The tissue microenvironment in which a cancer arises plays a critical role in inhibiting tumor development, but conversely can also be misappropriated by cancerous cells into providing factors that support malignant growth. Our long-term objective is to understand the molecular crosstalk between tumor and host cells, and to determine the mechanisms by which host tissues are co-opted to facilitate cancer progression. This proposal focuses on the contribution of the Cysteine Cathepsin family of degradative enzymes to tumor-host molecular interactions. Cysteine cathepsins are up-regulated in many human and mouse cancers and their increased expression is associated with malignant progression and a poor patient prognosis. Some cathepsin family members are upregulated in tumor cells, however others are additionally or exclusively provided by host cells including endothelial and innate immune cells. Using a broad-spectrum cathepsin inhibitor, we have shown that the cathepsin family is important for all stages of tumor development in the RIP1-Tag2 pancreatic cancer mouse model. Treatment with this inhibitor decreased angiogenic switching, blocked tumor growth, and significantly impaired tumor vascularization, cell proliferation and tumor invasion. Despite the important role for cathepsins in cancer progression, the molecular mechanisms by which they facilitate tumorigenesis are still largely unknown. Our hypothesis is that individual members of the cathepsin family are crucial for distinct steps in acquiring each distinct 'hallmark capability'of cancer. We will identify which of the 6 cathepsin family members upregulated in cancers are important for tumor development. We will test the hypothesis that cathepsins promote tumor invasion by a molecular mechanism requiring the extracellular cleavage of E-cadherin, and facilitate angiogenesis through the degradation and release of vascular basement membrane proteins. We will also determine if the cellular source of cathepsin expression in the cancer microenvironment is necessary for its pro-tumorigenic functions. To achieve these aims, we will analyze 6 mouse gene knockouts of cathepsin family members with a combination of cell co-culture, biochemical and pharmacological experiments. These studies will provide vital insights into the biology of cathepsins in cancer, the role of the microenvironment in tumor progression, and enable the development and application of therapeutic cancer strategies based on studies in this pre-clinical mouse model.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125162-05
Application #
8070515
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$350,170
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Yan, Dongyao; Wang, Hao-Wei; Bowman, Robert L et al. (2016) STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1? Activation. Cell Rep 16:2914-2927
Soboti?, Barbara; VizoviĆĄek, Matej; Vidmar, Robert et al. (2015) Proteomic Identification of Cysteine Cathepsin Substrates Shed from the Surface of Cancer Cells. Mol Cell Proteomics 14:2213-28
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Hunter, Karen E; Quick, Marsha L; Sadanandam, Anguraj et al. (2013) Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis. PLoS One 8:e64472
Jacobson, Lee S; Lima Jr, Heriberto; Goldberg, Michael F et al. (2013) Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants. J Biol Chem 288:7481-91
Pyonteck, S M; Gadea, B B; Wang, H-W et al. (2012) Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene 31:1459-67
Mason, Steven D; Joyce, Johanna A (2011) Proteolytic networks in cancer. Trends Cell Biol 21:228-37
Gocheva, Vasilena; Wang, Hao-Wei; Gadea, Bedrick B et al. (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24:241-55

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