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Review
. 2012 May-Jun;3(3):176-85.
doi: 10.4161/gmic.20288. Epub 2012 May 1.

Microbes-induced EMT at the crossroad of inflammation and cancer

Paul Hofman  1 , Valérie Vouret-Craviari
Affiliations
Review

"VSports手机版" Microbes-induced EMT at the crossroad of inflammation and cancer

Paul Hofman et al. Gut Microbes. 2012 May-Jun.

Abstract

It is noteworthy that bacterial or viral infections, and the resulting chronic inflammation, have been shown to predispose individuals to certain types of cancer. Remarkably, these microbes upregulated some transcription factors involved in the regulation of the epithelial to mesenchymal transition, referred herein as EMT VSports手机版. EMT is a cellular process that consists in the conversion of epithelial cell phenotype to a mesenchymal phenotype. Under physiological conditions EMT is clearly important for embryogenesis, organ development, wound repair and tissue remodeling. However, EMT may also be activated under pathologic conditions, more particularly in carcinogenesis and metastatic progression. In this review, we make a parallel between microbes- and growth factors- induced transcription factors. A unifying EMT model then emerges that may help in understanding the development of microbial pathogenesis and in defining new potential future therapeutic strategy in treating diseases linked to infections. .

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Figures

Figure 1.
Figure 1.
A basic view of epithelial to mesenchymal transition. EMT is a highly conserved and fundamental process that governs morphogenesis in multicellular organisms. EMT is the result of a transcriptional repression of E-cadherin gene leading to the loss of the epithelial phenotype and the remodeling of the actin cytoskeleton associated to the mesenchymal phenotype. EMT plays an important role in the emergence and progression of carcinoma by allowing carcinoma cells scattering. This cellular process is reversible; at secondary sites, solitary carcinoma cells can extravasate and form a new carcinoma trough a mesenchymal to epithelial transition (MET).
Figure 2.
Figure 2.
The transcription factors that govern EMT. The core EMT regulatory factors are composed of Helix Loop Helix (blue) and zing-finger DNA binding proteins. The green boxes represent zing-finger clusters. Homeo domains of the ZEB transcription factor family is represented as hatched circle and the Slug domain of SNAI2/Slug1 is represented as a gray motif. Once in the nucleus these transcription factors downregulate E-cadherin expression. The SNAI family of transcription factors can also activate vimentin and fibronectin expression and control the membrane basement 
degradation.
Figure 3.
Figure 3.
A schematic view of PPR-induced pathways involved in stimulation of NFκB and MAPK signaling. TLRs (TLR1, TLR2, TLR4, TLR5, TLR6, TLR7 and TLR9) do activate IKK and MAPK modules by binding of MyD88 to the receptor TIR domain and subsequently triggering IRAK, TRAF6 and TAK1. Alternatively, TIRAP (TIR domain-containing adaptor protein), a second TIR-domain-containing adaptor protein, is involved in the MyD88-dependent signaling pathway through TLR2 and TLR4. A third TIR-domain-containing adaptor, TRIF (TIR domain-containing adaptor protein inducing IFNβ), is essential for the MyD88-independent pathway. Further, the non-typical IKKs IKKε and TBK1 [TRAF-family-member-associated NFκB activator (TANK)-binding kinase 1] mediate activation of IRF3 downstream of TRIF. A fourth TIR-domain containing adaptor, TRAM (TRIF-related adaptor molecule), is specific to the TLR4-mediated, MyD88-independent/TRIF-dependent pathway. By contrast, activation of NLRs leads to the recruitment of the receptor-interacting protein 2 (RIP2) kinase, which is essential for the activation of the IKK complex. In addition, activation of NOD1 leads to JNK stimulation. Finally, double strand DNA has been linked to inflammasome activation. This protein complex, which is composed of NLRs of the NALP-family and adaptor-proteins apoptosis-associated speck-like protein (ASC), mediates the generation of IL-1β through cleavage of its precursor by caspase-1. Upon IKK complex activation, NFκB is freed and consequently translocate to the nucleus where it can bind to the promoter of its targeted genes. Similarly, once activated, ERK, JNK and p38 kinase translocate to the nucleus where they phosphorylate their respective transcription factors and therefore modulated gene expression. TLRs are connected to the PI3K/Akt pathway. Indeed, depending of the TLRs and the cells, PI3K has been shown to modulate transcription factor activities and cytokine production. Up to date, the molecular link between TLRs and PI3K are still unknown.
Figure 4.
Figure 4.
Microbe-induced chronic inflammation in predisposed individuals leads to EMT. Here we suggest a model in which microbe infection plays a critical role as an EMT promoter. In healthy individuals, microbe infection is contained by the innate immunity. By contrast in predisposed individuals the innate immunity is exceeded by microbe infection leading to chronic inflammation. Chronic inflammation, associated to chronic infection lead to sustained NFκB and MAPK module activation: the basement of EMT. Finally, EMT plays a critical role in onset of various human pathologies such as fibrinogenesis, cancer progression and metastasis.
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