Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice

Gravaghi, Claudia; Bo, Jianhua; LaPerle, Krista; Quimby, Fred W.; Kucherlapati, Raju; Edelmann, Winfried; Lamprecht, Sergio A.

doi:10.1038/ijo.2008.149

Cited by 34 publications

(30 citation statements)

References 24 publications

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“…Popivanova et al demonstrated that blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis [47]. Gravaghi et al reported that obesity enhances gastrointestinal tumorigenesis in Apc -mutant mice [48]. Nevertheless, this study demonstrated that an obesity-associated inflammatory status in the colon, particularly the elevation of TNF-α, is associated with alterations of the critical Wnt pathway.…”

Section: Discussionmentioning

confidence: 75%

Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

Liu

Brooks

Ciappio

et al. 2012

The Journal of Nutritional Biochemistry

149

146

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Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity-induced elevation of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Animal studies were conducted on C57BL/6 mice, and obesity was induced by utilizing a high-fat diet (60% kcal). An inflammation-specific microarray was performed, and results were confirmed with real-time polymerase chain reaction. The array revealed that diet-induced obesity increased the expression of TNF-α in the colon by 72% (P=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-α protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3β), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-α, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3β was elevated in the colonic mucosa of obese mice (P<.02). Moreover, β-catenin, the key effector of canonical Wnt signaling, was elevated in the colons of obese mice (P<.05), as was the expression of a downstream target gene, c-myc (P<.05). These data demonstrate that diet-induced obesity produces an elevation in colonic TNF-α and instigates a number of alterations of key components within the Wnt signaling pathway that are protransformational in nature. Thus, these observations offer evidence for a biologically plausible avenue, the Wnt pathway, by which obesity increases the risk of colorectal cancer.

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Section: Discussionmentioning

confidence: 75%

Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

Liu

Brooks

Ciappio

et al. 2012

The Journal of Nutritional Biochemistry

149

146

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show abstract

“…While mild pathology was observed in Apc KO mice, tumor multiplicity and pathology was markedly increased in Apc KO– Pten KO animals (Fig. 3A, Table 2; P <0.05 ), with significant range in tumor multiplicity, which is a typical observation of aggressive, Apc -deficient tumor models (Gravaghi et al 2008; Huffman et al 2013; Taketo and Edelmann 2009). Furthermore, no deaths were observed in WT, Pten KO, Apc Het or Apc KO mice over 16 wks, with the latter observation contrary to prior reports of rapid mortality in Lgr5+ specific, Apc KO mice (Holik et al 2014).…”

Section: Resultsmentioning

confidence: 87%

“…Obesity and diet are also strong regulators of CRC risk and progression in humans (Bardou, et al 2013; Cheskin and Prosser 2007; Giovannucci and Michaud 2007; Kim, et al 2006; Pischon, et al 2006; Schlesinger, et al 2015), and intestinal tumor development in rodent models (Beyaz, et al 2016; Day, et al 2013; Gravaghi, et al 2008; Hata, et al 2011; Huffman, et al 2013; Pettan-Brewer, et al 2011). Even prior to tumor initiation, obesity appears to ‘prime’ the normal intestinal epithelium toward tumor development, by promoting proliferation of ISCs and hypertrophy of the epithelium (Mao, et al 2013), while also altering the epigenomic landscape of the colonic epithelium in a manner resembling cancer progression (Li, et al 2014).…”

Section: Introductionmentioning

confidence: 99%

“…More recently, diet-induced obesity was found to increase the number and function of Lgr5+ ISCs, while also promoting stemness and tumorigenicity of progenitor cells after inactivation of Apc (Beyaz et al 2016). Although obesity can clearly instigate processes related to increase tumor risk, as well as accelerate intestinal tumorigenesis following loss of Apc in ISCs and epithelium (Beyaz et al 2016; Day et al 2013; Gravaghi et al 2008; Hata et al 2011; Huffman et al 2013; Pettan-Brewer et al 2011), whether obesity can promote Lgr5+-ISC-derived tumorigenesis via non-canonical mechanisms involving PI3K signaling (Huang and Chen 2009; Vucenik and Stains 2012), has not been investigated. Here we demonstrate that while obesity can modify the transcriptome of Lgr5+-ISCs and expression of specific metabolic pathways, it fails to alter genes related to the Akt signaling and other proliferative pathways in Lgr5+-ISCs.…”

Section: Introductionmentioning

confidence: 99%

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Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis

Tabrizian

Wang

Guan

et al. 2017

Endocrine-Related Cancer

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Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis following inactivation of Apc. However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 mo and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP Ptenflox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14–15 mo of age. Finally, various combinations of Lgr5+-ISC specific, Apc and Pten-deleted mice were generated, and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU positive cells in the small intestine (P<0.05). However, combining Pten and Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion (P<0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that Pten deficiency, is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining Pten and Apc deficiency in ISCs synergistically increases proliferation, tumor formation, and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ISC-derived tumorigenesis.

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“…33 In our study, obese mice exhibited approximately twofold higher colonic tumor numbers as compared with normal mice, suggesting an excess supply of energy and that the increased adipose tissue is possibly related to the abnormal cell proliferation of the colon tissue in vivo. Recent studies have suggested that obesity facilitates colon tumor formation in adiponectin-gene-deficient mice, 34 APC-genedeficient mice 35 and leptin-gene-deficient mice. 36 However, animal models of specific gene-deficient mice may exhibit different molecular mechanisms for developing tumors from those observed in diet-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice

et al. 2011

Int J Obes

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Objective: Studies have indicated that obesity is associated with a higher risk of colorectal cancer. This study was performed to determine the effect of diet-induced obesity on the formation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumors and to identify adiposity-related mechanisms. Methods: Male A/J mice were placed on either a high-fat diet (HFD; 45% of total calories from fat) or a normal diet (ND; 15% of calories from fat) for 12 weeks. To induce colon tumors, AOM was administered at a dose of 10 mg/kg body weight, followed by two cycles of DSS supply. Results: Study results indicated that the HFD group had twofold higher numbers of colonic tumors, as compared with the ND group. The HFD group also had significantly increased body weight and epididymal fat weight, which were associated with increases of serum insulin, insulin-like growth factor-1, leptin, epididymal fat pad leptin mRNA and colonic leptin receptor (Ob-R) mRNA. Animals on HFD showed higher expressions of Ob-R, insulin receptor, phosphorylated Akt, phosphorylated extracellular signal-regulated kinases, Bcl-xL and Cyclin D1 proteins in the colon. Conclusion:The results suggest that HFD-induced obesity facilitates colon tumor formation, possibly by regulating downstream targets of circulating adiposity-related factors via receptor-mediated signaling of the phosphatidylinositol 3-kinase/Akt pathway.

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Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice

Cited by 34 publications

References 24 publications

Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis

Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice

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