Abstract
Purpose
The insulin-like growth factor 1 receptor (IGF1R) is widely expressed in normal tissues and many malignancies in humans. We investigated the clinical significance of the expression of the IGF1R gene in human lung adenocarcinoma.
Methods
A total of 238 patients with lung adenocarcinoma were investigated. Quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) assays were performed to evaluate the gene expression of IGF1R, and immunohistochemical staining was done to evaluate the protein expression of IGF1R.
Results
Among the 238 patients with lung adenocarcinoma, 107 tumors (45.0%) were IGF1R-low and 131 tumors (55.0%) were IGF1R-high. The IGF1R gene expression ratio was significantly lower in moderately to poorly differentiated adenocarcinomas than in well-differentiated adenocarcinomas (P = 0.0388). Gene expression of IGF1R was significantly correlated with protein expression of IGF1R (r = 0.7163, P < 0.0001). Regarding patient survival, overall survival was significantly lower in patients with IGF1R-low tumors than in those with IGF1R-high tumors (63.2% versus 76.1% 5-year survival, P = 0.0188). Multivariate analysis using a Cox proportional-hazards model demonstrated that IGF1R gene status was a significant prognostic factor predicting overall survival of patients with lung adenocarcinoma (hazard ratio 1.800; P = 0.0321). Moreover, the disease-free survival rate was significantly lower in patients with IGF1R-low tumors than in those with IGF1R-high tumors (49.2% versus 64.6% 5-year survival, P = 0.0084).
Conclusion
The present study suggests the level of IGF1R expression to be a useful prognostic marker for patients with dedifferentiated lung adenocarcinoma.
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References
Asamura H, Goya T, Koshiishi Y, et al. A Japanese Lung Cancer Registry study: prognosis of 13,010 resected lung cancers. J Thorac Oncol. 2008;3:46–52.
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.
Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28.
Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res. 2008;14:6364–70.
Imsumran A, Adachi Y, Yamamoto H, et al. Insulin-like growth factor-I receptor as a marker for prognosis and a therapeutic target in human esophageal squamous cell carcinoma. Carcinogenesis. 2007;28:947–56.
Matsubara J, Yamada Y, Hirashima Y, et al. Impact of insulin-like growth factor type 1 receptor, epidermal growth factor receptor, and HER2 expressions on outcomes of patients with gastric cancer. Clin Cancer Res. 2008;14:3022–9.
Takahari D, Yamada Y, Okita NT, et al. Relationships of insulin-like growth factor-1 receptor and epidermal growth factor receptor expression to clinical outcomes in patients with colorectal cancer. Oncology. 2009;76:42–8.
Parker AS, Cheville JC, Janney CA, Cerhan JR. High expression levels of insulin-like growth factor-I receptor predict poor survival among women with clear-cell renal cell carcinomas. Hum Pathol. 2002;33:801–5.
Huang YF, Shen MR, Hsu KF, Cheng YM, Chou CY. Clinical implications of insulin-like growth factor 1 system in early-stage cervical cancer. Br J Cancer. 2008;99:1096–102.
van der Veeken J, Oliveira S, Schiffelers RM, Storm G, van Bergen En Henegouwen PM, Roovers RC. Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy. Curr Cancer Drug Targets. 2009;9:748–60.
Guix M, Faber AC, Wang SE, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118:2609–19.
Chakraborty AK, Liang K, DiGiovanna MP. Co-targeting insulin-like growth factor I receptor and HER2: dramatic effects of HER2 inhibitors on nonoverexpressing breast cancer. Cancer Res. 2008;68:1538–45.
Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007;13:2795–803.
Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 2002;62:200–7.
Hurbin A, Wislez M, Busser B, et al. Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma. J Pathol. 2011. doi:10.1002/path.2897.
Morgillo F, Woo JK, Kim ES, Hong WK, Lee HY. Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res. 2006;66:10100–11.
Ludovini V, Bellezza G, Pistola L, et al. High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients. Ann Oncol. 2009;20:842–9.
Cappuzzo F, Tallini G, Finocchiaro G, et al. Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients. Ann Oncol. 2010;21:562–7.
Dziadziuszko R, Merrick DT, Witta SE, et al. Insulin-like growth factor receptor 1 (IGF1R) gene copy number is associated with survival in operable non-small-cell lung cancer: a comparison between IGF1R fluorescent in situ hybridization, protein expression, and mRNA expression. J Clin Oncol. 2010;28:2174–80.
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:706–14.
Travis WD, Brambillia E, Müller-Hermelink HK, Haris CC. Tumors of the lung, pleura, thymus and heart. In: Kleihues P, Sobin LH, editors. World Health Organization classification of tumours, Edition Lyon: IARC; 2004.
Liu X, Turbyville T, Fritz A, Whitesell L. Inhibition of insulin-like growth factor I receptor expression in neuroblastoma cells induces the regression of established tumors in mice. Cancer Res. 1998;58:5432–8.
Allen GW, Saba C, Armstrong EA, et al. Insulin-like growth factor-I receptor signaling blockade combined with radiation. Cancer Res. 2007;67:1155–62.
Dunn SE, Ehrlich M, Sharp NJ, et al. A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. Cancer Res. 1998;58:3353–61.
Sachdev D, Hartell JS, Lee AV, Zhang X, Yee D. A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. J Biol Chem. 2004;279:5017–24.
Sachdev D, Zhang X, Matise I, Gaillard-Kelly M, Yee D. The type I insulin-like growth factor receptor regulates cancer metastasis independently of primary tumor growth by promoting invasion and survival. Oncogene. 2010;29:251–62.
Nakamura M, Miyamoto S, Maeda H, et al. Low levels of insulin-like growth factor type 1 receptor expression at cancer cell membrane predict liver metastasis in Dukes’ C human colorectal cancers. Clin Cancer Res. 2004;10:8434–41.
Kornprat P, Rehak P, Ruschoff J, Langner C. Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours. J Clin Pathol. 2006;59:202–6.
Ahlen J, Wejde J, Brosjo O, et al. Insulin-like growth factor type 1 receptor expression correlates to good prognosis in highly malignant soft tissue sarcoma. Clin Cancer Res. 2005;11:206–16.
Sutherland BW, Knoblaugh SE, Kaplan-Lefko PJ, Wang F, Holzenberger M, Greenberg NM. Conditional deletion of insulin-like growth factor-I receptor in prostate epithelium. Cancer Res. 2008;68:3495–504.
Dupont J, Holzenberger M. Biology of insulin-like growth factors in development. Birth Defects Res C Embryo Today. 2003;69:257–71.
Russo VC, Gluckman PD, Feldman EL, Werther GA. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev. 2005;26:916–43.
Laustsen PG, Russell SJ, Cui L, et al. Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function. Mol Cell Biol. 2007;27:1649–64.
Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D. Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer. 2000;89:506–13.
Allison AS, McIntyre MA, McArdle C, Habib FK. The insulin-like growth factor type 1 receptor and colorectal neoplasia: insights into invasion. Hum Pathol. 2007;38:1590–602.
Ichinose Y, Yano T, Asoh H, Yokoyama H, Yoshino I, Katsuda Y. Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg. 1995;110:601–5.
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Kikuchi, R., Sonobe, M., Kobayashi, M. et al. Expression of IGF1R Is Associated with Tumor Differentiation and Survival in Patients with Lung Adenocarcinoma. Ann Surg Oncol 19 (Suppl 3), 412–420 (2012). https://doi.org/10.1245/s10434-011-1878-x
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DOI: https://doi.org/10.1245/s10434-011-1878-x