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NF-kB mediated inflammation in tobacco-induced lung cancer

Institution: University of California, San Diego
Investigator(s): Michael Karin, Ph.D.
Award Cycle: 2006 (Cycle 15) Grant #: 15RT-0197 Award: $420,000
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
Chronic exposure to tobacco smoke leads to a large increase in the risk of development of lung cancer. It is well established that tobacco smoke contains chemicals that cause cancer, called carcinogens. Carcinogens act by causing damage to DNA and consequently a variety of genetic alterations. However, not every individual that has been exposed to the same amount of carcinogens through tobacco smoking develop lung cancer. Also some people suffer from lung cancer after a few years of smoking, while others develop cancer only after many years of heavy smoking. Thus additional factors, other than exposure to carcinogens, strongly modulate and affect the development of lung cancer. Based on previous work done in our laboratory we propose that one such additional factor is inflammation. We have shown that activation of inflammatory cells (such as macrophages and other phagocytes) makes an important and considerable contribution to the development of chemically-induced colon cancer and liver cancer. It is well established that tobacco smoke is full of irritants and various particles that can trigger an inflammatory response. Indeed, prolonged cigarette consumption results in chronic airway and lung inflammation. This inflammation can activate a regulatory protein called NF-B that promotes the production of various growth factors and protects pre-malignant cells from surveillance mechanisms that keep the incidence of cancer low by killing cells that suffered DNA damage as a result of carcinogen exposure. We have previously shown that NF-B plays a critical role in the development of colon and liver cancer and now we propose to examine its role in the development of lung cancer. We will use a mouse model of lung cancer in which cancer is induced by exposure to carcinogens and tobacco smoke. Genetic technology will be used to prevent the activation of NF-B in either the epithelial cells of the lung or in inflammatory cells and the consequences of these manipulations on the development of lung cancer will be determined. We will also investigate the molecular mechanisms through which NF-B contributes to cancer development in this model. These studies will provide us with critical and important information on the role of inflammation in lung cancer and should lay the foundations for new interventional strategies.

The p53-regulated sestrin gene products inhibit in TOR signaling.
Periodical: Cell Index Medicus:
Authors: Budanov AV, Karin M ART
Yr: 2008 Vol: 134 Nbr: Abs: Pg: 451-460

Carcinoma produced factors activate myeloid cells via TLR2 to stimulate metastasis.
Periodical: Nature Index Medicus:
Authors: Kim S, Takahashi H, Lin W, Descargues P, Grivennikov S, Kim Y, Luo J, Karin M. ART
Yr: 2009 Vol: 457 Nbr: Abs: Pg: 102-106