Abstract
A recent multicenter study led by our institution demonstrated that local recurrence of non-small cell lung cancer (NSCLC) was significantly more frequent in patients with diabetes, raising the possibility of different tumor biology in diabetics. Epithelial-to-mesenchymal transition (EMT) plays a key role in local tumor recurrence and metastasis. In the present study, we investigated differences of tumor microenvironment between patients with and without diabetes by examining expression of EMT markers. Seventy-nine NSCLC patients were selected from the cohort of our early multicenter study. These patients were classified into 4 groups: 39 with adenocarcinoma with (n = 19) and without (n = 20) diabetes, and 40 with squamous cell carcinoma with (n = 20) and without (n = 20) diabetes. Immunohistochemical expression of eight EMT markers was analyzed, including transforming growth factor-beta (TGF-β), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R), vimentin, E-cadherin, N-cadherin, HtrA1, and beta-catenin. Five markers (E-cadherin, HtrA1, TGF-β, IGF-1R and vimentin) demonstrated significantly higher expression in diabetics than in non-diabetics in both histology types. N-cadherin had higher expression in diabetics, though the difference did not reach statistical significance. EGFR showed a higher expression in diabetics in squamous cell carcinoma only. Beta-catenin was the only marker with no difference in expression between diabetics versus non-diabetics. Our findings suggest that diabetes is associated with enhanced EMT in NSCLC, which may contribute to growth and invasiveness of NSCLC.
Similar content being viewed by others
References
El-Sherif A, Fernando HC, Santos R, Pettiford B, Luketich JD, Close JM, et al. (2007) Margin and local recurrence after sublobar resection of non-small cell lung cancer. Ann Surg Oncol 14(8):2400–2405
Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, et al. (1995) Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109(1):120–129
Varlotto JM, Recht A, Flickinger JC, Medford-Davis LN, Dyer AM, Decamp MM (2009) Factors associated with local and distant recurrence and survival in patients with resected nonsmall cell lung cancer. Cancer 115(5):1059–1069
Varlotto J, Medford-Davis LN, Recht A, Flickinger J, Schaefer E, Shelkey J, et al. (2012) Confirmation of the role of diabetes in the local recurrence of surgically resected non-small cell lung cancer. Lung Cancer 75(3):381–390
Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273
Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428
Hills CE, Squires PE (2010) TGF-beta1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol 31(1):68–74
Chien J, Staub J, SI H, Erickson-Johnson MR, Couch FJ, Smith DI, et al. (2004) A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene 23(8):1636–1644
Baldi A, De LA, Morini M, Battista T, Felsani A, Baldi F, et al. (2002) The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 21(43):6684–6688
Boyd JA, Hubbs JL, Kim DW, Hollis D, Marks LB, Kelsey CR (2010) Timing of local and distant failure in resected lung cancer: implications for reported rates of local failure. J Thorac Oncol 5(2):211–214
Brundage MD, Davies D, Mackillop WJ (2002) Prognostic factors in non-small cell lung cancer: a decade of progress. Chest 122(3):1037–1057
Pollack JR (2007) A perspective on DNA microarrays in pathology research and practice. Am J Pathol 171(2):375–385
Neal JW, Gainor JF, Shaw AT (2015) Developing biomarker-specific end points in lung cancer clinical trials. Nat Rev Clin Oncol 12(3):135–146
Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16(4):1103–1123
Eliasz S, Liang S, Chen Y, De Marco MA, Machek O, Skucha S, et al. (2010) Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29(17):2488–2498
Hills CE, Siamantouras E, Smith SW, Cockwell P, Liu KK, Squires PE (2012) TGFbeta modulates cell-to-cell communication in early epithelial-to-mesenchymal transition. Diabetologia 55(3):812–824
Nerlich AG, Hagedorn HG, Boheim M, Schleicher ED (1998) Patients with diabetes-induced microangiopathy show a reduced frequency of carcinomas. In Vivo 12(6):667–670
Fuxe J, Vincent T, Garcia d HA (2010) Transcriptional crosstalk between TGF-beta and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle 9(12):2363–2374
Wendt MK, Allington TM, Schiemann WP (2009) Mechanisms of the epithelial-mesenchymal transition by TGF-beta. Future Oncol 5(8):1145–1168
Micalizzi DS, Farabaugh SM, Ford HL (2010) Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 15(2):117–134
Pallen MJ, Wren BW (1997) The HtrA family of serine proteases. Mol Microbiol 26(2):209–221
Wang N, Eckert KA, Zomorrodi AR, Xin P, Pan W, Shearer DA et al. (2012) Down-regulation of HtrA1 activates the epithelial-mesenchymal transition and ATM DNA damage response pathways. PLoS One 7(6):e39446.
Schmalhofer O, Brabletz S, Brabletz T (2009) E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev 28(1–2):151–166
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yang, X., Liu, Y., Mani, H. et al. Biologic Evaluation of Diabetes and Local Recurrence in Non-Small Cell Lung Cancer. Pathol. Oncol. Res. 23, 73–77 (2017). https://doi.org/10.1007/s12253-016-0086-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-016-0086-1