Interleukin-6 Stimulates Defective Angiogenesis

Gopinathan, Ganga; Milagre, Carla; Pearce, Oliver M.T.; Reynolds, Louise E.; Hodivala‐Dilke, Kairbaan; Leinster, David A.; Zhong, Haihong; Hollingsworth, Robert E.; Thompson, Richard G.; Whiteford, James R.; Balkwill, Frances R.

doi:10.1158/0008-5472.can-15-1227

Cited by 199 publications

(167 citation statements)

References 40 publications

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“…3F). This demonstrates that IL6 is involved in angiogenesis in some tumor types, and extends our previous findings studying ovarian cancer cells (22). Thus, the antitumor effects of MEDI5117 involve inhibition of tumor cell growth and suppression of angiogenesis.…”

Section: Medi5117 Inhibits Expression Of Il6 Target Genes and Angiogesupporting

confidence: 88%

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

Zhong¹,

Davis²,

Ouzounova

et al. 2016

Cancer Research

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Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2

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Section: Medi5117 Inhibits Expression Of Il6 Target Genes and Angiogesupporting

confidence: 88%

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

Zhong¹,

Davis²,

Ouzounova

et al. 2016

Cancer Research

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“…In this study, we provide evidence that MCPIP1 downregulation in ccRCC cells induces the secretion of proangiogenic factors by tumor cells, including VEGF, a key regulator of physiologic angiogenesis (6), IL8, an inducer of endothelial cell proliferation, survival, and capillary tube organization (38) and IL6, a major tumor-promoting cytokine and stimulator of angiogenesis (28). In addition, our results show that low representative Western blot analysis with a-tubulin as the loading control.…”

Section: Discussionmentioning

confidence: 56%

“…Among angiogenic stimuli, the best characterized are VEGF (6,7,26), IL6 (28), and a member of the CXC chemokine family, IL8 (29). In the next step of our study, we examined whether a change in the level of MCPIP1 protein in ccRCC cells affects the secretion of IL8, VEGF, and IL6 (Fig.…”

Section: Silencing Of Mcpip1 In Ccrcc Cells Increases the Secretion Omentioning

confidence: 99%

MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression

et al. 2017

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Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL6, IL1, and IL12. MCPIP1 is also a negative regulator of NFkB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patientderived tumors and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumor outgrowth, and vascularity. MCPIP1 activity regulated secretion of VEGF, IL8, and CXCL12 leading to chemotaxis of microvascular endothelial cells, phosphorylation of VEcadherin, and increased vascular permeability. Mechanistic investigations showed that MCPIP1 regulated ccRCC cell motility, lung metastasis, and mesenchymal phenotype by regulating key elements in the EMT signaling axis. Overall, our results illuminate how MCPIP1 serves as a key nodal point in coordinating tumor growth, angiogenesis, and metastatic spread in ccRCC.

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“…However, inflammation is a complex process that can also promote neovascularizarion. In particular, the inflammatory cytokine IL6 has been shown to be important for ischemia-induced neovascularization (McClintock, Wagner, 2005) and has been demonstrated to promote aberrant angiogenesis through a signaling process that does not require VEGF (Gopinathan et al , 2015). IL6 is also generally regarded as pro-tumorigenic as opposed to IFNγ which is regarded as anti-tumorigenic.…”

Section: Ido1 In Inflammatory Programming: Pathogenic Neovascularizatmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

Prendergast

Malachowski

Mondal

et al. 2018

International Review of Cell and Molecular Biology

233

214

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The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance ‘immunogenic’ chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation and metastasis beyond effects on adaptive immune tolerance. Discovery and development of small molecule enzyme inhibitors of IDO1 derived from the hydroxylamidine and phenylimidazole chemotypes have advanced furthest to date in Phase II/III human trials (epacadastat and GDC-0919/navoximod, respectively). Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer.

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Interleukin-6 Stimulates Defective Angiogenesis

Cited by 199 publications

References 40 publications

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

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