but do express the EGFR ligands TGF /EGF. Colon tumors produced by SW620CE2 cells treated with TGF shRNA were resistant to PKI166. The expression of activated EGFR by tumor associated endothelial cells is influenced by the production of TGF /EGF by adjacent tumor cells and immunohistochemical analyses of the orthotopic colon tumors revealed that tumor associated endothelial cells in SW620CE2 tumors expressed activated EGFR, whereas tumor associated endothelial cells in SW620CE2 TGF shRNA did not. Therapy with PKI166 and irinotecan produced additive apoptosis of tumor associated endothelial cells in the SW620CE2 cecal tumors but not in the SW620CE2 TGF shRNA cecal tumors. The apoptosis of tumorassociated endothelial cells was associated HCV Protease Inhibitors with a significant inhibition in cecal tumor growth and production of lymph node metastasis. Because neither set of tumors expressed EGFR or HER 2, the data clearly indicate that the susceptibility of the human colon cancer SW620CE2 to therapy by EGFR TKI is determined by expression of ligand TGF /EGF and that the primary target for therapy with the EGFR TKI is the tumor associated endothelial cells. The response of neoplasms to EGFR antagonists has been correlated with EGFR mutations, HER2 expression, Akt activation, and EGFR gene copy number. Our present data using colon cancer cells that do not express EGFR, HER2, or VEGFR suggest that the expression of TGF /EGF by tumor cells leading to the activation of the EGFR in tumor associated endothelial cells is a major determinant for response. These data agree with a previous report that human renal cancer that express TGF with activated EGFR in tumor associated endothelial cells respond to treatment by PKI166.