Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade

Eichten, Alexandra; Su, Jiahang; Adler, Alexander P.; Zhang, Lili; Ioffe, Ella; Parveen, Asma; Yancopouloš, George D.; Rudge, John F.; Lowy, Israel; Lin, Hong‐Cheu; MacDonald, Douglas; Daly, Christopher; Duan, Xunbao; Thurston, Gavin

doi:10.1158/0008-5472.can-15-1443

Cited by 53 publications

(39 citation statements)

References 44 publications

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“…A number of studies have revealed that IL-6 was released by autocrine and paracrine by malignant cells or immune cells and functioned in tumorigenesis [40, 46, 47]. Generally, IL-6 was secreted by noncancer stem cells in low-attachment culture conditions and enriched Oct4 gene expression by activating the IL-6R/JAK/STAT3 signaling pathway in chronic inflammatory disease, such as cholangiocarcinoma [47, 48].…”

Section: Discussionmentioning

confidence: 99%

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

et al. 2016

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BackgroundLong non-coding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, associated with chronic inflammation and damage to the biliary epithelium. The aim of the study is to identify if any lncRNA might associate with inflammation or oxidative stress in CCA and regulate the disease progression.MethodsIn this study, RNA-seqs datasets were used to identify aberrantly expressed lncRNAs. Small interfering RNA and overexpressed plasmids were used to modulate the expression of lncRNAs, and luciferase target assay RNA immunoprecipitation (RIP) was performed to explore the mechanism of miRNA-lncRNA sponging.ResultsWe firstly analyzed five available RNA-seqs datasets to investigate aberrantly expressed lncRNAs which might associate with inflammation or oxidative stress. We identified that two lncRNAs, H19 and HULC, were differentially expressed among all the samples under the treatment of hypoxic or inflammatory factors, and they were shown to be stimulated by short-term oxidative stress responses to H2O2 and glucose oxidase in CCA cell lines. Further studies revealed that these two lncRNAs promoted cholangiocyte migration and invasion via the inflammation pathway. H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.ConclusionsOur study revealed that H19 and HULC, up-regulated by oxidative stress, regulate CCA cell migration and invasion by targeting IL-6 and CXCR4 via ceRNA patterns of sponging let-7a/let-7b and miR-372/miR-373, respectively. The results suggest that these lncRNAs might be the chief culprits of CCA pathogenesis and progression. The study provides new insight into the mechanism linking lncRNA function with CCA and may serve as novel targets for the development of new countermeasures of CCA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0348-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

et al. 2016

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“…Cancer-associated adipocytes can also promote radio-resistance by secreting IL-6 [158], whilst IL-6 and IL-8 secreted by mesenchymal stem cells activate macrophages in the microenvironment of human colorectal and ovarian cancers, causing chemoresistance [159,160]. Besides causing resistance to chemo-and radiotherapy, autocrine secretion of IL-6 (induced by therapy) also confers resistance to some targeted therapies; for example, aflibercept (anti-VEGF, inhibitor)-resistant epidermoid carcinoma cells and herceptin (trastuzumab, anti-HER2)-resistant breast cancer cells secrete a large amount of IL-6 and show hyperactivation of STAT-3 signalling, causing resistance to therapy [161,162].…”

Section: Il-6 Induces Therapeutic Resistance In Cancermentioning

confidence: 99%

“…Tocilizumab has been shown to improve cachexia developed by IL-6 overexpression in lung cancer patients [175]. The combination of anti-IL-6R with herceptin and aflibercept enhances therapeutic gain, also in targeted therapy-resistant breast cancer and epidermoid carcinoma, respectively [161,162]. However, blocking IL-6 signalling can be harmful and may result in some adverse effects, such as gastrointestinal, nasopharyngeal and upper respiratory tract infections, gastrointestinal haemorrhage, thrombocytopenia and neutropenia [198].…”

Section: Il-6 Induces Therapeutic Resistance In Cancermentioning

confidence: 99%

Role of interleukin-6 in cancer progression and therapeutic resistance

et al. 2016

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In the last several decades, the number of people dying from cancer-related deaths has not reduced significantly despite phenomenal advances in the technologies related to diagnosis and therapeutic modalities. The principal cause behind limitations in the curability of this disease is the reducing sensitivity of the cancer cells towards conventional anticancer therapeutic modalities, particularly in advance stages of the disease. Amongst several reasons, certain secretory factors released by the tumour cells into the microenvironment have been found to confer resistance towards chemo- and radiotherapy, besides promoting growth. Interleukin-6 (IL-6), one of the major cytokines in the tumour microenvironment, is an important factor which is found at high concentrations and known to be deregulated in cancer. Its overexpression has been reported in almost all types of tumours. The strong association between inflammation and cancer is reflected by the high IL-6 levels in the tumour microenvironment, where it promotes tumorigenesis by regulating all hallmarks of cancer and multiple signalling pathways, including apoptosis, survival, proliferation, angiogenesis, invasiveness and metastasis, and, most importantly, the metabolism. Moreover, IL-6 protects the cancer cells from therapy-induced DNA damage, oxidative stress and apoptosis by facilitating the repair and induction of countersignalling (antioxidant and anti-apoptotic/pro-survival) pathways. Therefore, blocking IL-6 or inhibiting its associated signalling independently or in combination with conventional anticancer therapies could be a potential therapeutic strategy for the treatment of cancers with IL-6-dominated signalling.

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“…While no specific HIF1a blockers have been tested in this population, it is an active area of research. Preclinical models suggest that IL-6 blockade could be another mechanism to overcome resistance to VEGF therapy mediated by changes in the microenvironment (75).…”

Section: Hif-1αmentioning

confidence: 99%

Primary and acquired resistance to biologic therapies in gastrointestinal cancers

Lubner

Uboha

Deming

2017

J. Gastrointest. Oncol.

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Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds.Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways. Resistance to EGFR inhibitors: primaryAs many tumors of the gastrointestinal tract arise from epithelial origins, the attractiveness of treating with therapies blocking EGFR is readily evident. A series of colon cancer trials have shown, improvements in RRs and OS, particularly in populations without mutations in EGFR and/or downstream effectors, which are described in the next section. In most other GI cancers, however, blocking EGFR has not demonstrated clinically relevant improvements in outcome (2-4). New strategies to investigate anti-EGFR therapy in other tumor types are focusing on selecting for patients whose tumors overexpress EGFR, or do not harbor deleterious mutations (ENRICH study, NCT 01813253) (5). KRAS/NRASKRAS and NRAS belong to the family of RAS oncogenes.

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Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade

Cited by 53 publications

References 44 publications

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Role of interleukin-6 in cancer progression and therapeutic resistance

Primary and acquired resistance to biologic therapies in gastrointestinal cancers

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