Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

被引:76
作者
De Robertis, Mariangela [1 ]
Loiacono, Luisa [1 ,2 ,10 ]
Fusilli, Caterina [3 ]
Poeta, Maria Luana [4 ]
Mazza, Tommaso [3 ]
Sanchez, Massimo [5 ]
Marchionni, Luigi [6 ]
Signori, Emanuela [7 ]
Lamorte, Giuseppe [8 ]
Vescovi, Angelo Luigi [8 ]
Garcia-Foncillas, Jesus [9 ]
Fazio, Vito Michele [1 ,2 ]
机构
[1] Univ Campus Biomed Rome, Lab Genet & Clin Pathol, Via Alvaro del Portillo 21, I-00128 Rome, Italy
[2] IRCCS Casa Sollievo Sofferenza, Lab Oncol, San Giovanni Rotondo, Fg, Italy
[3] IRCCS Casa Sollievo Sofferenza, Unit Bioinformat, San Giovanni Rotondo, Fg, Italy
[4] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, Italy
[5] Ist Super Sanita, Dept Cell Biol & Neurosci, Rome, Italy
[6] Johns Hopkins Univ, Sch Med, Ctr Computat Genom, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA
[7] Natl Res Council CNR, Inst Translat Pharmacol, Lab Mol Pathol & Expt Oncol, Rome, Italy
[8] IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Fg, Italy
[9] FIIS Fdn Jimenez Diaz, Oncohlth Inst, Translat Oncol Div, Madrid, Spain
[10] Univ Foggia, Expt & Regenerat Med, Dept Med & Surg Sci, I-71100 Foggia, Italy
关键词
TARGETED THERAPY; TYROSINE KINASE; BREAST-CANCER; EPHRIN A2; EXPRESSION; RESISTANCE; OVEREXPRESSION; METASTASIS; ACTIVATION; RECEPTORS;
D O I
10.1158/1078-0432.CCR-16-0709
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC. Experimental Design: Gene expression analysis was performed in EphA2(high) cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. Results: We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I-III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Conclusions: These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations. (C) 2016 AACR.
引用
收藏
页码:159 / 170
页数:12
相关论文
共 53 条
[1]   EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer [J].
Amato, Katherine R. ;
Wang, Shan ;
Tan, Li ;
Hastings, Andrew K. ;
Song, Wenqiang ;
Lovly, Christine M. ;
Meador, Catherine B. ;
Ye, Fei ;
Lu, Pengcheng ;
Balko, Justin M. ;
Colvin, Daniel C. ;
Cates, Justin M. ;
Pao, William ;
Gray, Nathanael S. ;
Chen, Jin .
CANCER RESEARCH, 2016, 76 (02) :305-318
[2]   MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer [J].
Aydogdu, Eylem ;
Katchy, Anne ;
Tsouko, Efrosini ;
Lin, Chin-Yo ;
Haldosen, Lars-Arne ;
Helguero, Luisa ;
Williams, Cecilia .
CARCINOGENESIS, 2012, 33 (08) :1502-1511
[3]   β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB [J].
Batlle, E ;
Henderson, JT ;
Beghtel, H ;
van den Born, MMW ;
Sancho, E ;
Huls, G ;
Meeldijk, J ;
Robertson, J ;
van de Wetering, M ;
Pawson, T ;
Clevers, H .
CELL, 2002, 111 (02) :251-263
[4]   A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis [J].
Bin Fang, W ;
Brantley-Sieders, DM ;
Parker, MA ;
Reith, AD ;
Chen, J .
ONCOGENE, 2005, 24 (53) :7859-7868
[5]   The EphA2 Receptor Drives Self-Renewal and Tumorigenicity in Stem-like Tumor-Propagating Cells from Human Glioblastomas [J].
Binda, Elena ;
Visioli, Alberto ;
Giani, Fabrizio ;
Lamorte, Giuseppe ;
Copetti, Massimiliano ;
Pitter, Ken L. ;
Huse, Jason T. ;
Cajola, Laura ;
Zanetti, Nadia ;
DiMeco, Francesco ;
De Filippis, Lidia ;
Mangiola, Annunziato ;
Maira, Giulio ;
Anile, Carmelo ;
De Bonis, Pasquale ;
Reynolds, Brent A. ;
Pasquale, Elena B. ;
Vescovi, Angelo L. .
CANCER CELL, 2012, 22 (06) :765-780
[6]   Pathology of mouse models of intestinal cancer: Consensus report and recommendations [J].
Boivin, GP ;
Washington, K ;
Yang, K ;
Ward, JM ;
Pretlow, TP ;
Russell, R ;
Besselsen, DG ;
Godfrey, VL ;
Doetschman, T ;
Dove, WF ;
Pitot, HC ;
Halberg, RB ;
Itzkowitz, SH ;
Groden, J ;
Coffey, RJ .
GASTROENTEROLOGY, 2003, 124 (03) :762-777
[7]   Therapeutic targeting of EPH receptors and their ligands [J].
Boyd, Andrew W. ;
Bartlett, Perry F. ;
Lackmann, Martin .
NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (01) :39-62
[8]   Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab [J].
Brand, Toni M. ;
Iida, Mari ;
Wheeler, Deric L. .
CANCER BIOLOGY & THERAPY, 2011, 11 (09) :777-792
[9]   The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling [J].
Brantley-Sieders, Dana M. ;
Zhuang, Guanglei ;
Hicks, Donna ;
Bin Fang, Wei ;
Hwang, Yoonha ;
Cates, Justin M. M. ;
Coffman, Karen ;
Jackson, Dowdy ;
Bruckheirner, Elizabeth ;
Muraoka-Cook, Rebecca S. ;
Chen, Jin .
JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (01) :64-78
[10]   The PTEN-PI3K pathway: of feedbacks and cross-talks [J].
Carracedo, A. ;
Pandolfi, P. P. .
ONCOGENE, 2008, 27 (41) :5527-5541