A protein called YKL-40 is elevated in the blood serum of patients with breast, colorectal, and ovarian cancer, as well as myeloid leukemia. These patients with high YKL-40 serum levels have a poor prognosis and short survival, meaning that YKL-40 levels might offer a way to measure the progression of multiple cancers. As yet, researchers do not understand the role YKL-40 plays in cancer progression. Our preliminary data suggest that YKL-40 might cause new blood vessels to form in tumors, thereby facilitating their ability to invade and metastasize. In order for cancerous tumors to progress and metastasize they require the formation of new blood vessels, a process termed angiogenesis. These vessels carry blood to tumors at both the primary and secondary sites, allowing the cancerous cells to proliferate and expand. Without this nourishing blood supply, the cells die. Therefore, angiogenesis is a tantalizing target for therapeutic intervention. We hypothesize that YKL-40 is produced by cancer cells to promote angiogenesis in vascular endothelial cells, which are the cells lining small blood vessels. This enhanced angiogenesis facilitates tumor growth, invasion, and metastasis. To test this hypothesis, we will pursue three specific aims: 1) to identify correlations between YKL-40 level and markers of progression in human breast cancer;2) to determine molecular mechanisms underlying YKL-40-induced tumor angiogenesis and progression;and 3) to examine the effects of YKL-40 on tumor angiogenesis and metastasis in xenograft tumor models. We will utilize our extensive human tissue bank to analyze cancer samples to determine if there is a correlation between the amount of YKL-40 and cancer stage, cancer survival, and blood vessel density. We will use molecular studies to determine the mechanisms used by YKL-40 to direct a cell to form blood vessels. Finally, we will use cultured cells and animal models to directly observe the effects of YKL-40 on tumor growth, invasion, and metastasis.

Public Health Relevance

Our research may well lead to testing for YKL-40 levels in cancer diagnosis and prognosis. It may also point to YKL-40 as a target for therapeutic intervention in advanced cancers that have thus far proved difficult to treat.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Microenvironment Study Section (TME)
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Snyderwine, Elizabeth G
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University of Massachusetts Amherst
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Francescone, R; Ngernyuang, N; Yan, W et al. (2014) Tumor-derived mural-like cells coordinate with endothelial cells: role of YKL-40 in mural cell-mediated angiogenesis. Oncogene 33:2110-22
Shao, Rong; Francescone, Ralph; Ngernyuang, Nipaporn et al. (2014) Anti-YKL-40 antibody and ionizing irradiation synergistically inhibit tumor vascularization and malignancy in glioblastoma. Carcinogenesis 35:373-82
Scully, Steve; Francescone, Ralph; Faibish, Michael et al. (2012) Transdifferentiation of glioblastoma stem-like cells into mural cells drives vasculogenic mimicry in glioblastomas. J Neurosci 32:12950-60
Shao, Rong; Scully Jr, Steve J; Yan, Wei et al. (2012) The novel lupus antigen related protein acheron enhances the development of human breast cancer. Int J Cancer 130:544-54
Francescone, Ralph; Scully, Steve; Bentley, Brooke et al. (2012) Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation. J Biol Chem 287:24821-31
Francescone, Ralph A; Scully, Steve; Faibish, Michael et al. (2011) Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma. J Biol Chem 286:15332-43
Shao, R; Cao, Q J; Arenas, R B et al. (2011) Breast cancer expression of YKL-40 correlates with tumour grade, poor differentiation, and other cancer markers. Br J Cancer 105:1203-9
Faibish, Michael; Francescone, Ralph; Bentley, Brooke et al. (2011) A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers. Mol Cancer Ther 10:742-51
Francescone 3rd, Ralph A; Faibish, Michael; Shao, Rong (2011) A Matrigel-based tube formation assay to assess the vasculogenic activity of tumor cells. J Vis Exp :
Scully, Steve; Yan, Wei; Bentley, Brooke et al. (2011) Inhibitory activity of YKL-40 in mammary epithelial cell differentiation and polarization induced by lactogenic hormones: a role in mammary tissue involution. PLoS One 6:e25819

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