High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐Ay mice

Teraoka, Naoya; Mutoh, Michihiro; Takasu, Shinji; Ueno, Tetsuo; Nakano, Kenji; Takahashi, Mami; Imai, Toshio; Masuda, S.; Sügimura, Takashi; Wakabayashi, Keiji

doi:10.1002/ijc.25711

Cited by 30 publications

(26 citation statements)

References 34 publications

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“…Teraoka et al (48) also demonstrated that an obese mouse model KK-A(y) that does have an intact leptin and leptin receptor has higher sensitivity to azoxymethane. However, caution must be applied in interpreting sensitivity to azoxymethane, as mouse strains do differ in sensitivity to this chemical dependent on liver metabolism and DNA repair mechanisms (49,50) .…”

Section: Adipokine Regulation Of Colon Tissuementioning

confidence: 98%

Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Drew

2011

Proc. Nutr. Soc.

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Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesityrelated colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer.

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Section: Adipokine Regulation Of Colon Tissuementioning

confidence: 98%

Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Drew

2011

Proc. Nutr. Soc.

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“…Specifically, Zucker obese rats, KK-Ay mice and HFD-fed mice all show an increased incidence of colon cancer following treatment with azoxymethane as compared to controls. 55,56 …”

Section: Obesity-related Inflammationmentioning

confidence: 99%

Obesity and cancer—mechanisms underlying tumour progression and recurrence

Park¹,

Morley²,

Kim³

et al. 2014

Nat Rev Endocrinol

629

521

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Over the past several years, the field of cancer research has directed increased interest towards subsets of obesity-associated tumours, which include mammary, renal, oesophageal, gastrointestinal and reproductive cancers in both men and women. The increased risk of breast cancer that is associated with obesity has been widely reported; this has drawn much attention and as such, warrants investigation of the key mechanisms that link the obese state with cancer aetiology. For instance, the obese setting provides a unique adipose tissue microenvironment with concomitant systemic endocrine alterations that favour both tumour initiation and progression. Major metabolic differences exist within tumours that distinguish them from non-transformed healthy tissues. Importantly, considerable metabolic differences are induced by tumour cells in the stromal vascular fraction that surrounds them. The precise mechanisms that underlie the association of obesity with cancer and the accompanying metabolic changes that occur in the surrounding microenvironment remain elusive. Nonetheless, specific therapeutic agents designed for patients with obesity who develop tumours are clearly needed. This Review discusses recent advances in understanding the contributions of obesity to cancer and their implications for tumour treatment.

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“…Moreover, there were no significant differences in mRNA levels of p27 and p53 between the middle and distal parts (data not shown). Comparing the numbers of ACF in AOM-treated lean C57BL/6J mice with those of KK-A y mice, KK-A y mice increased the number of ACF in the proximal and middle colon (Teraoka et al, 2011). However, the effect of pioglitazone on different portions of the colon in obese mice could not be explained.…”

Section: Discussionmentioning

confidence: 72%

“…Real-time PCR was carried out using a DNA Engine OpticonTM 2 (MJ Japan Ltd., Tokyo, Japan) with SYBR Green Real-time PCR Master Mix (Toyobo Co., Osaka, Japan). Primers for mouse adiponectin (5'-AGGATGCTACTGTTGCAAGCTCTC, (Teraoka et al, 2011;Niho et al, 2005;Turmelle et al, 2006;Xiao et al, 2009). To assess the specificity of each primer set, amplicons generated from the PCR reaction were analyzed for melting curves.…”

Section: Real-time Polymerase Chain Reaction Analysismentioning

confidence: 99%

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Suppressive Effect of Pioglitazone, a PPAR Gamma Ligand, on Azoxymethane-induced Colon Aberrant Crypt Foci in KK-A^уMice

Ueno¹,

Teraoka²,

Takasu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferatoractivated receptorγ (PPARγ) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-A y obesity and diabetes model mice, and tried to clarify mechanisms by which the PPARγ ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-A y mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer.

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High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice

Cited by 30 publications

References 34 publications

Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Obesity and cancer—mechanisms underlying tumour progression and recurrence

Suppressive Effect of Pioglitazone, a PPAR Gamma Ligand, on Azoxymethane-induced Colon Aberrant Crypt Foci in KK-A^уMice

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High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐Ay mice

Cited by 30 publications

References 34 publications

Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Obesity and cancer—mechanisms underlying tumour progression and recurrence

Suppressive Effect of Pioglitazone, a PPAR Gamma Ligand, on Azoxymethane-induced Colon Aberrant Crypt Foci in KK-AуMice

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High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice

Suppressive Effect of Pioglitazone, a PPAR Gamma Ligand, on Azoxymethane-induced Colon Aberrant Crypt Foci in KK-A^уMice