Differential Response to EGFR- And VEGF-targeted Therapies in Patient-Derived Tumor Tissue Xenograft Models of Colon Carcinoma and Related Metastases

Int J Oncol. 2012 Aug;41(2):583-8. doi: 10.3892/ijo.2012.1469. Epub 2012 May 10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Carcinoma / drug therapy
  • Carcinoma / genetics
  • Carcinoma / secondary*
  • Cetuximab
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology*
  • DNA Mutational Analysis
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / genetics
  • Liver Neoplasms / secondary*
  • Lymphatic Metastasis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Tumor Burden / drug effects
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab