Excess FGF-7 in Corneal Epithelium Causes Corneal Intraepithelial Neoplasia in Young Mice and Epithelium Hyperplasia in Adult Mice

Abstract

We hypothesized that human ocular surface squamous neoplasia (OSSN) may result from the continuous growth stimulation of corneal epithelial progenitor cells. In the present study, we analyzed the effects of excess fibroblast growth factor-7 (FGF-7) on both the proliferation and differentiation of corneal epithelium in a novel Krt12-rtTA/tet-O-FGF-7 double transgenic mouse model in which cornea-specific FGF-7 overexpression is achieved by doxycycline (Dox) treatment. When such adult mice were exposed to Dox, they exhibited epithelial hyperplasia with increases in phospho-extracellular signal-regulated kinase 1/2-, nuclear beta-catenin-, and 5-bromo-2'-deoxyuridine-labeled cells and altered keratin (K) 14 (K14) expression pattern, a normal K12 expression pattern, and the normal absence of K10. Hyperplasia of the adult cornea was fully reversible 2 weeks after the removal of Dox from chow. In contrast, double transgenic embryos that were exposed to Dox from embryonic day 0.5 to postnatal day 21 developed papillomatous tumors in the cornea, resembling human OSSN, and ectopic gland-like structures in the limbus, accompanied by the down-regulation of K12 and the up-regulation of K14, Pax6, and p63. These epithelial anomalies observed in young experimental mice were not fully resolved after the termination of Dox induction. Taken together, Krt12-rtTA/tet-O-FGF-7 mice may be a suitable animal model for the study of the molecular and cellular mechanisms of human OSSN.

Aberrant expression of a β-catenin gain-of-function mutant induces hyperplastic transformation in the mouse cornea

“…We have demonstrated that forced expression of stabilized E3-catenin in the differentiated corneal epithelium can cause tumorigenesis. The phenotypes are similar but not identical to those observed previously in Dox-treated Krt12 rtTA/rtTA /tetO-FGF-7 mice, which also displayed hyperplastic nodules on the corneal surface (Chikama et al, 2008).…”

“…Alterations in cell cycling within the limbal area can cause abnormal maturation of the conjunctival and corneal epithelium, and lead to the formation of CIN. In addition, human papilloma virus 16 (HPV16) and/or long-term UVB exposure are known to be the major risk factors associated with human OSSN (Scott et al, 2002; Kiire and Dhillon, 2006) (Chikama et al, 2008). In this tumor model, we found -catenin nuclear translocalized in hyperplastic corneal epithelial cells upon Dox induction.…”

Excess Fibroblast Growth Factor-7 (FGF-7) Activates b-Catenin and Leads to Ocular Surface Squamous Neoplasia in Mice

“…The FGF-7/FGFR signaling is likely the hub that integrates the input through UVB and HPV with the genesis and formation of OSSN (Figure 2). This may explain why excess FGF-7 caused OSSN phenotype in the Dox-treated Krt12 rtTA/rtTA /tet-O-FGF-7 bi-transgenic mouse model (Chikama et al, 2008). Fig.…”

“…For example, over-expression of FGF-7 driven by A-crystalline promoter, which is activated in mouse lens at E11.5, resulted in the suppression of cornea-type epithelial differentiation and the induction of ectopic lacrimal gland formation in the corneas of the transgenic mice Govindarajan et al, 2000;Lovicu et al, 1999). In order to understand such an influence at a later stage when epithelial cells have undergone corneal type epithelial differentiation, we developed a Krt12 rtTA/rtTA /tetO-FGF-7 bi-transgenic mouse line in which over-expression of FGF-7 by Dox induction caused squamous cell carcinoma of the cornea resembling OSSN in human (Chikama et al, 2008). Less is known, however, about the signaling pathways by which FGF-7 mediates control of corneal epithelial cell proliferation.…”

Massive carcinoma of the cornea in an immunocompetent patient

“…Recently, Chikama et al demonstrated in transgenic mice lines that upregulation of FGF-7 signalling pathway(s) may be common in tumorigenesis derived from limbal stem cells that undergo oncogenic transformation by insults, such as long-term ultraviolet B (UVB) exposure, infection of human papilloma virus (HPV) and human immune deficiency virus (HIV), and cigarette smoking, etc. [2].…”