International Journal of Dental Sciences and Research
ISSN (Print): 2333-1135 ISSN (Online): 2333-1259 Website: Editor-in-chief: Marcos Roberto Tovani Palone
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International Journal of Dental Sciences and Research. 2018, 6(1), 6-11
DOI: 10.12691/ijdsr-6-1-2
Open AccessArticle

Could Int-8 Receptors and VEGF be Considered as Potential Prognostic Markers in OSCC?

Omneya R. Ramadan1, , Maged H. El-Abany1 and Wafaa A. Awedat1

1Oral Pathology, Faculty of Dentistry, Alexandria University

Pub. Date: January 29, 2018

Cite this paper:
Omneya R. Ramadan, Maged H. El-Abany and Wafaa A. Awedat. Could Int-8 Receptors and VEGF be Considered as Potential Prognostic Markers in OSCC?. International Journal of Dental Sciences and Research. 2018; 6(1):6-11. doi: 10.12691/ijdsr-6-1-2


Objectives: The goal of this study was to determine the correlation of clinicopathological factors and the up-regulation of Int-8 receptors and vascular endothelial growth factor (VEGF) expression in oral squamous cell carcinoma (OSCC). Materials and Methods: Clinical data (age, gender, size of the tumor, location of the tumor, lymph nodes status,..) were collected from 20 patients with OSCC, tabulated and statistically analyzed (SPSS17). Immunohistochemical stainings of Int-8 receptors, CXCR1 and CXCR2 (united states biological, United Bio, USA) and VEGF (Abcam, Cambridge, MA, USA) were done. Results: Our immunohistochemical study demonstrated: 1) expression of Int-8 receptors in all cases of OSCC with variable intensities, 2) high-level staining of VEGF In poorly differentiated and invasive oral squamous cell carcinoma. Significant correlation was observed between immunohistochemical expression of Int-8 receptors, VEGF and histologic differentiation and clinical stages (Analysis of variance ANOVA, P<0.05). Conclusion: Our findings suggest that the reactivity to Int-8 receptors observed in OSCC cases could be used as a parameter for tumor aggressiveness and as potential prognostic marker. Also, up-regulation of VEGF may play a role in the angiogenesis and progression of oral squamous cell carcinoma.

squamous cell carcinoma int-8 receptors vascular endothelial growth factor

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[1]  Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag 2006; 2: 213-219.
[2]  Feldman AL, Restifo NP, Alexander HR, Bartlett DL, Hwu P, Seth P, et al. Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice. Cancer Res 2000; 60: 1503-1506.
[3]  Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 Directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 2003; 170: 3369-3376.
[4]  Kerbel RS. Tumour angiogenesis: past future and present. Carcinogenesis 2000; 21: 505-515.
[5]  Mehrotra R, Yadav S. Oral squamous cell carcinoma: Etiology, pathogenesis and prognostic value of genomic alterations. Indian Journal of Cancer 2000; 43:60-66.
[6]  Watanabe H, Iwase M, Ohashi M, Nagumo M. Role of interleukin-8 secreted from human oral squamous cell carcinoma cell lines. Oral Oncology 2002; 38: 670-679.
[7]  Keeley EC, Mehrad B, Strieter RM. CXC chemokines in cancer angiogenesis and metastases; Adv Cancer Res 2010; 106: 91-111.
[8]  Zuccari DA, Leonel C, Castro R, Gelaleti GB, Jardim BV, Moscheta MG, et al. An immunohistochemical study of interleukin-8 (IL-8) in breast cancer. Acta Histochemica 2012; 114: 571-576.
[9]  Leek RD, Harris AL, Lewis CE. Cytokine networks in solid human tumours: regulation of angiogenesis. J Leukoc Biol 1994; 42: 423-435.
[10]  Ning Y, Manegold PC, Hong YK, Zhang W, Pohl A, Lurie G, et al. Interleukin-8 is associated with proliferation, migration angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. Int J Cancer 2010; 128: 2038-2049.
[11]  Fernando RI, Castillo MD, Litzinger M, Hamilton DH, Palena C. IL-8 Signaling plays a critical role in the epithelial–mesenchymal transition of human carcinoma cells. Cancer Res 2011; 71: 5296.
[12]  Singh JK, Simões BM, Howell SJ, Farnie G, Clarke RB. Recent advances reveal IL-8 signaling as a potential key to targeting breast cancer stem cells. Breast Cancer Res 2013; 15: 210.
[13]  Elder BL, Arlian LG, Morgan MS. Extract modulates expression of cytokines and adhesion molecules by human dermal microvascular endothelial cells. J Med Entomol 2006; 43: 910-915
[14]  Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncol 2005; 7: 122-133.
[15]  Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 directly enhanced endothelial cell survival, proliferation,and matrix metalloproteinases productionand regulated angiogenesis. J Immunol 2003; 170: 3369-3376.
[16]  Takamori H, Oades ZG, Hoch OC, Burger M, Schraufstatter IU. Autocrine growth effect of IL-8 and GROa on a human pancreatic cancer cell line. Capan-Pancreas 2000; 21: 52-56.
[17]  Kamohara H, Takahashi M, Ishiko T, Ogawa M, Baba H. Induction of interleukin-8 (CXCL-8) by tumor necrosis factor-alpha and leukemia inhibitory factor in pancreatic carcinoma cells: Impact of CXCL-8 as an autocrine growth factor. Int J Oncol 2007; 31: 627-632.
[18]  Lang K, Niggemann B, Zanker KS, Entschladen F. Signal processing inmigratingT24 human bladder carcinoma cells: role of the autocrine interleukin-8 loop. Int J Cancer 2002; 99: 673-680.
[19]  Yao C, Lin Y, Chua MS, Ye CS, Bi J, Li W, et al. Interleukin-8 modulates growth and invasiveness of estrogen receptor negative breast cancer cells. Int J Cancer 2007; 121: 1949-1957.
[20]  Araki S, Omori Y, Lyn D, Singh RK, Meinbach DM, Sandman Y, et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Res 2007; 67 6854-6862.
[21]  Maxwell P, Gallagher R, Seaton A, Wilson C, Scullin P, Pettigrew J, et al. HIF-1and NF-nB-mediated upregulation of CXCR1and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene 2007; 26: 7333-7345.
[22]  Singh S, Nannuru KC, Sadanandam A, Varney ML, Singh RK. CXCR1 and CXCR2 enhance human melanoma tumourigenesis, growth and invasion. Br J Cancer 2009; 100: 1638-1646.
[23]  Sharma B, Singh S, Varney ML, Singh RK. Targeting CXCR1/CXCR2 receptor antagonism in malignant melanoma. Expert Opin Ther Targets 2010; 14: 435-442.
[24]  Nannuru KC, Sharma B, Varney ML, Singh RK. Role of chemokine receptor CXCR2 expression in mammary tumor growth, angiogenesis and metastasis. J Carcinog 2011; 10: 40-48.
[25]  Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 2010; 120: 485-497.
[26]  Snoussi K, Mahfoudh W, Bouaouina N, Fekih M, Khairi H, Helal A, et al. Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. BMC Cancer 2010; 10: 283-299.
[27]  Lin BR, Chang CC, Chen LR, Wu MH, Wang MY, Kuo IH, et al. Cysteine-rich 61 (CCN1) enhances chemotactic migration, trans-endothelial cell migration, and intravasation by concomitantly up-regulating chemokine receptor 1 and 2. Mol Cancer Res 2007; 5: 1111-1123.
[28]  Hu W, Wang J, Luo G, Luo B, Wu C, Wang W, et al. Proteomics-based analysis of differentially expressed proteins in the CXCR1-knockdown gastric carcinoma MKN45 cell line and its parental cell. Acta Biochim Biophys Sin (Shanghai) 2013; 45: 857-866.
[29]  Chen L, Fan J, Chen H, Meng Z, Chen Z, Wang P, et al. The IL-8/CXCR1 axis is associated with cancer stem cell-like properties and correlates with clinical prognosis in human pancreatic cancer cases. Sci Rep 2014; 4: 1-7.
[30]  Wang Y, Yao X, Ge J, Hu F, Zhao Y. Can vascular endothelial growth factor and microvessel density be used as prognostic biomarkers for colorectal cancer? A systematic review and meta-analysis. Scientific World journal 2014; 2014: 102736. Epub 2014 Mar 27.
[31]  Kim SK., Park SG, Kim KW. Expression of vascular endothelial growth factor in oral squamous cell carcinoma. J Korean Assoc Oral Maxillofac Surg. 2015 Feb; 41(1): 11-18. Epub 2015 Feb 24.
[32]  Kerbel R.S. Tumor angiogenesis: past, present and the near future. Carcinogenesis. 2000; 21: 505-515.
[33]  Khurram SA, Bingle L, Mc Cabe BM, Farthing PM, Whawell SA. The chemokine receptors CXCR1 and CXCR2 regulate oral cancer cell behaviour. J Oral Pathol Med 2014; 43: 667-674.
[34]  Liang B, Zhao H, Che JB, Wang HJ, Shi G. Overexpression of interleukin-8 receptor 2 (IL-8R2) indicates better prognosis in esophageal adenocarcinoma and squamous cell carcinoma procession. Med Oncol 2014; 31: 89.
[35]  Ewington L, Taylor A, Sriraksa R, Horimoto Y, Lam EW, El- Bahrawy MA. The expression of interleukin-8 and interleukin-8 receptors in endometrial carcinoma. Cytokine 2012; 59: 417-422.
[36]  Browne A, Sriraksa R, Guney T, Rama N, Van Noorden S, Curry E, et al. Differential expression of IL-8 and IL-8 receptors in benign, borderline and malignant ovarian epithelial tumors. Cytokine 2013; 64: 413-421.
[37]  Li Z, Wang Y, Dong S, Ge C, Xiao Y, Li R, et al. Association of CXCR1 and 2 expressions with gastric cancer metastasis in ex vivo and tumor cell invasion in vitro. Cytokine2014; 69: 6-13.
[38]  Richards BL, Eisma RJ, Spiro JD, Lindquist RL, Kreutzer DL. Co-expression of interleukin-8 receptors in head and neck squamous cell carcinoma. Am J Surg 1997; 174: 507-512.
[39]  Kuwada Y, Sasaki T, Morinaka K, Kitadai Y, Mukaida N, Chayama K. Potential involvement of IL-8 and its receptors in the invasiveness of pancreatic cancer cells. Int J Oncol 2003; 22: 765-571.
[40]  Han SJ, Lee JH. Anti-tumor effects of vascular endothelial growth factor inhibitor on oral squamous cell carcinoma cell lines. J Korean Assoc Oral Maxillofac Surg. 2009; 35: 66-73.
[41]  Byun JH, Park BW, Chung IK, Kim UK, Park BS, et al. Correlation between vascular endothelial growth factor expression and malignancy grading in biopsy specimens of tongue cancers. J Korean Assoc Maxillofac Plast Reconstr surg. 2005; 27: 528-534.
[42]  Lalla RV, Boisoneau DS, Spiro JD, Kreutzer DL. Expression of vascular endothelial growth factor receptors on tumor cells in head and neck squamous cell carcinoma. Arch Otolaryngol head Neck Surg. 2003; 129: 882-888.
[43]  Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004;9 (Suppl 1):2-10.