IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment
The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis...
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| Published in: | Cancer research (Chicago, Ill.) Vol. 78; no. 17; p. 4957 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
01.09.2018
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| ISSN: | 1538-7445, 1538-7445 |
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| Abstract | The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth
in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.
These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers.
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| AbstractList | The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth
in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.
These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers.
. The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.Significance: These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. Cancer Res; 78(17); 4957-70. ©2018 AACR.The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.Significance: These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. Cancer Res; 78(17); 4957-70. ©2018 AACR. |
| Author | Wong, K K Klein-Szanto, Andres J Tang, Qiaosi Frank, David A Raj, Arjun Ohashi, Shinya Qiao, Edmund Baba, Kiichiro Bass, Adam J Long, Qi Walker, Sarah R Rustgi, Anil K Dunagin, Margaret C Waldron, Todd J Wileyto, E Paul Soni, Monica Sahu, Varun Karakasheva, Tatiana A Giaccone, Zachary T Diehl, J Alan Lin, Eric W Basu, Devraj |
| Author_xml | – sequence: 1 givenname: Tatiana A surname: Karakasheva fullname: Karakasheva, Tatiana A organization: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania – sequence: 2 givenname: Eric W surname: Lin fullname: Lin, Eric W organization: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania – sequence: 3 givenname: Qiaosi surname: Tang fullname: Tang, Qiaosi organization: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania – sequence: 4 givenname: Edmund surname: Qiao fullname: Qiao, Edmund organization: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania – sequence: 5 givenname: Todd J surname: Waldron fullname: Waldron, Todd J organization: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania – sequence: 6 givenname: Monica surname: Soni fullname: Soni, Monica organization: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania – sequence: 7 givenname: Andres J surname: Klein-Szanto fullname: Klein-Szanto, Andres J organization: Fox Chase Cancer Center, Philadelphia, Pennsylvania – sequence: 8 givenname: Varun surname: Sahu fullname: Sahu, Varun organization: Department of Otolaryngology - Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania – sequence: 9 givenname: Devraj surname: Basu fullname: Basu, Devraj organization: Surgery Service, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania – sequence: 10 givenname: Shinya surname: Ohashi fullname: Ohashi, Shinya organization: Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan – sequence: 11 givenname: Kiichiro surname: Baba fullname: Baba, Kiichiro organization: Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan – sequence: 12 givenname: Zachary T surname: Giaccone fullname: Giaccone, Zachary T organization: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts – sequence: 13 givenname: Sarah R surname: Walker fullname: Walker, Sarah R organization: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts – sequence: 14 givenname: David A surname: Frank fullname: Frank, David A organization: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts – sequence: 15 givenname: E Paul surname: Wileyto fullname: Wileyto, E Paul organization: Department of Biostatistics, Epidemiology and Bioinformatics, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 16 givenname: Qi surname: Long fullname: Long, Qi organization: Department of Biostatistics, Epidemiology and Bioinformatics, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 17 givenname: Margaret C surname: Dunagin fullname: Dunagin, Margaret C organization: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 18 givenname: Arjun surname: Raj fullname: Raj, Arjun organization: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 19 givenname: J Alan surname: Diehl fullname: Diehl, J Alan organization: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina – sequence: 20 givenname: K K surname: Wong fullname: Wong, K K organization: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts – sequence: 21 givenname: Adam J surname: Bass fullname: Bass, Adam J organization: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts – sequence: 22 givenname: Anil K surname: Rustgi fullname: Rustgi, Anil K email: anil2@pennmedicine.upenn.edu organization: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29976575$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Animals Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Carcinogenesis - genetics Cell Line, Tumor Esophageal Neoplasms - genetics Esophageal Neoplasms - pathology Gastrointestinal Neoplasms - genetics Gastrointestinal Neoplasms - pathology Humans Interleukin-6 - genetics MAP Kinase Signaling System - genetics Mice Receptors, Interleukin-6 - genetics Signal Transduction STAT3 Transcription Factor - genetics Tumor Microenvironment - genetics Xenograft Model Antitumor Assays |
| Title | IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment |
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