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