IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling

Shintani, Yasushi; Fujiwara, Ayako; Kimura, Tōru; Kawamura, Tomohiro; Funaki, Soichiro; Minami, Masato; Okumura, Meinoshin

doi:10.1016/j.jtho.2016.05.025

Cited by 209 publications

(154 citation statements)

References 35 publications

(23 reference statements)

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“…has also demonstrated that increased osteoblast-derived IL6 promotes tumor cell seeding and bone metastases in a model of breast cancer cells injected in the arterial circulation [42]. IL6 is a pleiotropic cytokine, which is secreted from several cell types, including CAFs and plays a crucial role in the expansion of cancer stem cells [43, 44] as well as in the proliferation potential of CAFs [45, 46]. …”

Section: Discussionmentioning

confidence: 99%

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles

et al. 2017

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The hypothesis that microvesicle (MV)-mediated microRNA transfer converts non-cancer stem cells into cancer stem cells (CSCs) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how MV derived from cancer associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived MV horizontally transferred miR221 to tumor cells and, in combination with hormone therapy activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi CSC. Importantly, MV from patients with HTR metastatic disease expressed high levels of miR221. We further determined that the IL6-pStat3 pathway in promoted the biogenesis of onco-miR-221hi CAF MV and established stromal CSC niches in experimental and patient-derived breast cancer models. Co-injection of patient-derived CAF from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated PDX models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and MV. Murine and human CAF were enriched in HTR tumors expressing high levels of CD133hi cells. Depletion of murine CAF from PDX restored sensitivity to HT, with a concurrent reduction of CD133hi CSC. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAF promoted de novo HT resistance via the generation of CD133hi CSC that expressed low levels of estrogen receptor alpha (ER). Overall, our results illuminate how MV-mediated horizontal transfer of genetic material from host stromal cells to cancer cells trigger the evolution of therapy-resistant metastases, with potentially broad implications for their control.

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Section: Discussionmentioning

confidence: 99%

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles

et al. 2017

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“…This heterogeneity is related to the density of specific stromal cells into TIM as well [27]. It has been reported that cancer-associated fibroblasts (a subset of stromal cells) secrete IL6 that enhances epithelial-to-mesenchymal transition changes in NSCLC cells: this transformation results in increased chemoresistance and worse outcome [28]. Thus, it is not surprising that higher levels of chemokines secreted by TIM (such as IL6 that increases also plasmatic CRP levels) are associated with worse NSCLC prognosis [29].…”

Section: Discussionmentioning

confidence: 99%

Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer

Pastorino

Morelli

Leuzzi

et al. 2017

European Journal of Cancer

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Background: Higher blood levels of C-reactive protein (CRP) have been associated with shorter survival in patients with cardiovascular, chronic obstructive pulmonary disease and cancer. We investigated the impact of baseline and postoperative CRP levels on survival of patients with operable lung cancer (LC). Patients and methods: CRP values at baseline (CRP 0 ) and 3 days after surgery (CRP 3 ) were measured in a consecutive series of 1750 LC patients who underwent complete resection between 2003 and 2015. Patients were classified as having 0 (N Z 593), 1 (N Z 658) or 2 (N Z 553) risk factors: CRP 0 and/or CRP 3 values above the respective median value. The effect of higher CRP was evaluated by KaplaneMeier mortality curves and adjusted hazard ratio (HR) with 95% confidence interval (CI), by fitting Cox proportional hazards models. Results: Cumulative proportions of 5-year survival were 67% for 0 risk factors, 58% for 1 risk factor and 41% for 2 risk factors (P < 0.0001). The overall 5-year mortality risk was significantly higher in patients with 1 risk factor (adjusted hazard ratio [aHR] 1.43 [95% CI 1.14e1.79]), or 2 risk factors (aHR 2.49 [95% CI 1.99e3.11]). A significant impact on survival was observed in each tumour-node-metastasis stage group, and in the subset of non-smokers. Postoperative 30-

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“…IL-6 is now recognized as one of the most ubiquitously expressed and dysregulated cytokines in cancer, with increased expression found in multiple cancers (Becker et al, 2004; Fulciniti et al, 2009; Okamoto et al, 1997; Qu et al, 2015; Salgado et al, 2003). This cytokine has also been shown to induce mesenchymal features in cancers of the cervix (Miao et al, 2014), prostate (Shiota et al, 2013), lung (Shintani et al, 2016), and head and neck (Yadav et al, 2011), among others. Sullivan and colleagues (Sullivan et al, 2009) showed that exposure to exogenous IL-6 repressed E-cadherin expression in breast cancer cells, and ectopic expression resulted in a mesenchymal-like phenotype and gene expression pattern both in vitro and in vivo .…”

Section: Blocking and Reverting Tumor Mesenchymalizationmentioning

confidence: 99%

Pharmacological and immunological targeting of tumor mesenchymalization

David

Dominguez

Palena

2017

Pharmacology & Therapeutics

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Controlling the spread of carcinoma cells to distant organs is the foremost challenge in cancer treatment, as metastatic disease is generally resistant to therapy and is ultimately incurable for the majority of patients. The plasticity of tumor cell phenotype, in which the behaviors and functions of individual tumor cells differ markedly depending upon intrinsic and extrinsic factors, is now known to be a central mechanism in cancer progression. Our expanding knowledge of epithelial and mesenchymal phenotypic states in tumor cells, and the dynamic nature of the transitions between these phenotypes has created new opportunities to intervene to better control the behavior of tumor cells. There are now a variety of innovative pharmacological approaches to preferentially target tumor cells that have acquired mesenchymal features, including cytotoxic agents that directly kill these cells, and inhibitors that block or revert the process of mesenchymalization. Furthermore, novel immunological strategies have been developed to engage the immune system in seeking out and destroying mesenchymalized tumor cells. This review highlights the relevance of phenotypic plasticity in tumor biology, and discusses recently developed pharmacological and immunological means of targeting this phenomenon.

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IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling

Abstract: IL-6 from CAFs enhanced EMT in NSCLC cells. IL-6 may contribute to maintenance of a paracrine loop that functions as part of the communication between CAFs and NSCLC cells, resulting in chemoresistance.

Cited by 209 publications

References 35 publications

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles

Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer

Pharmacological and immunological targeting of tumor mesenchymalization

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