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

Abstract

The role of Transforming growth factor beta (TGF-b) in carcinogenesis is complex. There are reports on both tumor inhibition and tumor promotion by TGF-b. To elucidate the complex role of TGF-b in epithelial carcinogenesis, we generated transgenic mice overexpressing a dominant negative type II TGF-b receptor in the basal cell compartment and in follicular cells of the skin. Despite the reduced responsiveness of transgenic keratinocytes to TGF-b, both proliferation and di erentiation were normal in non-irritated epidermis of these transgenic mice. Thus, interruption of signaling of all three isoforms of TGF-b in basal and follicular cells does not disturb tissue homeostasis. However, during tumor promotion transgenic mice showed an elevated level of proliferation in the epidermis. This hyperproliferation correlated with a very early onset of carcinoma development and a malignant conversion frequency of 30% from benign papillomas to carcinomas. By comparison, the conversion frequency in wild-type mice of this strain has previously been reported as 5.5%. Even without induction of hyperproliferation by tumor promoters, transgenic mice developed far more carcinomas as controls when treated with a carcinogen. This result indicates that there is a synergistic e ect between loss of TGF-b responsiveness and mutations caused by initiation with a carcinogen leading to an endogeneous tumor promotion in initiated cells only.

Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

“…Previous studies showed that transgenic mice expressing a dominant-negative type II TGFb receptor, which blocks signaling of TGFb subfamily, exhibited epidermal Smad4 deficiency results in skin tumor formation W Qiao et al hyperproliferation (Wang et al, 1997). These mice do not develop spontaneous skin tumors; however, they are more sensitive to chemically induced carcinogenesis than control mice (Amendt et al, 1998;Go et al, 1999). Thus, the spontaneous skin tumor formation in Smad4 Co/Co MMTV-Cre mice could be due to the fact that Smad4 is a common mediator of both TGFb and BMP signaling.…”

“…For instance, targeted disruption of TGFb1 resulted in tumorigenesis of v-rasHa oncogenetransfected keratinocytes after they were grafted into nude mice (Glick et al, 1994). Consistently, transgenic mice expressing a dominant-negative type II TGFb receptor exhibited epidermal hyperproliferation (Wang et al, 1997) and were more sensitive to chemically induced carcinogenesis (Amendt et al, 1998;Go et al, 1999). Benign hair follicle tumors were also observed in mice carrying a targeted disruption of BMP receptor 1A (BMPR1A) (Andl et al, 2004;Ming Kwan et al, 2004).…”

Smad3 Knockout Mice Exhibit a Resistance to Skin Chemical Carcinogenesis

“…For instance, loss of TGF-␤1 expression results in early progression to malignancy (3). Similarly, transgenic mice overexpressing the dominant negative TGF-␤ type II receptor (⌬␤RII) in the epidermis exhibited a higher susceptibility to skin chemical carcinogenesis (4,5).…”

Attenuated type II TGF‐β receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination

“…In transgenic animals with targeted expression of dominant-negative T␤R-II in specific tissues, there is acceleration of tumorigenesis after carcinogen treatment. [11][12][13][14] Dysregulation of cell cycle progression is thought to be the driving force that facilitates tumour advancement in these circumstances but, conceivably, other mechanisms could account for this phenomenon in view of the plethora of effects of TGF-␤1.…”