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"YKL-40 in Normal and Pathogenic Processes"

by
Daniel J. Hoover III
Molecular Pathology & Immunology Program
BS, PA-C, 1999, City University of New York


Thesis Advisor: Frederick D. Coffman, Ph.D.
Associate Professor
Department of Pathology and Laboratory Medicine

Tuesday, May 25, 2010
MSB C-555, 2:00 P.M.


Abstract

YKL-40 is a glycosylated chitinase like protein secreted by certain in vivo cancers, select ex vivo cancer cell lines, non-cancer cells adjacent to certain cancers, cultured chondrocytes, neutrophils, and ‘mature’ macrophages. Expression tends to be in mesenchymal tissues, in EMT transition and typically correlates with disease severity. These patterns suggest roles in tissue remodeling, cell survival, chemo- and radio- resistance, metastasis, and the cell stress response.
Our results demonstrate that in MG-63 osteosarcoma cells, YKL-40 expression is strongly linked to stress. YKL-40 expression was punctate, cell cycle related and up-regulated by serum deprivation and confluence. In proliferating cells, YKL-40 synthesis appears limited to mid-interphase. In confluent cells, YKL-40 expression was coincident with the onset of autophagy and phospho-FAK expression.
YKL-40 expression in macrophages is maturity dependent, possibly enhanced in infections and inflammation. Experiments demonstrated M1 cytokines/factors increased YKL-40 expression while the M2 cytokines/factors did not; An intriguing result considering YKL-40 knockout mice were reported deficient in Th2 responses.
In small cell lung cancer (SCLC), it was reported that SCLC cells and cell lines do not synthesize YKL-40, but peritumor macrophages did. We found conditioned media from the SCLC cell line H69 induced YKL-40 expression in U937s. Thus, the SCLC tumor cells can benefit from local YKL-40 activity without secreting the protein themselves.
As YKL-40 is often expressed by cells of mesenchymal origin, we examined the expression of YKL-40 in mesenchymal stem cells (MSCs). Undifferentiated MSCs contained YKL-40 mRNA but no YKL-40 protein. Differentiation into chondrocytes and osteocytes induced expression of the protein while neuronal differentiation did not. This correlates with the general absence of YKL-40 protein in normal adult brain tissues.
YKL-40/heparin binding experiments found binding is specific. Since YKL-40 has been shown to activate PI3K and AKT pathways within target cells, yet no cell surface binding partner has been identified, we examined YKL-40/growth factor interactions. We recently found, through immunoprecipitation, that YKL-40 interacts with VEGFA165. This interaction may involve heparin, and as VEGF is known to activate PI3K and is a potent regulator of angiogenesis, it is likely an important component of YKL-40’s reported cellular and biological activities.


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