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HIF1α deficiency reduces inflammation in a mouse model of proximal colon cancer.

Mladenova DN, Dahlstrom JE, Tran PN, Benthani F, Bean EG, Ng I, Pangon L, Currey N, Kohonen-Corish MR - Dis Model Mech (2015)

Bottom Line: Microscopically, Hif1α(ΔIEC) mice had significantly less severe colon inflammation than Hif1α(F/F) mice.Molecular analysis showed reduced MIF expression and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1α(ΔIEC) mice.Taken together, HIF1α expression augments inflammation in the proximal colon of sulindac-treated mice, and AHR activation by sulindac might lead to the reduction of E-cadherin protein levels through the mitogen-activated protein kinase (MAPK) pathway.

View Article: PubMed Central - PubMed

Affiliation: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, 2010, Australia.

No MeSH data available.


Related in: MedlinePlus

Photomicrographs of sulindac-diet-induced colon inflammation and cancer. (A) Hematoxylin and eosin (H&E)-stained sections of proximal colon from the P2 region of a control-fed Hif1αF/F mouse that appeared to be macroscopically normal. (B) Mild-active moderate chronic inflammation in a proximal lesion harvested from a sulindac-treated Hif1αΔIEC mouse. The inflammation is confined to the mucosa and submucosa. Yellow arrows indicate mucosal inflammation. Green arrows indicate submucosal inflammation. (C) Well-differentiated mucinous adenocarcinoma arising in an area of moderate-active moderate chronic inflammation with mucosal erosion in a Hif1αΔIEC mouse. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate mucosal erosion. (D) Well-differentiated adenocarcinoma extending into the muscularis propria arising in an area of moderate-active severe chronic inflammation in a Hif1αF/F mouse. Note the inflammation extends into the adventia. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate adventitial inflammation.
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DMM019000F2: Photomicrographs of sulindac-diet-induced colon inflammation and cancer. (A) Hematoxylin and eosin (H&E)-stained sections of proximal colon from the P2 region of a control-fed Hif1αF/F mouse that appeared to be macroscopically normal. (B) Mild-active moderate chronic inflammation in a proximal lesion harvested from a sulindac-treated Hif1αΔIEC mouse. The inflammation is confined to the mucosa and submucosa. Yellow arrows indicate mucosal inflammation. Green arrows indicate submucosal inflammation. (C) Well-differentiated mucinous adenocarcinoma arising in an area of moderate-active moderate chronic inflammation with mucosal erosion in a Hif1αΔIEC mouse. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate mucosal erosion. (D) Well-differentiated adenocarcinoma extending into the muscularis propria arising in an area of moderate-active severe chronic inflammation in a Hif1αF/F mouse. Note the inflammation extends into the adventia. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate adventitial inflammation.

Mentions: We then analysed the mucosal surface microscopically by scoring the severity of inflammation, depth of inflammation and crypt damage, which were combined to produce a total inflammation score. Hif1αΔIEC mice had significantly less-severe colon inflammation in the mucosa between lesions in the P2 region compared with mice from the control genotype (Fig. 1B,C), including the score for crypt damage and the total inflammation score (P<0.05). Based on the histological score, the most severely inflamed lesion for each mouse was chosen for further analysis, and there was a trend for lower total inflammation scores in the Hif1αΔIEC mice compared with Hif1αF/F mice (P=0.057; Fig. 1D). As in our previous experiment, a subset of sulindac-induced lesions in the colon progressed to adenocarcinoma. The inflammatory microenvironment is rich in mutagenic reactive oxygen species and pro-inflammatory factors that can promote cancer initiation and growth, and lead to tissue remodelling (Mladenova and Kohonen-Corish, 2012). Surprisingly, the frequency of colon adenocarcinoma was similar in Hif1αΔIEC (18%; two out of 11) and Hif1αF/F mice (16%; four out of 25) although there was less mucosal inflammation in the Hif1αΔIEC mice. The distribution of total inflammation scores in neoplastic and non-neoplastic lesions is shown in Fig. 1E. The photomicrographs in Fig. 2 and supplementary material Figs S1 and S2 show some of the typical pathological changes observed in the proximal colon of sulindac-treated mice, ranging from mild inflammation with no neoplasia to moderate and severe inflammation with dysplasia and adenocarcinoma. A subset of sulindac-fed mice also developed small foci of acute or chronic hepatitis. Sulindac is a rare but known cause of hepatitis in humans (Wood et al., 1985).Fig. 2.


HIF1α deficiency reduces inflammation in a mouse model of proximal colon cancer.

Mladenova DN, Dahlstrom JE, Tran PN, Benthani F, Bean EG, Ng I, Pangon L, Currey N, Kohonen-Corish MR - Dis Model Mech (2015)

Photomicrographs of sulindac-diet-induced colon inflammation and cancer. (A) Hematoxylin and eosin (H&E)-stained sections of proximal colon from the P2 region of a control-fed Hif1αF/F mouse that appeared to be macroscopically normal. (B) Mild-active moderate chronic inflammation in a proximal lesion harvested from a sulindac-treated Hif1αΔIEC mouse. The inflammation is confined to the mucosa and submucosa. Yellow arrows indicate mucosal inflammation. Green arrows indicate submucosal inflammation. (C) Well-differentiated mucinous adenocarcinoma arising in an area of moderate-active moderate chronic inflammation with mucosal erosion in a Hif1αΔIEC mouse. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate mucosal erosion. (D) Well-differentiated adenocarcinoma extending into the muscularis propria arising in an area of moderate-active severe chronic inflammation in a Hif1αF/F mouse. Note the inflammation extends into the adventia. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate adventitial inflammation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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DMM019000F2: Photomicrographs of sulindac-diet-induced colon inflammation and cancer. (A) Hematoxylin and eosin (H&E)-stained sections of proximal colon from the P2 region of a control-fed Hif1αF/F mouse that appeared to be macroscopically normal. (B) Mild-active moderate chronic inflammation in a proximal lesion harvested from a sulindac-treated Hif1αΔIEC mouse. The inflammation is confined to the mucosa and submucosa. Yellow arrows indicate mucosal inflammation. Green arrows indicate submucosal inflammation. (C) Well-differentiated mucinous adenocarcinoma arising in an area of moderate-active moderate chronic inflammation with mucosal erosion in a Hif1αΔIEC mouse. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate mucosal erosion. (D) Well-differentiated adenocarcinoma extending into the muscularis propria arising in an area of moderate-active severe chronic inflammation in a Hif1αF/F mouse. Note the inflammation extends into the adventia. Blue arrows indicate islands of adenocarcinoma. Green arrows indicate adventitial inflammation.
Mentions: We then analysed the mucosal surface microscopically by scoring the severity of inflammation, depth of inflammation and crypt damage, which were combined to produce a total inflammation score. Hif1αΔIEC mice had significantly less-severe colon inflammation in the mucosa between lesions in the P2 region compared with mice from the control genotype (Fig. 1B,C), including the score for crypt damage and the total inflammation score (P<0.05). Based on the histological score, the most severely inflamed lesion for each mouse was chosen for further analysis, and there was a trend for lower total inflammation scores in the Hif1αΔIEC mice compared with Hif1αF/F mice (P=0.057; Fig. 1D). As in our previous experiment, a subset of sulindac-induced lesions in the colon progressed to adenocarcinoma. The inflammatory microenvironment is rich in mutagenic reactive oxygen species and pro-inflammatory factors that can promote cancer initiation and growth, and lead to tissue remodelling (Mladenova and Kohonen-Corish, 2012). Surprisingly, the frequency of colon adenocarcinoma was similar in Hif1αΔIEC (18%; two out of 11) and Hif1αF/F mice (16%; four out of 25) although there was less mucosal inflammation in the Hif1αΔIEC mice. The distribution of total inflammation scores in neoplastic and non-neoplastic lesions is shown in Fig. 1E. The photomicrographs in Fig. 2 and supplementary material Figs S1 and S2 show some of the typical pathological changes observed in the proximal colon of sulindac-treated mice, ranging from mild inflammation with no neoplasia to moderate and severe inflammation with dysplasia and adenocarcinoma. A subset of sulindac-fed mice also developed small foci of acute or chronic hepatitis. Sulindac is a rare but known cause of hepatitis in humans (Wood et al., 1985).Fig. 2.

Bottom Line: Microscopically, Hif1α(ΔIEC) mice had significantly less severe colon inflammation than Hif1α(F/F) mice.Molecular analysis showed reduced MIF expression and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1α(ΔIEC) mice.Taken together, HIF1α expression augments inflammation in the proximal colon of sulindac-treated mice, and AHR activation by sulindac might lead to the reduction of E-cadherin protein levels through the mitogen-activated protein kinase (MAPK) pathway.

View Article: PubMed Central - PubMed

Affiliation: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, 2010, Australia.

No MeSH data available.


Related in: MedlinePlus