Superfund Research Program

Effects of Superfund Toxicants on Liver Cancer Progenitor Cells

Project Leader: Michael Karin
Grant Number: P42ES010337
Funding Period: 2000-2017

Project-Specific Links

Final Progress Reports

Year:   2016  2009  2004 

The Karin group (Project 1) has demonstrated a critical role for inflammation and the inflammation-activated transcription factor NF-κB in chemical carcinogenesis.  Although a link between inflammation and cancer has been suspected for over 2,000 years, a mechanistic link between the two remained elusive.  Using cell-type specific descriptions of the gene for IκB kinaseβ (IKKβ) and mouse models of colitis associated cancer (CAC), the Karin group was able to demonstrate a critical role for IKKκ-driven NF-κB activation in linking inflammation to tumor development.

In the CAC model, mice are given a procarcinogen-azoxymethane (AOM), which is metabolically activated to induce oncogenic mutations in intestinal epithelial cells.  This alone, however, is not sufficient and AOM-treated mice need to also be subjected to colonic inflammation, which can be induced by the irritant dextrane sodium salt (DSS), given in drinking water.  The Karin group has shown that the major function of NF-κB is during the tumor promotion step, where it prevents the death of initiated cells and stimulates their proliferation.  These functions of NF-κB are carried out in different cell types.  In intestinal epithelial cells, it leads to activation of anti-apoptotic genes, for instance Bcl-X_L, which prevents the death of initiated cells, which otherwise could be eliminated through surveillance mechanisms.  In myeloid cells (macrophages), NF-κB leads to proliferation of growth factors such as IL-6, which stimulate the proliferation of initiated epithelial cells.  It is the concerted action of NF-κB in these different cell types that ultimately drives the development of CAC.

The Karin group has also used a model of chemically-induced liver cancer to further demonstrate the critical role of NF-κB activation in myeloid cells for production of growth factors that stimulate the proliferation of oncogenically initiated cells.  In addition, they have shown that NF-κB is an important regulator of anti-oxidant genes and that one of its most important pro-survival functions depends on inhibition of reactive oxygen species (ROS) accumulation.