Upregulation of fibroblast growth factors and their receptors during multi-stage epidermal carcinogenesis in K14-HPV16 transgenic mice.
Upregulation of acidic and basic fibroblast growth factors (FGF-1 and -2), and their cognate receptors FGFR-1 and -2, has been demonstrated in a variety of epithelial malignancies. However, the patterns of FGF/FGFR expression at specific stages of epithelial carcinogenesis have not been extensively characterized. In this report, the levels of FGF-1, FGF-2, FGF-7 mRNA and their receptors FGFR-1 and FGFR-2, were investigated during epidermal carcinogenesis in transgenic mice expressing the early region of the 'high risk' papillomavirus type 16 (HPV16) under control of the human keratin-14 enhancer/promoter (K14-HPV16 transgenic mice). FGF-1 was first upregulated in dysplasias, while FGF-2 was constitutively expressed in non-transgenic, neoplastic, and malignant keratinocytes throughout carcinogenesis. Expression of FGF-7 was undetectable in non-transgenic epidermis, and remained at threshold levels at all stages of progression. In well differentiated squamous cancers, FGFR-1 was upregulated and co-localized with angiogenic capillaries in the dermis underlying dysplastic lesions and within papillary fronds of invasive cancers. In contrast, FGFR-1 was upregulated specifically within the malignant squamous cells of moderate-poorly differentiated squamous cancers. The expression of FGFR-2 was essentially constitutive in both non-transgenic and neoplastic epidermis. Collectively the data suggest that the FGF/FGFR signaling pathways may potentially contribute to several facets of multi-stage epithelial carcinogenesis, including auto- or paracrine growth stimulation, upregulation of angiogenesis, and stromal remodeling.
Arbeit
J M
JM
Hormone Research Institute, Department of Surgery, University of California, San Francisco, 94143-0534, USA.
Olson
D C
DC
Hanahan
D
D
D000818:Animals; D051526:Fibroblast Growth Factor 10; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027383:Papillomaviridae / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics*
C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2