Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels

Kim, Hong Sun; Chen, Yu‐Chih; Nör, Felipe; Warner, Kristy A.; Andrews, April; Wagner, Vivian Petersen; Zhang, Zhaocheng; Zhang, Zhixiong; Martins, Manoela Domingues; Pearson, Alexander T.; Yoon, Euisik; Nör, Jacques E.

doi:10.18632/oncotarget.22225

Cited by 26 publications

(35 citation statements)

References 45 publications

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“…The motility and survival of these CSCs were reduced upon treatment with the humanized anti-IL-6R antibody (Tocilizumab) leading to slower tumor growth with reduced CSC fraction. This study shows a possible mechanism how endothelial cells might contribute to the CSC regulation and metastatic spread [160].…”

Section: Clinical Implication Of Hnscc Stem Cellsmentioning

confidence: 99%

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications

Peitzsch

Nathansen

Schniewind

et al. 2019

Cancers

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide. Despite advances in the treatment management, locally advanced disease has a poor prognosis, with a 5-year survival rate of approximately 50%. The growth of HNSCC is maintained by a population of cancer stem cells (CSCs) which possess unlimited self-renewal potential and induce tumor regrowth if not completely eliminated by therapy. The population of CSCs is not only a promising target for tumor treatment, but also an important biomarker to identify the patients at risk for therapeutic failure and disease progression. This review aims to provide an overview of the recent pre-clinical and clinical studies on the biology and potential therapeutic implications of HNSCC stem cells.

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Section: Clinical Implication Of Hnscc Stem Cellsmentioning

confidence: 99%

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications

Peitzsch

Nathansen

Schniewind

et al. 2019

Cancers

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“…The biological mechanisms through which specific cytokines are associated with cancer mortality has been widely investigated. Th2 cytokines such as IL-6 and IL-10 enhance motility and survival of highly tumorigenic cancer stem cells and thus metastasis [44], while IL-8 is involved in the regulation of angiogenesis, cancer cell growth and survival, tumor cell motion, leukocyte infiltration, and modification of immune responses [45]. IL-6 and IL-10 are believed to influence tumor progression by activating Janus Kinase (JAK) causing the phosphorylation of signal transducer and activation of transcription 3 (STAT3), initiation and transcription of STAT3 target genes including cyclin D1, Bcl-xL, c-myc, Mcl1 and vascular endothelial growth factor (VEGF) [46].…”

Section: Discussionmentioning

confidence: 99%

Association of baseline inflammatory biomarkers with cancer mortality in the REGARDS cohort

et al. 2019

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This study examines the association between inflammatory biomarkers and risk of cancer mortality by race. Data were obtained from 1,856 participants in the prospective REGARDS cohort who were cancer-free at baseline, and analyzed in relation to cancer mortality prospectively. Biomarkers were log-transformed and categorized into tertiles due to non-normal distributions, and Cox proportional hazard regression models were utilized to compute hazard ratios with 95% confidence intervals using robust sandwich methods. Individuals in the highest tertile of IL-6 had over a 12-fold increased risk of cancer mortality (HR: 12.97, 95% CI: 3.46–48.63); those in the highest tertile of IL-8 had over a 2-fold increased risk of cancer mortality (HR: 2.21, 95% CI: 0.86–5.71), while those in the highest tertile of IL-10 had over a 3-fold increased risk of cancer mortality (HR: 3.06, 95% CI: 1.35–6.89). In race-stratified analysis, each unit increase in IL-6 was associated with increased risk of cancer mortality among African-Americans (HR: 3.88, 95% CI: 1.17–12.88) and Whites (5.25, 95% CI: 1.24–22.31). If replicated in larger, racially diverse prospective cohorts, these results suggest that cancer patients may benefit from clinical or lifestyle approaches to regulate systemic inflammation as a cancer prevention strategy.

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“…IL-6 signaling is initiated when IL-6 binds to IL-6Rα and the IL-6/IL-6Rα complex binds to gp130. Subsequent dimerization of gp130 leads to the formation of a heterohexameric signaling complex that recruits JAK proteins, leading to phosphorylation and nuclear localization of STAT3 [29,[34][35][36][37]. Both IL-6Rα and gp130, in addition to IL-6, are required to initiate IL-6 signaling [29,35,36]; thus, if IL-6 signaling is required to maintain cetuximab resistance in the PE/ .…”

Section: Inhibition Of the Il-6 Pathway Does Not Impact Cetuximab Resmentioning

confidence: 99%

Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

et al. 2020

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The epidermal growth factor receptor inhibitor cetuximab is the only oncogene-targeted agent that has been FDA approved for the treatment of head and neck squamous cell carcinoma (HNSCC). Currently, there are no biomarkers used in the clinic to predict which HNSCC tumors will respond to cetuximab, and even in tumors that regress with treatment, acquired resistance occurs in the majority of cases. Though a number of mechanisms of acquired resistance to cetuximab have been identified in preclinical studies, no therapies targeting these resistance pathways have yet been effectively translated into the clinic. To address this unmet need, we examined the role of the cytokine interleukin 6 (IL-6) in acquired cetuximab resistance in preclinical models of HNSCC. We found that IL-6 secretion was increased in PE/CA-PJ49 cells that had acquired resistance to cetuximab compared to the parental cells from which they were derived. However, addition of exogenous IL-6 to parental cells did not promote cetuximab resistance, and inhibition of the IL-6 pathway did not restore cetuximab sensitivity in the cetuximab-resistant cells. Further examination of the IL-6 pathway revealed that expression of IL6R, which encodes a component of the IL-6 receptor, was decreased in cetuximab-resistant cells compared to parental cells, and that treatment of the cetuximab-resistant cells with exogenous IL-6 did not induce phosphorylation of signal transducer and activator of transcription 3, suggesting that the IL-6 pathway was functionally impaired in the cetuximab-resistant cells. These findings demonstrate that, even if IL-6 is increased in the context of cetuximab resistance, it is not necessarily required for maintenance of the resistant phenotype, and that targeting the IL-6 pathway may not restore sensitivity to cetuximab in cetuximab-refractory HNSCC.

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Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels

Cited by 26 publications

References 45 publications

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications

Association of baseline inflammatory biomarkers with cancer mortality in the REGARDS cohort

Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

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