Analysis of A Disintegrin and Metalloprotease 17 (ADAM17) in the metastatic niche of the lung

Stevanovic, Marija

Most cancer deaths are not the result of primary cancer development, but rather the result of its spread, a process called metastasis. Metastasis is a complex process where cancer cells leave the original tumor site, intravasate into the bloodstream, migrate to a distant organs and initiate invasive growth. Numerous studies have contributed to better understanding the underlying cellular and molecular processes of metastasis. It has become increasingly clear that inflammation can enhance tumor growth and tumor progression. ADAM17, as primary sheddase of transmembrane protein TNF-α, and sheddase of adhesion molecules, is required for recruitment of immune cells into the tissue and is implicated in inflammatory responses. It is also shown that the metalloprotease ADAM17 is responsible for cleavage of growth factor receptors and ligands of EGFR, which are necessary for tumor growth and proliferation. In the present study, it was investigated the importance of ADAM17 in the tumor stroma for metastatic progression and spread. To address this, we used Lewis Lung Carcinoma (LLC) cells and ADAM17 hypomorphic mice (ADAM17ex/ex mice) in a model of experimental metastasis. In an experimental metastasis model, tumor cells are injected via the tail vain. At different time points we analyzed the thickness of alveolar septa, infiltration of immune cells, cytokine and chemokine expression to determine the level of lung damage in control and hypomorphic mice. We could see that ADAM17ex/ex animals, that express low levels of ADAM17, had a much reduced tumor burden. The reduced metastatic growth was accompanied with reduced expression of inflammatory chemokines like e.g. MCP-1 and MIP-2. We observed a reduced infiltration of inflammatory cells, in particular Ly6G/Gr1+CD11b+ myeloid derived suppressor cells in ADAM17ex/ex mice. ADAM17ex/ex mice revealed significantly lower metastasis than ADAM17wt/wt mice at all followed time points. We demonstrated that ADAM17 in the host lung supports tumor growth via inflammatory and proliferatory stimuli.

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Stevanovic, Marija: Analysis of A Disintegrin and Metalloprotease 17 (ADAM17) in the metastatic niche of the lung. 2014.

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