Differential response to EGFR- and VEGF-targeted therapies in patient-derived tumor tissue xenograft models of colon carcinoma and related metastases

• Published in: International journal of oncology Vol. 41; no. 2; pp. 583 - 588
• Main Authors: JIN, KETAO, LAN, HUANRONG, CAO, FEILIN, HAN, NA, XU, ZHENZHEN, LI, GUANGLIANG, HE, KUIFENG, TENG, LISONG
• Format: Journal Article
• Language: English
• Published: Athens D.A. Spandidos 01.08.2012; Editorial Academy of the International Journal of Oncology; Spandidos Publications UK Ltd
• Subjects: Adult; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Base Sequence; Bevacizumab; Biological and medical sciences; Brain cancer; Cancer therapies; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - secondary; Cetuximab; Colon; colon carcinoma; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colorectal cancer; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Humans; Immunoglobulins; Immunotherapy; Laboratory animals; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Lymphatic Metastasis; Medical sciences; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Monoclonal antibodies; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Response rates; Rodents; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; Targeted cancer therapy; Tumor Burden - drug effects; Tumor Cells, Cultured; Tumors; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism; xenograft model; Xenograft Model Antitumor Assays; Antineoplastic agent; Human; Targeted therapy; Tumoral tissue; Monoclonal antibody; Malignant tumor; Metastasis; Epidermal growth factor receptor; Bevacizumab; Colonic disease; xenograft model; Colon cancer; Cancerology; Vascular endothelium growth factor; Treatment; Animal; Digestive diseases; Intestinal disease; Antiangiogenic agent; Colon carcinoma; Cetuximab; Cancer
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2012.1469

Heterogeneity in primary tumors and related metastases may result in failure of antitumor therapies, particularly in targeted therapies for the treatment of cancer. In this study, patient-derived tumor tissue (PDTT) xenograft models of colon carcinoma with lymphatic and hepatic metastases were used to evaluate the response to EGFR-and VEGF-targeted therapies. Our results showed that primary colon carcinoma and its corresponding lymphatic and hepatic metastases have a different response rate to anti-EGFR (cetuximab) and anti-VEGF (bevacizumab) therapies. However, the underlying mechanism of these types of phenomenon is still unclear. To investigate whether such phenomena may result from the heterogeneity in primary colon carcinoma and related metastases, we compared the expression levels of cell signaling pathway proteins using immunohistochemical staining and western blotting, and the gene status of KRAS using pyrosequencing in the same primary colon carcinoma and its corresponding lymphatic and hepatic metastatic tissues which were used for establishing the PDTT xenograft models. Our results showed that the expression levels of EGFR, VEGF, Akt/pAkt, ERK/pERK, MAPK/pMAPK, and mTOR/pmTOR were different in primary colon carcinoma and matched lymphatic and hepatic metastases although the KRAS gene status in all cases was wild-type. Our results indicate that the heterogeneity in primary colon carcinoma and its corresponding lymphatic and hepatic metastases may result in differences in the response to dual-inhibition of EGFR and VEGF.