The development and characterization of animal models of squamous cell carcinoma: The roles of parathyroid hormone-related protein, transforming growth factor-beta, and the osteoclast in disease progression

Squamous cell carcinoma (SCC) is a malignant tumor of keratinocytes which can be found in many locations throughout the body including the skin, lung, and oral cavity. The diagnosis of oral SCC can be devastating and late stage tumors are associated with a low survival rate.; The destruction of bone by oral SCCs can be devastating and a cause of morbidity in both humans and cats with late-stage SCCs. SCCs often produce and secrete parathyroid hormone related-protein (PTHrP) which induces osteoclastic resorption. Bone resorption results in the release and activation of the bone-associated growth factor transforming growth factor-beta (TGF-beta), which plays a role in the regulation of PTHrP via Smad signaling proteins.; We developed and characterized a feline oropharyngeal SCC cell line (SCCF1) to facilitate the development of the cat as a natural model for human H/N SCC. The cells were characterized immunohistochemically by strong cytokeratin and weak vimentin staining. Electron microscopy demonstrated typical features of keratinocytes as well as features of anaplasia. Karyotype analysis revealed aneuploidy. SCCF1 expressed PTHrP messenger ribonucleic acid (mRNA) and secreted PTHrP protein. Treatment of cells with TGF-beta increased PTHrP production, but did not affect PTHrP mRNA stability.; Using an intratibial injection model of tumor-bone interaction, and a human pulmonary SCC line (HARA), we investigated the role of tumor-produced PTHrP and the osteoclast in both the growth of pulmonary SCC in bone, and in its osteodestructive nature. We disrupted normal osteoclast function by treating tumor-bearing mice with a bisphosphonate, zoledronic acid, or osteoprotegerin (OPG).; In conclusion, we propose the use of the cat as an excellent natural model for human H/N SCC. In vitro studies using the feline laryngeal SCC cell line SCCF1, as well as in vivo studies using the mouse xenograft model of luciferase-expressing SCCF1, are useful for investigating molecular aspects and pathogenesis of this devastating disease. Production of osteoclast-activating factors, such as PTHrP, by neoplastic cells may lead to high local levels of bone-resorbing factors, which could modify the effectiveness of anti-osteoclast-based treatments. Smads play on important role in TGF-beta signaling in the keratinocyte, and disruption of this pathway in chemically-induced epithelial skin tumors supports regulation of different targets for Smad2 and Smad3, despite their homology. (Abstract shortened by UMI.)...