Abstract
The aim of the present study was to determine the role of vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) in lip carcinogenesis, to investigate correlations between these markers with microvessel density (MVD) and clinicopathological aspects. Medical records from 27 cases of actinic cheilitis (AC) and 46 cases of lower lip squamous cell carcinoma (LLSCC) were analysed and submitted to immunohistochemistry. VEGFR1- and VEGFR2-immunostained sections were analysed based on percentage of positive epithelial and inflammatory cells, while CD31 was submitted to quantitative analysis to determine MVD. Different patterns of VGFR1 and VEGFR2 expression were observed between AC and LLSCC. VEGFR1 expression in epithelial and inflammatory cells and VEGFR2 expression in epithelial cells were higher in AC compared to LLSCC (p < 0.05). VEGFR1 expression in epithelial cells was higher in LLSCC compared to AC (p < 0.001). Expression of both receptors was not associated to MVD or clinicopathological aspects. A direct correlation was found between epithelial VEGFR1 and VEGFR2 expression (p = 0.02) and between VEGFR2 epithelial and inflammatory expression (p < 0.001). Our findings indicate that activation of VEGFR1 and VEGFR2 in epithelial and inflammatory cells appears to be an early event in lip carcinogenesis.
Similar content being viewed by others
References
Savage NW, McKay C, Faulkner C. Actinic cheilitis in dental practice. Aust Dent J. 2010;55 Suppl 1:78–84.
dos Santos JN, de Sousa SO, Nunes FD, Sotto MN, de Araujo VC. Altered cytokeratin expression in actinic cheilitis. J Cutan Pathol. 2003;4:237–41.
Corso FM, Wild C, Gouveia LO, Ribas MO. Actinic cheilitis: prevalence in dental clinics from PUCPR, Curitiba, Brazil. Clin Pesq Odontol. 2006;2:227–81.
Henrique PR, Junior MB, Araujo VC, Junqueira JLC, Furuse C. Prevalence of oral mucosal changes in the adult population from Uberaba, Minas Gerais. RGO. 2009;57:261–7.
de Souza Lucena EE, Costa DC, da Silveira EJ, Lima KC. Prevalence and factors associated to actinic cheilitis in beach workers. Oral Dis. 2012;18(6):575–9.
Miranda AM, Soares LG, Ferrari TM, Silva DG, Falabella ME, Tinoco EM. Prevalence of actinic cheilitis in a population of agricultural sugarcane workers. Acta Odontol Latinoam. 2012;25(2):201–6.
Sugerman PB, Savage NW. Oral cancer in Australia: 1983–1996. Aust Dent J. 2002;47(1):45–56.
Leelahavanichkul K, Amornphimoltham P, Molinolo AA, Basile JR, Koontongkaew S, Gutkind JS. A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis. Mol Oncol. 2014;8(1):105–18.
Sasahira T, Kirita T, Kuniyasu H. Update of molecular pathobiology in oral cancer: a review. Int J Clin Oncol. 2014;19(3):431–6.
Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci. 2001;114(Pt 5):853–65.
Wey JS, Stoeltzing O, Ellis LM. Vascular endothelial growth factor receptors: expression and function in solid tumors. Clin Adv Hematol Oncol. 2004;2(1):37–45.
Shibuya M. Role of VEGF-flt receptor system in normal and tumor angiogenesis. Adv Cancer Res. 1995;67:281–316.
Margaritescu C, Pirici D, Simionescu C, Mogoanta L, Raica M, Stinga A, et al. VEGF and VEGFRs expression in oral squamous cell carcinoma. Rom J Morphol Embryol Rev Roum Morphol Embryol. 2009;50(4):527–48.
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4–25.
Reinmuth N, Liu W, Jung YD, Ahmad SA, Shaheen RM, Fan F, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J Off Publ Fed Am Soc Exp Biol. 2001;15(7):1239–41.
Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, et al. Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci U S A. 2001;98(19):10857–62.
Kyzas PA, Stefanou D, Agnantis NJ. Immunohistochemical expression of vascular endothelial growth factor correlates with positive surgical margins and recurrence in T1 and T2 squamous cell carcinoma (SCC) of the lower lip. Oral Oncol. 2004;40(9):941–7.
Margaritescu C, Pirici D, Stinga A, Simionescu C, Raica M, Mogoanta L, et al. VEGF expression and angiogenesis in oral squamous cell carcinoma: an immunohistochemical and morphometric study. Clin Exp Med. 2010;10(4):209–14.
Stinga AC, Margaritescu O, Stinga AS, Pirici D, Ciurea R, Bunget A, et al. VEGFR1 and VEGFR2 immunohistochemical expression in oral squamous cell carcinoma: a morphometric study. Rom J Morphol Embryol Rev Roum Morphol Embryol. 2011;52(4):1269–75.
Cabebe E, Wakelee H. Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Curr Treat Options in Oncol. 2007;8(1):15–27.
Murakami M, Nguyen LT, Hatanaka K, Schachterle W, Chen PY, Zhuang ZW, et al. FGF-dependent regulation of VEGF receptor 2 expression in mice. J Clin Invest. 2011;121(7):2668–78.
Florence ME, Massuda JY, Brocker EB, Metze K, Cintra ML, Souza EM. Angiogenesis in the progression of cutaneous squamous cell carcinoma: an immunohistochemical study of endothelial markers. Clinics. 2011;66(3):465–8.
Konger RL, Xu Z, Sahu RP, Rashid BM, Mehta SR, Mohamed DR, et al. Spatiotemporal assessments of dermal hyperemia enable accurate prediction of experimental cutaneous carcinogenesis as well as chemopreventive activity. Cancer Res. 2013;73(1):150–9.
Shinkaruk S, Bayle M, Lain G, Deleris G. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr Med Chem Anti Cancer Agents. 2003;3(2):95–117.
Michi Y, Morita I, Amagasa T, Murota S. Human oral squamous cell carcinoma cell lines promote angiogenesis via expression of vascular endothelial growth factor and upregulation of KDR/flk-1 expression in endothelial cells. Oral Oncol. 2000;36(1):81–8.
Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ. Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2. Mod Pathol Off J U S Can Acad Pathol Inc. 2005;18(4):485–94.
Moriyama M, Kumagai S, Kawashiri S, Kojima K, Kakihara K, Yamamoto E. Immunohistochemical study of tumour angiogenesis in oral squamous cell carcinoma. Oral Oncol. 1997;33(5):369–74.
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(8):882–8.
Ciurea R, Margaritescu C, Simionescu C, Stepan A, Ciurea M. VEGF and his R1 and R2 receptors expression in mast cells of oral squamous cells carcinomas and their involvement in tumoral angiogenesis. Rom J Morphol Embryol Rev Roum Morphol Embryol. 2011;52(4):1227–32.
Thompson L. Health Organization classification of tumours. Pathology and genetics of tumours of the head and neck. Ear Nose Throat J. 2005;85(2):74.
Bryne M, Koppang HS, Lilleng R, Kjaerheim A. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol. 1992;166(4):375–81.
Dhakal HP, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, et al. Expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2 in invasive breast carcinoma: prognostic significance and relationship with markers for aggressiveness. Histopathology. 2012;61(3):350–64.
Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8.
Christopoulos A, Ahn SM, Klein JD, Kim S. Biology of vascular endothelial growth factor and its receptors in head and neck cancer: beyond angiogenesis. Head Neck. 2011;33(8):1220–9.
Raica M, Cimpean AM, Ribatti D. Angiogenesis in pre-malignant conditions. Eur J Cancer. 2009;45(11):1924–34.
Zhang Z, Neiva KG, Lingen MW, Ellis LM, Nor JE. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ. 2010;17(3):499–512.
Jackson MW, Roberts JS, Heckford SE, Ricciardelli C, Stahl J, Choong C, et al. A potential autocrine role for vascular endothelial growth factor in prostate cancer. Cancer Res. 2002;62(3):854–9.
Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(4):1434–40.
Carlile J, Harada K, Baillie R, Macluskey M, Chisholm DM, Ogden GR, et al. Vascular endothelial growth factor (VEGF) expression in oral tissues: possible relevance to angiogenesis, tumour progression and field cancerisation. J Oral Pathol Med Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol. 2001;30(8):449–57.
Johnstone S, Logan RM. The role of vascular endothelial growth factor (VEGF) in oral dysplasia and oral squamous cell carcinoma. Oral Oncol. 2006;42(4):337–42.
Gandolfo M, Keszler A, Lanfranchi H, Itoiz ME. Increased subepithelial vascularization and VEGF expression reveal potentially malignant changes in human oral mucosa lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(4):486–93.
Sawane M, Kajiya K. Ultraviolet light-induced changes of lymphatic and blood vasculature in skin and their molecular mechanisms. Exp Dermatol. 2012;21 Suppl 1:22–5.
Li Y, Bi Z, Yan B, Wan Y. UVB radiation induces expression of HIF-1alpha and VEGF through the EGFR/PI3K/DEC1 pathway. Int J Mol Med. 2006;18(4):713–9.
Shintani S, Li C, Ishikawa T, Mihara M, Nakashiro K, Hamakawa H. Expression of vascular endothelial growth factor A, B, C, and D in oral squamous cell carcinoma. Oral Oncol. 2004;40(1):13–20.
Astekar M, Joshi A, Ramesh G, Metgud R. Expression of vascular endothelial growth factor and microvessel density in oral tumorigenesis. J Oral Maxillofac Pathol JOMFP. 2012;16(1):22–6.
Ravi D, Ramadas K, Mathew BS, Nalinakumari KR, Nair MK, Pillai MR. Angiogenesis during tumor progression in the oral cavity is related to reduced apoptosis and high tumor cell proliferation. Oral Oncol. 1998;34(6):543–8.
Macluskey M, Baillie R, Chandrachud LM, Pendleton N, Schor AM. High levels of apoptosis are associated with improved survival in non-small cell lung cancer. Anticancer Res. 2000;20(3B):2123–8.
Acknowledgments
The authors are grateful to Flavia Rejane Giusti for technical support.
Conflicts of interest
None.
Funding support
This study was supported by the Postgraduate Research Group of the Porto Alegre University Hospital (GPPG/FIPE: 14-0042). Luise Meurer and Manoela Domingues Martins are research fellows funded by the Brazilian National Council for Scientific and Technological Development (CNPq).
Author information
Authors and Affiliations
Corresponding author
Additional information
Carla Ariotti and Vivian Petersen Wagner contributed equally to this work.
Rights and permissions
About this article
Cite this article
Ariotti, C., Wagner, V.P., Salvadori, G. et al. VEGFR1 and VEGFR2 in lip carcinogenesis and its association with microvessel density. Tumor Biol. 36, 7285–7292 (2015). https://doi.org/10.1007/s13277-015-3454-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-3454-7