Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis

• Published in: Cancer research (Chicago, Ill.) Vol. 63; no. 16; pp. 4819 - 4828
• Main Authors: MATSUMOTO, Takashi, JIANGHONG JIANG, KIGUCHI, Kaoru, RUFFINO, Lynnsie, CARBAJAL, Steve, BELTRAN, Linda, BOL, David K, ROSENBERG, Michael P, DIGIOVANNI, John
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-08-2003
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Amino Acid Sequence; Animals; Biological and medical sciences; c-src gene; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - pathology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Female; Fundamental and applied biological sciences. Psychology; Male; Mice; Mice, Transgenic; Molecular and cellular biology; Molecular Sequence Data; Neoplasm Metastasis; Protein-Tyrosine Kinases - analysis; Protein-Tyrosine Kinases - physiology; Skin - pathology; Skin Neoplasms - etiology; Skin Neoplasms - pathology; src-Family Kinases; Tetradecanoylphorbol Acetate - pharmacology; Skin disease; Rodentia; Transgenic animal; Gene overexpression; Epidermis; Metastasis; Malignant tumor; Gene expression; Carcinogenesis; Vertebrata; Mammalia; Mouse; Animal; C-Onc gene; Tumor progression; Skin; Mechanism of action; Tumor promotion; Basal cell
• ISSN: 0008-5472; 1538-7445

In this study, we generated transgenic mice that overexpressed either a constitutively active human c-src mutant (src(530)) or a wild-type human c-src (src(wt)) in epidermal basal cells driven by human keratin 14 (HK14) or bovine keratin 5 (BK5) promoters, respectively. HK14.src(530) transgenic mice developed severe epidermal hyperplasia and hyperkeratosis, and did not survive beyond 3 weeks of age. Four transgenic founders were obtained after injection of a BK5.src(wt) construct with variable phenotypes, and three lines (lines A-C) were established. BK5.src(wt) founder D exhibited a severe skin phenotype similar to HK14.src(530) transgenic mice and died 5 days after birth. Line C transgenic mice also exhibited significant epidermal hyperplasia and hyperkeratosis, and developed spontaneous squamous cell carcinomas (SCCs) of the skin beginning at approximately 3 months of age (70% incidence at 1 year). Mice from lines A and B did not show a marked phenotype; however, elevated human src(wt) protein in the epidermis of line B mice was clearly evident. Additional analyses of line B transgenic mice showed an enhanced responsiveness to 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and cell proliferation. Analysis of the susceptibility of line B mice to two-stage skin carcinogenesis revealed that papillomas and SCCs arose earlier and in greater numbers compared with nontransgenic littermates. In addition, malignant conversion occurred more rapidly, and the SCCs that developed in line B transgenic mice had a greater propensity to metastasize to peripheral lymph nodes and other organs. These observations support the hypothesis that c-src plays an important role in skin tumor promotion. In addition, the data show that elevated c-src activity enhances malignant progression and metastasis in this model system.