Expression of Interleukin-11 and Interleukin-11 receptor α in human colorectal adenocarcinoma; Immunohistochemical analyses and correlation with clinicopathological factors

Yamazumi, Kazuyuki; Nakayama, Toshiyuki; Kusaba, Takafumi; Wen, Chun Yang; Yoshizaki, Ayumi; Yakata, Yuichi; Nagayasu, Takeshi; Sekine, Ichiro

doi:10.3748/wjg.v12.i2.317

Cited by 40 publications

(34 citation statements)

References 32 publications

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“…In women with endometrial cancer, IL11 levels are elevated in uterine lavage fluid and are positively associated with higher endometrial tumor grades (16). IL11 protein (16) and mRNA (17), along with IL11Ra protein levels are progressively increased with increased endometrial tumor grade (16), which is in line with findings in other tumor types such as ovarian and colorectal (18,19). Studies have reported protumorigenic roles for IL11 in several epithelial cancers, including breast (20) and colorectal cancer (19) and one recent study highlighted a predominant role for IL11 rather than IL6 in mediating gastric cancer (21).…”

Section: Introductionsupporting

confidence: 74%

“…Recently, IL11 was implicated in experimental models of chronic inflammation and associated tumorigenesis, mediated, at least in part, by overactivation of STAT3 (38). In addition, high IL11 and IL11Ra expression are associated with tumor progression, cellular growth, and differentiation and poor prognosis in a number of cancers including colorectal (19), gastric (38), hepatocellular (39), and breast (20). IL11 is also highly expressed in metastatic lesions of hepatocellular carcinoma (40), and increases the metastatic potential of breast cancer (41).…”

Section: Discussionmentioning

confidence: 99%

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Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

Winship

Sinderen

Donoghue

et al. 2016

Molecular Cancer Therapeutics

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Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. IL11 is a cytokine that regulates cell cycle, invasion, and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumors and uterine lavage fluid in women with endometrial cancer, and alters endometrial epithelial cancer cell adhesion and migration in vitro, but its role in endometrial tumorigenesis in vivo is unknown. We injected mice subcutaneously with human-derived Ishikawa or HEC1A endometrial epithelial cancer cells (ectopic), or HEC1A cells into the uterus (orthotopic) to develop endometrial cancer mouse models. Administration of anti-human IL11 receptor (R) a blocking antibody dramatically reduced HEC1A-derived tumor growth in both models and reduced peritoneal metastatic lesion spread in the orthotopic model, compared with IgG. Anti-human IL11Ra retained a well-differentiated, endometrial epithelial phenotype in the HEC1A ectopic mice, suggesting it prevented epithelial-to-mesenchymal transition. Blockade of mouse IL11Ra with anti-mouse IL11Ra antibody did not alter tumor growth, suggesting that cancer epithelial cell IL11 signaling is required for tumor progression. In vitro, anti-human IL11Ra antibody significantly reduced Ishikawa and HEC1A cell proliferation and invasion and promoted apoptosis. Anti-human, but not anti-mouse, IL11Ra antibody reduced STAT3, but not ERK, activation in HEC1A cells in vitro and in endometrial tumors in xenograft mice. We demonstrated that targeted blockade of endometrial cancer epithelial cell IL11 signaling reduced primary tumor growth and impaired metastasis in ectopic and orthotopic endometrial cancer models in vivo. Our data suggest that therapeutically targeting IL11Ra could inhibit endometrial cancer growth and dissemination. Mol Cancer Ther; 15(4); 720-30. Ó2016 AACR.

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Section: Introductionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

Winship

Sinderen

Donoghue

et al. 2016

Molecular Cancer Therapeutics

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“…We discovered that IL11 is a novel hypoxia-inducible and VHL-regulated gene in human cancer cells. The expression of IL-11 and its receptor (IL-11Ra) has been extensively described in several human malignancies, including but not limited to prostate cancer and osteosarcoma (30)(31)(32)(33)(34)(35)(36)(37)(38)(39), suggesting its potential involvement in human tumorigenesis. However, the regulation of IL-11 expression is still poorly understood and its contribution, if any, to tumor progression is not known.…”

Section: Discussionmentioning

confidence: 99%

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Onnis

Fer²,

Rapisarda³

et al. 2013

J. Clin. Invest.

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IL-11 and its receptor, IL-11Ra, are expressed in human cancers; however, the functional role of IL-11 in tumor progression is not known. We found that IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells and that expression of IL11 mRNA was dependent, at least in part, on HIF-1. A cooperative interaction between HIF-1 and AP-1 mediated transcriptional activation of the IL11 promoter. Additionally, we found that human cancer cells expressed a functional IL-11Ra subunit, which triggered signal transduction either by exogenous recombinant human IL-11 or by autocrine production of IL-11 in cells cultured under hypoxic conditions. Silencing of IL11 dramatically abrogated the ability of hypoxia to increase anchorage-independent growth and significantly reduced tumor growth in xenograft models. Notably, these results were phenocopied by partial knockdown of STAT1 in a human prostate cancer cell line (PC3), suggesting that this pathway may play an important role in mediating the effects of IL-11 under hypoxic conditions. In conclusion, these results identify IL11 as an oxygen-and VHL-regulated gene and provide evidence of a pathway "hijacked" by hypoxic cancer cells that may contribute to tumor progression.

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“…Studies of the expression of IL-11 and the IL-11 receptor in colon cancer have been contradictory (38,39), but IL-11 has no direct effect on the growth of colon carcinoma cell lines in vitro (40). Moreover, whereas s.c. injections with recombinant IL-11 protects mice from thoracic radiation injury, the radiosensitivity of pulmonary breast cancer metastases is not affected (41).…”

Section: Discussionmentioning

confidence: 99%

Local Administration of Interleukin-11 Ameliorates Intestinal Radiation Injury in Rats

Boerma

Wang²,

Burnett³

et al. 2007

Cancer Research

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Intestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 F 0.6 in the vehicle group versus 4.0 F 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 F 0.1 versus 0.5 F 0.03; P < 0.0001), and intestinal wall thickening (842 F 66 Mm versus 643 F 54 Mm; P = 0.02), reduced postradiation transforming growth factor-B overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic. [Cancer Res 2007;67(19):9501-6]

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Expression of Interleukin-11 and Interleukin-11 receptor α in human colorectal adenocarcinoma; Immunohistochemical analyses and correlation with clinicopathological factors

Abstract: IL-11 and IL-11Ra are highly expressed in human colorectal adenocarcinoma and the IL-11Ra expression is correlated with clinicopathological factors. These findings suggest that the expression of IL-11Ra is an important factor for the invasion of human colorectal adenocarcinoma.

Cited by 40 publications

References 32 publications

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

Local Administration of Interleukin-11 Ameliorates Intestinal Radiation Injury in Rats

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