Collagen Matrix in Development and Progression of Experimentally Induced Respiratory Neoplasms in the Hamster

Abstract

Intratracheal instillations of 7H-dibenzo(c, g)carbazole (DBC), a tobacco smoke component, into Syrian golden hamsters, resulted in preneoplastic lesions and benign and malignant respiratory neoplasms. Neoplastic progression was associated with specifi cchanges in the extracellular matrix (ECM), dependent on the stage of tumor development. DBC-induced tracheobronchial squamous metaplasia was associated with an increase in collagen type I and type III deposition in the subepithelial ECM, as observed by computer-assisted image analysis of immunohistochemical staining for the aminoterminal propeptides of collagen type I (PINP) and collagen type III (PIIINP). Increased collagen matrix synthesis was detected in dysplasia by in situ hybridization of α1(I) mRNA for collagen I and α1(III) mRNA for collagen type III after continued exposure to DBC. In well-differentiated squamous cell carcinomas with an expansive growth pattern, collagen deposition increased, as did fi ber size. In moderately differentiated neoplasms, basement membrane (BM) destruction and invasion was associated with a destructive growth pattern and decreases in collagen synthesis and the deposition of new collagen. Preserved deposition of mature collagen was detected by staining for the telopeptide of collagen type I propeptide. In less differentiated tumors, ECM development was minimal, with few and small fi bers, possibly explaining the rapid development of these neoplasms. Transforming growth factor β (TGF β 1) immunoreactivity was increased in hyperplastic epithelium and well differentiated neoplasms and decreased in dysplasia and less differentiated squamous cell carcinomas, while TGF β 2 and TGF β3 expression was also distinct in neoplastic cells. Collagen synthesis and epithelial differentiation were associated with an increased number of myofibroblasts in the ECM and with increased TGF β3 immunoreactivity in differentiated cells and in the matrix. The nature of the composition of the ECM was related to neoplastic growth and progression when analyzed by computer-associated image analysis, revealing alterations in collagen structure, size, and shape.