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

Oncogene. 1999 Sep 23;18(39):5435-47. doi: 10.1038/sj.onc.1202926.

Abstract

Transgenic mice which express the simian virus 40 large T-antigen (Tag) under the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor formation 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 tumors arising in several types of human cancers. Based upon electron microscopic examination and immunocytochemical analyses of cellular differentiation markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial cells. The proliferation of these two types of cells results in hyperplasia and adenomatous transformation of the epithelial component, whereas the proliferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develops focally between areas of epithelial proliferation and subsequently ossifies through a process of endochondrial bone formation. The metaplasia of myoepithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cells, including members of the TGF-beta superfamily. We demonstrate that TGF-beta1 protein accumulates in the extracellular matrix of the lesions, whereas RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelial cells during the development of ectopic bone. The formation of sarcomatous 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 occur during embryonic bone formation. These transgenic mice may provide new insights into the processes of ectopic endochondrial bone formation associated with mixed tumor formation and serve as a useful model for human heterotopic bone disease.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / analysis
  • Androgen-Binding Protein / genetics
  • Animals
  • Antigens, Viral, Tumor / analysis
  • Antigens, Viral, Tumor / genetics
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / biosynthesis
  • Bone Morphogenetic Proteins / physiology*
  • Ectodysplasins
  • Female
  • Foot Diseases / etiology
  • Foot Diseases / genetics
  • Foot Diseases / pathology
  • Gonadal Steroid Hormones / physiology
  • Immunohistochemistry
  • In Situ Hybridization
  • Keratins / analysis
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neoplasms, Complex and Mixed / genetics
  • Neoplasms, Complex and Mixed / physiopathology
  • Neoplasms, Complex and Mixed / ultrastructure
  • Ossification, Heterotopic / genetics*
  • Ossification, Heterotopic / pathology
  • Ossification, Heterotopic / physiopathology
  • Phosphatidylethanolamine Binding Protein
  • Proliferating Cell Nuclear Antigen / analysis
  • Prostatein
  • Secretoglobins
  • Tolonium Chloride
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / physiology*
  • Tumor Suppressor Protein p53 / analysis
  • Tumor Suppressor Protein p53 / physiology
  • Uteroglobin
  • Vimentin / analysis

Substances

  • Actins
  • Androgen-Binding Protein
  • Antigens, Viral, Tumor
  • BMP2 protein, human
  • Bmp2 protein, mouse
  • Bmp2 protein, rat
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • EDA protein, human
  • Ectodysplasins
  • Eda protein, mouse
  • Gonadal Steroid Hormones
  • Membrane Proteins
  • PEBP1 protein, human
  • Phosphatidylethanolamine Binding Protein
  • Proliferating Cell Nuclear Antigen
  • Prostatein
  • Scgb1d2 protein, rat
  • Scgb1d4 protein, rat
  • Scgb2a2 protein, rat
  • Secretoglobins
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Vimentin
  • Tolonium Chloride
  • Keratins
  • Uteroglobin