This collaborative project will investigate the role of necrosis, hypoxia and inflammation in cancer development, focusing on individual and interdependent contributions to tumor promotion and progression. We will test two related hypotheses that are based on preliminary results obtained in a model of chemically- induced liver cancer. 1. Inhibition of NF-kappaB activity in epithelial cells or carcinomas, brought about by certain cytokines or persistent NO production, can dismantle antioxidant defenses and lead to accumulation of reactive oxygen species (ROS). The latter can induce necrotic cell death through prolonged Jun kinase (JNK) activation. The necrotic death of premalignant hepatocytes during early tumor promotion and necrosis of nutrient- and oxygen-starved cancer cells during tumor progression trigger a localized inflammatory response that further augments tumor promotion and progression. 2. As solid tumors grow beyond a critical size they exhaust available supplies of oxygen, energy, nutrients and growth factors. Decreased oxygen supply results in tumor hypoxia and activation of the HIF-1 transcription factor in both cancer cells and tumor- and tissue-associated macrophages. Necrosis, causing the release of normal cellular constituents, leads to activation of tumor-infiltrating macrophages and triggers an inflammatory response dependent on transcription factor NF-kappaB. Within inflammatory cells, HIF-1 and NF-kappaB collaborate to induce expression of growth and angiogenesis factors that increase tumor blood supply and stimulate tumor growth and progression. We propose that this constant cycle of tumor growth, tumor starvation, hypoxia and necrosis, tumor-induced activation of inflammatory cells and re-stimulation of tumor growth and angiogenesis is a major and critical contributor to cancer progression. We will test these hypotheses in a mouse model of hepatocellular carcinoma (HCC) that allows critical evaluation of effects on tumor promotion, progression, and angiogenesis. Mouse molecular genetics will be used to dissect the different mechanisms involved in tumor-driven inflammation and ROS accumulation and determine their contribution to early tumor promotion as well as to tumor progression and angiogenesis. While providing new information on the role of inflammation in carcinogenesis and tumor progression, this work can lead to development of chemopreventive and therapeutic strategies based on inhibition of necrosis-induced inflammation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA118165-02S1
Application #
7685838
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ogunbiyi, Peter
Project Start
2007-04-01
Project End
2012-02-29
Budget Start
2008-02-29
Budget End
2009-02-28
Support Year
2
Fiscal Year
2008
Total Cost
$53,343
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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