IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden

Zee, Marten van der; Sacchetti, Andrea; Cansoy, Medine; Joosten, Rosalie; Teeuwssen, Miriam; Heijmans-Antonissen, Claudia; Ewing‐Graham, Patricia C.; Burger, Curt W.; Blok, Leen J.; Fodde, Riccardo

doi:10.1158/0008-5472.can-14-2498

Cited by 77 publications

(65 citation statements)

References 42 publications

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“…In addition to its effect on androgen receptor signaling, IL6 is also important for the maintenance of stem cell properties in several cancers (5,(16)(17)(18), and blocking STAT3 activity has been shown to inhibit prostate cancer stem-like cells (5,16). Treatment of LNCaP with a combination of IL6 and enzalutamide led to a significant increase in stemness/self-renewal genes.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the IL6/JAK/STAT3 and AR signaling pathways, which are investigated in this study, are linked to prostate cancer progression and the development of castration resistance. In addition, several groups have demonstrated that activation of the IL6/JAK/STAT3 pathway is required for maintenance of stem cell properties in human malignancies (5,(16)(17)(18), whereas androgen receptor activity is known to induce differentiation and suppress self-renewal and proliferation of prostate cancer cells (19).…”

Section: Introductionmentioning

confidence: 99%

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SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment.Implications: SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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“…In addition, tumor-associated inflammation factors within the tumor niche play a pivotal role in the maintenance of cancer cell stemness and the resultant tumor initiation/malignancy [6, 7]. However, tumor-associated inflammation genes or pathways that govern cancer cell stemness remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

ICAM3 mediates inflammatory signaling to promote cancer cell stemness

et al. 2018

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In this study, we present a medium throughput siRNA screen platform to identify inflammation genes that regulate cancer cell stemness. We identified several novel candidates that decrease OCT4 expression and reduce the ALDH+ subpopulation both of which are characteristic of stemness. Furthermore, one of the novel candidates ICAM3 up-regulates in the ALDH+ subpopulation, the side population and the developed spheres. ICAM3 knockdown reduces the side population, sphere formation and chemo-resistance in MDA-MB-231 human breast cancer cells and A549 lung cancer cells. In addition, mice bearing MDA-MB-231-shICAM3 cells develop smaller tumors and fewer lung metastases versus control. Interestingly, ICAM3 recruits and binds to Src by the YLPL motif in its intracellular domain which further activates the PI3K-AKT phosphorylation cascades. The activated p-AKT enhances SOX2 and OCT4 activity and thereby maintains cancer cell stemness. Meanwhile, the p-AKT facilitated p50 nuclear translocation/activation enhances p50 feedback and thereby promotes ICAM3 expression by binding to the ICAM3 promoter region. On this basis, Src and PI3K inhibitors suppress ICAM3-mediated signaling pathways and reduce chemo-resistance which results in tumor growth suppression in vitro and in vivo. In summary, we identify a potential CSC regulator and suggest a novel mechanism by which ICAM3 governs cancer cell stemness and inflammation.

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“…In particular, antibodies that neutralize IL6 or block IL6 receptor (R) a are in clinical trials for ovarian, prostate, and renal cancers (7,8). In an orthotopic nude endometrial carcinoma model, IL6 promoted tumor growth (9), while targeted inhibition of the IL6 receptor dramatically reduced tumor growth in HEC1A cell-derived subcutaneous xenografts in immunodeficient mice (10).…”

Section: Introductionmentioning

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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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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IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden

Cited by 77 publications

References 42 publications

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

ICAM3 mediates inflammatory signaling to promote cancer cell stemness

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

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