Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma.

Abstract

To study the contribution of autocrine and paracrine TGF-pi to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-pi gene were initiated in vitro with the v-ras"^^ oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v-ras""-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well-differentiated papillomas. Malignant progression was not associated with mutations in the c-ras^' gene, alterations in p53 protein, or loss of responsiveness to TGF-pi. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-pi null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-pi from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-pl positive even though they did not express TGF-pi mRNA. These results demonstrate that autocrine TGF-pl suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-pi can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-pi by a mechanism that operates in normal cells.

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

“…The dominant negative type II TGF-b receptor is able to provide the secondary genetic alteration beside the Harvey-ras mutation to induce carcinoma development. This agrees with a previous report using skin grafts of v-ras Ha initiated TGF-b1 null keratinocytes which produce squamous cell carcinomas (Glick et al, 1994).…”

“…Therefore, it has been suggested that TGF-b plays an important role in skin carcinogenesis (Glick et Glick et al, 1994;Cui et al, 1996). To elucidate the function of TGF-b signaling in tumor development we subjected our transgenic mice to skin carcinogenesis protocols (DiGiovanni, 1991;Hennings et al, 1993).…”

“…Additionally, loss of TGF-b expression in benign skin papillomas is correlated with a high risk for malignant conversion (Missero et al, 1991;Glick et al, 1993;Cui et al, 1994;Glick et al, 1994). On the other hand, TGF-b can also stimulate malignant progression, possibly by its action on cell-matrix interaction, by its immunosuppressive activities or by enhancing angiogenesis (Roberts et al, 1986;Torre-Amione et al, 1990;Arrick et al, 1992;Glick et al, 1994;Cui et al, 1996). TGF-b conveys signals via two serine/threonine kinase receptors, type I and type II, both of which are necessary for signal transduction Derynck, 1994).…”

Synergistic effect between EGF and TGF-β1 in inducing oncogenic properties of intestinal epithelial cells

“…Targeted deletion of TGF-b1 gene predisposes mice to the development of squamous cell carcinoma (Glick et al, 1994). Hemizygous or homozygous Tgfb1-null animals show increased incidence of chemically or spontaneously induced tumors (Tang et al, 1998).…”

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

“…TGF-b is a potent negative growth-regulator for epithelial cells and TGF-b receptor signaling appears to serve an important tumor suppressor function in the earliest stages of breast, colorectal, cutaneous and pancreatic carcinogenesis (Pierce et al, 1995;Sun et al, 1994;Wang et al, 1995a;Eppert et al, 1996;Markowitz et al, 1995;Takagi et al, 1996;Glick et al, 1993Glick et al, , 1994Cui et al, 1994;Hahn et al, 1996).…”