Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma.

Seema Nayak,S P Agarwal,Saumya Chandra,Annu Makker,Sandeep Kumar,Madhu Mati Goel,Vikram Bhatia,Chih-Hsin Tang

doi:10.1371/journal.pone.0138801

Abstract

There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to oral squamous cell carcinoma (OSCC). Fibroblast growth factor-2 (FGF-2) is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP) and Oral submucous fibrosis (OSMF) to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10) of PMOLs which showed malignant transformation (transformed) expressed FGF-2, only 24.19% cases (15/62) of PMOLs which were not transformed (untransformed) to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81%) of untransformed PMOLs and 8/10 (80%) cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10%) cases of untransformed PMOLs and 6/10 (60%) cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP.

Highlights

Oral squamous cell carcinoma (OSCC) is a multifactorial and complex disease
Fibroblast growth factor-2 (FGF-2) positivity was observed in 49.08% (53/108) OSCC cases, 31.95% (23/72) potentially malignant oral lesions (PMOLs) and in 26.92% (14/ 52) control cases
FGFR-2 expression was observed in 57.41% (62/108) cases of OSCC, 33.33% (24/72) cases of PMOLs and 15.38% (8/ 52) cases of controls

Summary

Introduction

Oral squamous cell carcinoma (OSCC) is a multifactorial and complex disease. Several factors including angiogenesis, lymphangiogenesis, alterations in expression or structure of tumor suppressor genes and oncogenes and their proteins, etc are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to OSCC [1, 2].The malignant transformation rates of PMOLs show a great variation; for example, 10–20% of hyperkeratosis or epithelial hyperplasia or epithelial dysplasia may transform to cancer and the estimated annual rate is 1.4–7% [3, 4]. Lymphangiogenesis, alterations in expression or structure of tumor suppressor genes and oncogenes and their proteins, etc are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to OSCC [1, 2]. Lumerman in 1995 reported that 6.6%–36% of epithelial dysplasias may transform to invasive SCC [5]. The malignant transformation rate of leukoplakia (LKP) has been reported to range from 0.13 to 17.5% [6,7], 1.1% in Oral lichen planus [8] and 2.3–7.6% in oral submucous fibrosis (OSMF), during 10–17 years of follow-up [9,10]. In a study from Taiwan [11], the malignant transformation rate in an average follow-up period of 42.6 months ranged from 1.9 to 5.4% for various types of PMOLs

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