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

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.

[1]  S. Eberhardt,et al.  Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  H. Lan,et al.  Assessment of a Novel VEGF Targeted Agent Using Patient-Derived Tumor Tissue Xenograft Models of Colon Carcinoma with Lymphatic and Hepatic Metastases , 2011, PloS one.

[3]  K. Jin,et al.  Establishment of a PDTT xenograft model of gastric carcinoma and its application in personalized therapeutic regimen selection. , 2011, Hepato-gastroenterology.

[4]  K. Jin,et al.  Heterogeneity in primary tumors and corresponding metastases: could it provide us with any hints to personalize cancer therapy? , 2011, Personalized medicine.

[5]  Zhongqi Li,et al.  Heterogeneity in primary colorectal cancer and its corresponding metastases: a potential reason of EGFR-targeted therapy failure? , 2011, Hepato-gastroenterology.

[6]  K. Jin,et al.  Personalized cancer therapy using a patient-derived tumor tissue xenograft model: a translational field worthy of exploring further? , 2010, Personalized medicine.

[7]  K. Jin,et al.  Patient-derived human tumour tissue xenografts in immunodeficient mice: a systematic review , 2010, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[8]  K. Schaefer,et al.  Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases , 2010, Clinical Cancer Research.

[9]  P. Jänne,et al.  Discordance of Molecular Biomarkers Associated with Epidermal Growth Factor Receptor Pathway between Primary Tumors and Lymph Node Metastasis in Non-small Cell Lung Cancer , 2009, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[10]  L. Mazzucchelli,et al.  Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant , 2009, British Journal of Cancer.

[11]  P. Jänne,et al.  Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients , 2008, British Journal of Cancer.

[12]  F. Meric-Bernstam,et al.  Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases , 2008, Cancer.

[13]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Marc Ladanyi,et al.  Heterogeneity of Breast Cancer Metastases: Comparison of Therapeutic Target Expression and Promoter Methylation Between Primary Tumors and Their Multifocal Metastases , 2008, Clinical Cancer Research.

[15]  R. Berardi,et al.  Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options , 2007, British Journal of Cancer.

[16]  Inti Zlobec,et al.  HER2 gene status in primary breast cancers and matched distant metastases , 2007, Breast Cancer Research.

[17]  Silvia Benvenuti,et al.  Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. , 2007, Cancer research.

[18]  R. Hruban,et al.  An In vivo Platform for Translational Drug Development in Pancreatic Cancer , 2006, Clinical Cancer Research.

[19]  M. Loda,et al.  Sensitive sequencing method for KRAS mutation detection by Pyrosequencing. , 2005, The Journal of molecular diagnostics : JMD.

[20]  N. Sneige,et al.  Comparison of HER‐2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma , 2005, Cancer.

[21]  Silvia Benvenuti,et al.  Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. , 2005, The Lancet. Oncology.

[22]  R. Berardi,et al.  Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  P. Regitnig,et al.  Change of HER‐2/neu status in a subset of distant metastases from breast carcinomas , 2004, The Journal of pathology.

[24]  Armando Santoro,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.

[25]  Neal J Meropol,et al.  Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  I. Bauerfeind,et al.  Association between HER-2/neu and Vascular Endothelial Growth Factor Expression Predicts Clinical Outcome in Primary Breast Cancer Patients , 2004, Clinical Cancer Research.

[27]  N. Personeni,et al.  HER‐2/neu amplification by fluorescence in situ hybridization in cytologic samples from distant metastatic sites of breast carcinoma , 2003, Cancer.

[28]  D. Larsimont,et al.  Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[29]  J. Luketich,et al.  Comparison of accumulated allele loss between primary tumor and lymph node metastasis in stage II non-small cell lung carcinoma: implications for the timing of lymph node metastasis and prognostic value. , 2002, Cancer research.

[30]  H. Huynh,et al.  A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. , 2002, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[31]  T. H. van der Kwast,et al.  High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. , 2001, Cancer research.

[32]  J. Isola,et al.  Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. , 2001, Cancer research.

[33]  R. Perez-soler,et al.  Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  R. Henriksson,et al.  Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  P. Vermeulen,et al.  Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. , 1999, The cancer journal from Scientific American.

[36]  O. Vinante,et al.  Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. , 1997, Journal of the National Cancer Institute.