Abstract
Purpose
Research for reliable and patient-specific markers in colorectal cancer (CRC) is based on solid evidence that staging alone is not informative enough. Employing four cellular receptors, we embarked to identify aggressive tumour behaviour and impact of surrogate marker expression on patient prognosis.
Methods
One-hundred eighty-three CRC patients were enrolled in our investigation that focused on an array of biological markers, namely epidermal growth factor receptor (EGFR), c-Met, focal adhesion kinase (FAK) and CD44v6. Tissue samples, clinicopathological data and patient’s follow-up information were collected, and immunohistochemical assays evaluated the levels of the aforementioned molecules. All available data were correlated with tumour grade, stage, patient age, gender and survival.
Results
Expression of all receptors correlated closely with tumour stage (P < 0.01) exhibiting a connection with cancer’s invasiveness and progress. Survival also proved to depend significantly on molecular expression (log-rank test for Kaplan–Meier; EGFR P = 0.030, c-Met P = 0.050, FAK P < 0.001, CD44v6 P < 0.001). Stage, FAK and CD44v6 emerged as independent predictors of survival in a stepwise regression analysis (FAK P = 0.001 Exp(B) = 2.517, 95 % confidence interval (CI) = 1.704–5.831 and CD44v6 P = 0.005, Exp(B) = 2.299, 95 % CI = 1.287–4.110). T-stage, nodal metastasis, all metastatic types (N/M) and size correlated with at least one of the receptors or their co-expression. Notably, increased staining for each receptor was followed by statistically significant expression elevation of at least one of the other markers.
Conclusions
Our results suggest that the selected cellular receptors are suitable for use as biomarkers of survival and tumour progression in CRC. Furthermore, we provide additional evidence for receptor interaction, properly clarifying their importance, which could potentially lead to more effective anti-CRC regimens.
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References
Cohen SUH, Stoscheck CM, Chinkers M (1982) A native 170,000 Da epidermal growth factor receptor kinase complex from shed plasma membrane vesicles. J Biol Chem 257:1523–1531
Harris RC, Chung E, Coffey RJ (2004) EGF receptor ligands. In: Carpenter G (ed) The EGF receptor family biologic mechanisms and role in cancer. Elsevier, California, pp 3–14
De Jong KP, Stellema R, Karrenbeld A, Koudstaal J, Gouw AS, Sluiter WJ, Peeters PM, Slooff MJ, De Vries EG (1998) Clinical relevance of transforming growth factor, epidermal growth factor receptor, p53 and Ki67 in colorectal liver metastasis and corresponding primary tumors. Hepatology 28:971–979
Barozzi C, Ravaioli M, D'Errico A, Grazi GL, Poggioli G, Cavrini G, Mazziotti A, Grigioni WF (2002) Relevance of biologic markers in colorectal carcinoma: a comparative study of a broad panel. Cancer 94:647–657
Garrett CR, Eng C (2011) Cetuximab in the treatment of patients with colorectal cancer. Expert Opin Biol Ther 11:937–949
Birchmeier C, Gherardi E (1998) Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 8:404–410
Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, Wehland J, Birchmeier C, Birchmeier W (2007) c-Met is essential for wound healing in the skin. J Cell Biol 177:151–162
Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC (2000) Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem 275:8806–8811
Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361
Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR (2001) Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci USA 98:247–252
Jiang W, Hiscox S, Matsumoto K, Nakamura T (1999) Hepatocyte growth factor/scatter factor, its molecular, cellular and clinical implications in cancer. Crit Rev Oncol Hematol 29:209–248
Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M, Kuo C, Wang HJ, Hoon DS (2003) c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 9:1480–1488
Schaller MD (2001) Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta 1540:1–21
Su JM, Gui L, Zhou YP, Zha XL (2002) Expression of focal adhesion kinase and alpha5 and beta1 integrins in carcinomas and its clinical significance. World J Gastroenterol 8:613–618
Judson PL, He X, Cance WG, Van Le L (1999) Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma. Cancer 86:1551–1556
Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD (2000) FAK integrates growth factor and integrin signals to promote cell migration. Nat Cell Biol 2:249–256
Weiner TM, Liu ET, Craven RJ, Cance WG (1993) Expression of focal adhesion kinase gene and invasive cancer. Lancet 342:1024–1025
Golubovskaya VM, Gross S, Kaur AS, Wilson RI, Xu LH, Yang XH, Cance WG (2003) Simultaneous inhibition of focal adhesion kinase and Src enhances detachment and apoptosis in colon cancer cell lines. Mol Canc Res 1:755–764
Yu HG, Tong SL, Ding YM, Ding J, Fang XM, Zhang XF, Liu ZJ, Zhou YH, Liu QS, Luo HS, Yu JP (2006) Enhanced expression of cholecystokinin-2 receptor promotes the progression of colon cancer through activation of focal adhesion kinase. Int J Cancer 119:2724–2732
Theocharis SE, Kouraklis GP, Kakisis JD, Kanelli HG, Apostolakou FE, Karatzas GM, Koutselinis AS (2003) Focal adhesion kinase expression is not a prognostic predictor in colon adenocarcinoma patients. Eur J Surg Oncol 29:571–574
Sneath RJ, Mangham DC (1998) The normal structure and function of CD44 and its role in neoplasia. Mol Pathol 51:191–200
Hofmann M, Rudy W, Zöller M, Tölg C, Ponta H, Herrlich P, Günthert U (1991) CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines. Cancer Res 51:5292–5297
Imazeki F, Yokosuka O, Yamaguchi T, Ohto M, Isono K, Omata M (1996) Expression of variant CD44-messenger RNA in colorectal adenocarcinomas and adenomatous polyps in humans. Gastroenterology 110:362–368
Ni HM, Leong AF, Cheong D, Hooi SC (2002) Expression of CD44 variants in colorectal carcinoma quantified by real-time reverse transcriptase polymerase chain reaction. J Lab Clin Med 139:59–65
Lakshman M, Subramaniam V, Rubenthiran U, Jothy S (2004) CD44 promotes resistance to apoptosis in human colon cancer cells. Exp Mol Pathol 77:18–25
Bendardaf R, Algars A, Elzagheid A, Korkeila E, Ristamäki R, Lamlum H, Collan Y, Syrjänen K, Pyrhönen S (2006) Comparison of CD44 expression in primary tumours and metastases of colorectal cancer. Oncol Rep 16:741–746
Kluftinger AM, Robinson BW, Quenville NF, Finley RJ, Davis NL (1992) Correlation of epidermal growth factor receptor and c-erbB2 oncogene product to known prognostic indicators of colorectal cancer. Surg Oncol 1:97–105
Wielenga VJ, Heider KH, Offerhaus GJ, Adolf GR, van den Berg FM, Ponta H, Herrlich P, Pals ST (1993) Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res 53:4754–4756
Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu ET, Cance WG (1995) Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res 55:2752–2755
Coppola D, Hyacinthe M, Fu L, Cantor AB, Karl R, Marcet J, Cooper DL, Nicosia SV, Cooper HS (1998) CD44V6 expression in human colorectal carcinoma. Hum Pathol 29:627–635
Piazzi G, Paterini P, Ceccarelli C, Pantaleo MA, Biasco G (2006) Molecular determination of epidermal growth factor receptor in normal and neoplastic colorectal mucosa. Br J Cancer 95:1525–1528
Chen Y, Wang Z, Chang P, Xiang L, Pan F, Li J, Jiang J, Zou L, Yang L, Bian Z, Liang H (2010) The effect of focal adhesion kinase gene silencing on 5-fluorouracil chemosensitivity involves an Akt/NF-kappaB signaling pathway in colorectal carcinomas. Int J Cancer 127:195–206
McKay JA, Murray LJ, Curran S, Ross VG, Clark C, Murray GI, Cassidy J, McLeod HL (2002) Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases. Eur J Cancer 38:2258–2264
Kim JY, Bae BN, Kwon JE, Kim HJ, Park K (2011) Prognostic significance of epidermal growth factor receptor and vascular endothelial growth factor receptor in colorectal adenocarcinoma. APMIS 119:449–459
Resnick MB, Routhier J, Konkin T, Sabo E, Pricolo VE (2004) Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin Cancer Res 10:3069–3075
Kammula US, Kuntz EJ, Francone TD, Zeng Z, Shia J, Landmann RG, Paty PB, Weiser MR (2007) Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett 248:219–228
Han NM, Fleming RY, Curley SA, Gallick GE (1997) Overexpression of focal adhesion kinase p125 in human colorectal carcinoma liver metastases: independence from c-src or c-yes activation. Ann Surg Oncol 4:264–268
Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzig R, Attar A, Benichou J, Martin A, Morere JF, Raphael M, Penault-Llorca F, Breau JL, Fagard R, Khayat D, Wind P (2005) Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 16:102–108
Kim Y, Lee YS, Choe J, Lee H, Kim YM, Jeoung D (2008) CD44-epidermal growth factor receptor interaction mediates hyaluronic acid-promoted cell motility by activating protein kinase C signaling involving Akt, Rac1, Phox, reactive oxygen species, focal adhesion kinase, and MMP-2. J Biol Chem 283:22513–22528
Véronique Orian-Rousseau LC, Sleeman JP, Herrlich P, Ponta H (2002) CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16:3074–3086
Markman B, Javier Ramos F, Capdevila J, Tabernero J (2010) EGFR and KRAS in colorectal cancer. Adv Clin Chem 51:71–119
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Garouniatis, A., Zizi-Sermpetzoglou, A., Rizos, S. et al. FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk. Int J Colorectal Dis 28, 9–18 (2013). https://doi.org/10.1007/s00384-012-1520-9
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DOI: https://doi.org/10.1007/s00384-012-1520-9