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Banerjea, Ayan; Ahmed, Shafi; Hands, Rebecca; Huang, Fei; Han, Xia; Shaw, Peter M.; Feakins, Roger; Bustin, Stephen A.; Dorudi, Sina

doi:10.1186/1476-4598-3-21

Cited by 136 publications

(41 citation statements)

References 29 publications

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“…6 Interestingly, in these good-outcome patients, there was also an increase in the immune cells infiltrating the tumor. 14,[23][24][25][26] In this work, we demonstrated that these two events associated with a good CRC prognosis (i.e., HSP110 expression and tumor immunosurveillance) may be linked. Indeed, we showed that HSP110 is secreted by CRC cells and skews the macrophage inflammatory profile.…”

Section: Discussionmentioning

confidence: 94%

Extracellular HSP110 skews macrophage polarization in colorectal cancer

et al. 2016

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HSP110 is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps the cells to survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently showed that colorectal cancer (CRC) patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110 inactivating mutation (HSP110DE9). In this work, we have used patients' biopsies and human CRC cells grown in vitro and in vivo (xenografts) to demonstrate that (1) HSP110 is secreted by CRC cells and that the amount of this extracellular HSP110 is strongly decreased by the expression of the mutant HSP110DE9, (2) Supernatants from CRC cells overexpressing HSP110 or purified recombinant human HSP110 (LPS-free) affect macrophage differentiation/polarization by favoring a pro-tumor, anti-inflammatory profile, (3) Conversely, inhibition of HSP110 (expression of siRNA, HSP110DE9 or immunodepletion) induced the formation of macrophages with a cytotoxic, pro-inflammatory profile. (4) Finally, this effect of extracellular HSP110 on macrophages seems to implicate TLR4. These results together with the fact that colorectal tumor biopsies with HSP110 high were infiltrated with macrophages with a pro-tumoral profile while those with HSP110 low were infiltrated with macrophages with a cytotoxic profile, suggest that the effect of extracellular HSP110 function on macrophages may also contribute to the poor outcomes associated with HSP110 expression.

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Section: Discussionmentioning

confidence: 94%

Extracellular HSP110 skews macrophage polarization in colorectal cancer

et al. 2016

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“…Compared to their microsatellite-stable counterparts, MSI+ CRCs have a heightened immune response that is evident macroscopically and at the molecular level [13]. This tumour-specific immune response is caused by antigenic MSI-induced frameshift mRNAs and/or peptides [14,15].…”

Section: Resultsmentioning

confidence: 99%

Bacterially-Associated Transcriptional Remodelling in a Distinct Genomic Subtype of Colorectal Cancer Provides a Plausible Molecular Basis for Disease Development

2016

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The relevance of specific microbial colonisation to colorectal cancer (CRC) disease pathogenesis is increasingly recognised, but our understanding of possible underlying molecular mechanisms that may link colonisation to disease in vivo remains limited. Here, we investigate the relationships between the most commonly studied CRC-associated bacteria (Enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, Fusobacterium spp., afaC+ E. coli, Enterococcus faecalis & Enteropathogenic E. coli) and altered transcriptomic and methylation profiles of CRC patients, in order to gain insight into the potential contribution of these bacteria in the aetiopathogenesis of CRC. We show that colonisation by E. faecalis and high levels of Fusobacterium is associated with a specific transcriptomic subtype of CRC that is characterised by CpG island methylation, microsatellite instability and a significant increase in inflammatory and DNA damage pathways. Analysis of the significant, bacterially-associated changes in host gene expression, both at the level of individual genes as well as pathways, revealed a transcriptional remodeling that provides a plausible mechanistic link between specific bacterial colonisation and colorectal cancer disease development and progression in this subtype; these included upregulation of REG3A, REG1A and REG1P in the case of high-level colonization by Fusobacterium, and CXCL10 and BMI1 in the case of colonisation by E. faecalis. The enrichment of both E. faecalis and Fusobacterium in this CRC subtype suggests that polymicrobial colonisation of the colonic epithelium may well be an important aspect of colonic tumourigenesis.

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“…This may be explained, in part, by the absence of a probeset specific for ascl2 in the earlier Affymetrix GeneChips. However, recently Banerjea et al (2004) observed that the mean expression of ascl2 was 4.3-fold greater in microsatellite stable colorectal cancers compared to cancers with high-level microsatellite instability using Affymetrix HG-U133 GeneChips. To our knowledge, this is the only publication to date that specifically cites ascl2 expression in colorectal cancers and provides external validation for our findings.…”

Section: Discussionmentioning

confidence: 98%

Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia

Jubb

Chalasani²,

Frantz³

et al. 2006

Oncogene

121

112

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Achaete-scute like (ASCL)2 is a basic helix-loop-helix transcription factor essential for the maintenance of proliferating trophoblasts during placental development. Using oligonucleotide microarrays we identified ascl2 as a gene significantly upregulated in colorectal adenocarcinomas (n ¼ 36 cancers, n ¼ 16 normals; 15-fold, Po0.0001). This finding was confirmed by quantitative reverse transcriptase (RT)-PCR on large intestinal cancers (n ¼ 29 cancers, n ¼ 16 normals; 10-fold, Po0.0001).In situ hybridization for ascl2 demonstrated expression at the base of small and large intestinal crypts (n ¼ 304), but in no other normal tissues excepting placenta. By in situ hybridization, 52-71% of colorectal adenomas (n ¼ 187), 50-73% of large (n ¼ 327) and 33-64% of small intestinal adenocarcinomas (n ¼ 124) were positive for ascl2 expression. Upregulation of murine ascl2 was also observed using oligonucleotide microarrays, quantitative RT-PCR and in situ hybridization on apc min/ þ and apc 1638N/ þ smad4 À/ þ tumours. Tumour cell lines stably transfected with LEF1 DN or APC2, or transiently transfected with short-interfering RNA (siRNA) against b-catenin showed a significant downregulation of ascl2. Colocalization of ascl2 with nuclear b-catenin was observed in 73 small intestinal adenocarcinomas (P ¼ 0.0008) and apc min/ þ tumours. Preliminary in vitro data suggest ascl2 may promote progression through the G2/M cell cycle checkpoint. In summary, ascl2 is a putative regulator of proliferation that is overexpressed in intestinal neoplasia.

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Cited by 136 publications

References 29 publications

Extracellular HSP110 skews macrophage polarization in colorectal cancer

Extracellular HSP110 skews macrophage polarization in colorectal cancer

Bacterially-Associated Transcriptional Remodelling in a Distinct Genomic Subtype of Colorectal Cancer Provides a Plausible Molecular Basis for Disease Development

Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia

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