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The world according to mast cells – the role of Kit in normal and neoplastic canine mast cells

Lin, Tzu-Yin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1189098916

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Mast cell disorders are common in dogs, ranging from atopy to mast cell tumors. Nevertheless, the biology of canine mast cells has not been well-characterized largely due to a lack of a reliable source of normal mast cells for study. It is known that the receptor tyrosine kinase Kit is important in normal mast cell biology and activating Kit mutations are found in human and canine neoplastic mast cells. The purpose of this dissertation was to evaluate the role of Kit in both normal and malignant mast cells. We first established a protocol to generate canine bone marrow derived cultured mast cells (cBMCMCs) to provide a ready source of normal cells. We demonstrated that cBMCMCs exhibit features typical of mast cells including expression of Kit, FcεRI and CD11b/CD18, expression of granules containing tryptase, chymase, and chemokines, and release of histamine, proteases, and a variety of cytokines/chemokines following stimulation. We found that similar to human BMCMCs, cBMCMCs release significantly larger amounts of MMP9, MCP-1 and tryptase and significantly smaller amounts of IL-6 following stimulation when compared to murine BMCMCs. Our data demonstrate that SCF/Kit signaling is essential for cBMCMC development, proliferation, survival, and migration. Furthermore, both IL-4 and IL-10 promote cBMCMC proliferation, possibly through upregulation of Kit expression, while TGF-β inhibits proliferation. Finally, we found that STA-9090, a novel HSP90 inhibitor, induces down-regulation of phospho- and total Kit and Akt in normal mast cells, malignant mast cell lines, and fresh malignant mast cells resulting in growth inhibition and apoptosis. STA-9090 was active against cells expressing WT or mutant Kit, while a small molecule Kit inhibitor, SU11654, was effective only against cells expressing mutant Kit, suggesting that STA-9090 is likely to exhibit broad clinical activity in vivo. In summary, the data presented in this dissertation establishes a hallmark in the field of canine mast cell biology by providing a novel tool for investigating the characteristics of canine mast cells, validating the utility of canine mast cell related disorders as a model for human disease, and defining the role of Kit in the growth and survival of normal and neoplastic canine mast cells.
Cheryl London (Advisor)
Mary Jo Burkhard (Other)
William Kisseberth (Other)
Stefan Niewiesk (Other)
Biology, Veterinary Science
canine; mast cells; mast cell tumors; KIT; bone marrow; HSP90; HSP90 inhibitor

Recommended Citations

Citations

  • Lin, T.-Y. (2007). The world according to mast cells – the role of Kit in normal and neoplastic canine mast cells [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1189098916

    APA Style (7th edition)

  • Lin, Tzu-Yin. The world according to mast cells – the role of Kit in normal and neoplastic canine mast cells. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1189098916.

    MLA Style (8th edition)

  • Lin, Tzu-Yin. "The world according to mast cells – the role of Kit in normal and neoplastic canine mast cells." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1189098916

    Chicago Manual of Style (17th edition)

osu1189098916
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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.