Circulating Levels of Inflammatory Cytokines and Risk of Colorectal Adenomas

Kim, Sangmi; Keku, Temitope O.; Martin, Christopher F.; Galanko, Joseph A.; Woosley, John T.; Schroeder, Jane C.; Satia, Jessie A.; Halabi, Susan; Sandler, Robert S.

doi:10.1158/0008-5472.can-07-2924

Cited by 254 publications

(221 citation statements)

References 43 publications

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“…Our findings for colorectal adenoma agree with the results of a cross-sectional study in which Kim and colleagues (16) found a positive association with the highest tertiles of IL-6 compared with the lowest tertiles. In that study, however, the levels of IL-6 were below the detection limit (<0.104 pg/mL) in about 50% of the individuals with colorectal adenoma and 65% of the controls, and thus no clear difference in the IL-6 level was demonstrable between the groups.…”

Section: Discussionsupporting

confidence: 92%

“…To our knowledge, only two previous studies have investigated the relationship between the circulating level of IL-6 and the risk of colorectal adenoma (16,17). Our findings for colorectal adenoma agree with the results of a cross-sectional study in which Kim and colleagues (16) found a positive association with the highest tertiles of IL-6 compared with the lowest tertiles.…”

Section: Discussionsupporting

confidence: 90%

“…One study has shown a positive association between the circulating level of IL-6 and the risk of colorectal adenoma (16), whereas another study has found no such association (17).…”

Section: Introductionmentioning

confidence: 99%

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Serum Interleukin-6, Insulin, and HOMA-IR in Male Individuals with Colorectal Adenoma

Sasaki

Takeda

Satô

et al. 2012

Clinical Cancer Research

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Purpose: It is widely acknowledged that chronic low-grade inflammation plays a key role in the development of obesity-related insulin resistance and type 2 diabetes. The level of circulating interleukin-6 (IL-6), one of the major proinflammatory adipokines, is correlated with obesity and insulin resistance, which are known to be risk factors for colorectal adenoma. We examined the association between the circulating level of IL-6 and the presence of colorectal adenoma.Experimental Design: In a total colonoscopy-based cross-sectional study conducted between January and December 2008, serum levels of IL-6 were measured in samples of venous blood obtained from 336 male participants attending health checkups (118 individuals with colorectal adenoma and 218 agematched controls) after an overnight fast.Results: In the colorectal adenoma group, the median levels of serum IL-6 (1.24 vs. 1.04 pg/mL; P ¼ 0.01), triglyceride, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were to be significantly higher than those in the control group. When restricted to individuals with adenoma, levels of IL-6 were positively correlated with body mass index, insulin, and HOMA-IR. Multiple logistic analyses adjusted to include insulin or HOMA-IR showed that high levels of IL-6 were associated with the presence of colorectal adenoma. There was no significant interaction of IL-6 with HOMA-IR to modify this association.Conclusions: Our findings suggest that increased serum levels of IL-6 are positively associated with the presence of colorectal adenoma in men, independently of insulin and HOMA-IR.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

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Serum Interleukin-6, Insulin, and HOMA-IR in Male Individuals with Colorectal Adenoma

Sasaki

Takeda

Satô

et al. 2012

Clinical Cancer Research

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“…Furthermore, IL-6 possesses critical protumorigenic functions thereby increasing the risk for the development of colorectal tumors (7). These findings are consistent with the here-described decrease in tumor incidence in NFATc2-deficient mice when subjected to DSS/AOM model.…”

Section: Discussionsupporting

confidence: 90%

Transcription Factor NFATc2 Controls the Emergence of Colon Cancer Associated with IL-6–Dependent Colitis

et al. 2012

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NFAT transcription factors control T-cell activation and function. Specifically, the transcription factor NFATc2 affects the regulation of cell differentiation and growth and plays a critical role in the development of colonic inflammation. Here, we used an experimental model of colitis-associated colorectal carcinoma to investigate the contribution of NFATc2 to the promotion of colonic tumors. Compared with wild-type animals that readily presented with multiple colon tumors, NFATc2-deficient mice were protected from tumor development. This observed decrease in colonic tumor progression was associated with reduced endoscopic inflammation, increased apoptosis of lamina propria T lymphocytes, and significantly reduced levels of the critical proinflammatory cytokines interleukin (IL)-21 and IL-6. Administration of hyper IL-6 abrogated protection from tumor progression in NFATc2-knockout mice and restored tumor incidence to control levels. Taken together, our findings highlight a pivotal role for NFATc2 in the establishment of inflammation-associated colorectal tumors mediated by control of IL-6 expression. Cancer Res; 72(17); 4340-50. Ó2012 AACR.

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“…The transition from an adenoma to a CRC may take many years and can inevitably result in a series of changes that include altered cytokine secretion and immune cell function in the tumor microenvironment (3)(4)(5). Since the cytokines play an essential role in the communication between tumor cell initiation/progression and host anti-tumor immunity (6)(7)(8)(9)(10)(11), it is important to investigate the cytokine changes in the tumor microenvironment, in order to better understand the transitional mechanisms and design novel interventional strategies. Indeed, in previous studies, we and others have revealed that the colorectal neoplastic transformation leads to a remarkable alteration of cytokine secretion in the tumor immune microenvironment (6,8,12,13), this may have a significant role in predicting the progression from the adenomas to CRCs (12,14,15) and prognosis of the CRCs (7,9,10,12,13,16).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

Cui

Gundersen

et al. 2014

Cancer Immunol Immunother

108

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Most sporadic colorectal cancers (CRCs) develop from preexisting adenomas. The transition from an adenoma to a CRC leads to disruption in cytokine secretion and immune imbalance.Interleukin-33 (IL-33) is a newly discovered proinflammatory cytokine belonging to the IL-1 cytokine family, and involved in the regulation of immune function and development of chronic colorectal inflammation and cancers. However, the activation of the IL33/ST2 axis alongside the colorectal adenoma-carcinoma sequence is poorly understood. Our aim is to evaluate the dynamics between the IL-33/ST2 axis and the human colorectal normaladenoma -carcinoma sequence. The expression of IL-33 in adenomas (n=50) determined by real-time PCR was significantly higher than that in the colorectal mucosa from normal individuals. The expression of IL-33 was also increased in CRCs (n=50) when compared to the normal control group. Significantly lower levels of IL-33 where found in the CRCs compared with the adenomas; moreover, the analysis revealed that a high IL-33 level was associated with a low dysplasia degree in the adenomas, as well as with a statistically nonsignificant increase of survival time in the CRC patients. The increased expression of IL-33 in adenomas/CRCs was confirmed by immunohistochemistry (IHC) which showed that IL-33 immunoreactivity was expressed in the adenomatous/cancerous epithelium, whereas it was undetectable in the normal controls. IHC also confirmed that the IL-33 receptor (ST2) is increased in tumor stromal cells. Double IHCs identified that IL-33 immunoreactivity was in the tumor stromal myofibroblasts and microvessels. In conclusion, the expression of IL-33 in the tumor microenvironment was dynamically altered along the colorectal adenomacarcinoma sequence; and may be a potential predictor for the progression of the adenoma to the CRC.3

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Circulating Levels of Inflammatory Cytokines and Risk of Colorectal Adenomas

Cited by 254 publications

References 43 publications

Serum Interleukin-6, Insulin, and HOMA-IR in Male Individuals with Colorectal Adenoma

Serum Interleukin-6, Insulin, and HOMA-IR in Male Individuals with Colorectal Adenoma

Transcription Factor NFATc2 Controls the Emergence of Colon Cancer Associated with IL-6–Dependent Colitis

Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

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