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

Tannehill-Gregg, Sarah

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Squamous cell carcinoma (SCC) is a malignant tumor of keratinocytes. Head and neck SCC (H/N SCC) is a common diagnosis in the cat. SCCs often secrete parathyroid hormone related-protein (PTHrP) which induces osteoclastic resorption and contributes to bone destruction. Bone resorption results in the release of transforming growth factor-Β (TGF-Β), which regulates PTHrP via Smad signaling proteins.We developed a PTHrP-secreting feline oropharyngeal SCC cell line (SCCF1). Treatment of cells with TGF-Β increased PTHrP production. A segment of feline PTHrP had a high degree of homology to human and canine PTHrP cDNA and predicted amino acid sequence. PTHrP mRNA was alternatively spliced to the 1-139 and 1-141 isoforms. A mouse xenograft model of feline oral SCC was developed using luciferase-expressing SCCF1 cells. This allowed serial in vivo monitoring of tumor growth using bioluminescent imaging. Using a human pulmonary SCC line (HARA) in an intratibial metastasis model, we investigated the role of tumor-produced PTHrP in the growth of HARA in bone. We disrupted normal osteoclast function by treatment with zoledronic acid or osteoprotegerin. Tumor burden in bone was decreased with either treatment. Osteoclast numbers along tumor-associated bone were not decreased. High local levels of PTHrP may have partially antagonized the anti-osteoclast effects of either drug. Chemical induction of skin tumors in mice heterozygous for Smad2 and Smad3 was used to investigate the role of disruption of the TGF-Β signaling pathway on the development of SCC. Smad3± mice developed fewer tumors than wild-type mice, suggesting an oncogene role. Smad2± mice formed less-differentiated tumors than wild-type mice, supporting a tumor-suppressor role. There was a significant difference in tumor type between the two groups, suggesting that Smad2 and Smad3 regulate different targets. In conclusion, we propose the use of the cat as a natural model for human H/N SCC. In vitro and in vivo studies using SCCF1 are useful for investigating molecular aspects and pathogenesis of SCC. Production of osteoclast-activating factors, such as PTHrP, by neoplastic cells in bone may lead to high local levels, which could modify the effectiveness of anti-osteoclast-based treatments. Smads play on important role in the development of chemically-induced skin tumors.
Thomas Rosol (Advisor)
169 p.

Recommended Citations

Citations

  • Tannehill-Gregg, S. (2005). The development and characterization of animal models of squamous cell carcinoma: the roles of parathyroid hormone-related protein, transforming growth factor-Β, and the osteoclast in disease progression [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1110380593

    APA Style (7th edition)

  • Tannehill-Gregg, Sarah. The development and characterization of animal models of squamous cell carcinoma: the roles of parathyroid hormone-related protein, transforming growth factor-Β, and the osteoclast in disease progression. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1110380593.

    MLA Style (8th edition)

  • Tannehill-Gregg, Sarah. "The development and characterization of animal models of squamous cell carcinoma: the roles of parathyroid hormone-related protein, transforming growth factor-Β, and the osteoclast in disease progression." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1110380593

    Chicago Manual of Style (17th edition)