Heterotopic endochondrial ossification with mixed tumor formation in C3(1)/Tag transgenic mice is associated with elevated TGF-beta1 and BMP-2 expression

Transgenic mice which express the simian virus 40 large T-antigen (Tag) und er the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor form ation arising from eccrine sweat glands found only in the foot pads of mice , ischiocavernosus muscle adjacent to bulbourethral glands and occasionally the salivary and mammary glands. These lesions are very similar to mixed t umors arising in several types of human cancers. Based upon electron micros copic examination and immunocytochemical analyses of cellular differentiati on markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial ce lls. The proliferation of these two types of cells results in hyperplasia a nd adenomatous transformation of the epithelial component, whereas the prol iferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develop s focally between areas of epithelial proliferation and subsequently ossifi es through process of endochondrial bone formation, The metaplasia of myoep ithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cel ls, including members of the TGF-beta superfamily, We demonstrate that TGF- beta1 protein accumulates in the extracellular matrix of the lesions, where as RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelia l cells during the development of ectopic bone. The formation of sarcomatou s tumors within the mixed tumors appears to be androgen-dependent and more frequent in mice lacking a normal allele of p53. This process of cartilage and bone induction may mimic epithelial-mesenchymal interactions which occu r during embryonic bone formation. These transgenic mice may provide new in sights into the processes of ectopic endochondrial bone formation associate d with mixed tumor formation and serve as a useful model for human heteroto pic bone disease.