Inflammation And Cancer Flashcards
Karin suggests that NF-kB activation in cancer may be the result of either:
1) exposure to proinflammatory stimuli in the tumor microenvironment, or
2) mutational activation of upstream components in IKK-NFkB signaling pathways
Oncogenic mutations that endow RelA, c-Rel or other NF-kB were to found rare and mainly limited to
Lymphoid malignancies
With respect to tumor progression, NF-kB can:
1) Inhibit apoptosis
2) stimulate cell proliferation
3) Promote a migratory and invasive phenotype
The first hint to a link between NF-kB and cancer had emerged with the cloning of RelA and the realization of its close kinship to
The viral oncoprotein v-Rel and its cellular homolog c-Rel
Colitis-associated cancer (CAC) appears in patients suffering from
Ulcerative colitis
The mouse model for CAC, mice are given
azoxymethane (AOM) that can give use to oncogenic mutations such activation of B catenin
B-catenin is the most commonly activated oncogene in
Colon cancer
Azoxymethane (AOM) alone produce a small number of large bowel adenomas, which can be strongly augmented through colonic inflammation by repeated administration of the irritant
Dextrane sulfate sodium (DSS)
In the mice model using AOM and DSS and conditional disruption of IKKB, make them found that IKKB driven NF-kB activation in intestinal epithelial cells (IEC) is essential for the development of
Colonic adenomas
The oncogenic role of NFkB appears to be mediated through its
Antiapoptotic functions, mainly through induction of Bcl-Xl
In addition to anti apoptosis function IKKB driven NFkB contribute to CAC by stimulating the proliferation of malignant IEC through
The secretions of growth factors by myeloid cells, most likely within lamina propia macrophages.
During CAC development, IL6 is mainly produced by
Lamina propia macrophages and dendritic cells.
IL6 have effects both
Proliferative and the survival of IEC
Proliferative and the survival effect of IL6 on IEC are mediated through activation of
STAT3 transcription factor
Ablation of STAT3 in IEC dramatically compromised IEC survival and greatly reduced CAC growth, which suggest that some of protumorigenic effects of NFkB activation in myeloid cells could by caused by
Paracrine signaling to STAT3 in IEC
In addition to IL6 other cytokines contribute to Proliferative and prosurvival effects of myeloids cells NFkB on premalignant IEC:
IL-22, IL-11, IL-12 IL 23 and EGF family members.
Hageman 2008 found that inhibition of NFkB activity in tumor associated macrophages (TAM) through the conditional delection of IKKB:
Re-educated these immunosuppressive and protumorigenic cells to acquire a cytotoxic, antitumorigenic phenotype.
Another tumor promoting function exerted by IKKB and NFkB in TAM is the maintenance of a tumor suppressive phenotype characterized by
Low levels of inducible NO synthase (iNOS) and IL12 expression, and high levels of IL-10, TNF alpha, and arginase-1
Inhibition of NFkB in TAM result in
Up regulation of iNOS and IL-12, leading to elevated production of tumoricidal NO and enhanced activation of NK cell-mediated antitumorigenic immunity, respectively.
Hepatocelular carcinoma (HCC) is the most common form of liver cancer. It develops in context of
Chronic viral hepatitis, either HBV or HCV
Mices don’t develop HBV or HCV infection. Mice model Mdr2 -/- knockout mouse develops
Hepatoesteatosis caused by defective phospholipid and bile acid export, which leads to low grade hepatitis, and eventually HCC.
There are two mechanism by which NFkB exert its tumor promoting function in Mdr2 -/- mice:
1) the mayor mechanism is suppression of apoptosis
2) A role of hepatocyre NFkB in the maintenance of chronic inflammation
If procarcinogenic dyethylnitrosamine (DEN) is injected into two weeks old mice, it acts as carcinogenic without inflammation. However, DEN induced HCC requires NFkB activation in
Myeloids cells, in this case Kupffer cells, the resident liver macrophages
As found in CAC, DEN induced HCC requires the NFkB dependent production of
IL-6 by Kupffer cells and activation of STAT3 by IL-6 in hepatocytes
DEN induced HCC is strongly enhanced by activation in hepatocytes through the targeted delection of
IKKB. It’s also seen upon the conditional delection of hepatocytes IKKy/NEMO (in this case spontaneous develop hepatosteatosis, hepatitis, liver fibrosis and HCC without any injection of carcinogen.
Enhanced chemical hepatocarcinogenic was also observed in hepatocyte-specific p38alpha knockout mice. Mice lacking IKKB or p38alpha exhibit greatly enhanced accumulation of
Reactive oxygen species (ROS) in zone 3 after DEN exposure.
The major cause of enhanced HCC in IKKy, p38, IKKy knockout mouse is
The compensatory proliferation, driven by circles of injury and regenerations, rather than low grade chronic inflammation.
