The DOI matches its Crossref record, with a small difference in title or year; 7 of the 7 references it cites were found in a registry or an index.
IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment
Published version of a preprint
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 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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“A notable point in this regard is that the primary CAFs separated from human carcinomas have been shown to remain active even in laboratory conditions for a long period of time [133,134].”
From Cell Immortality: In Vitro Effective Techniques to Achieve and Investigate Its Applications and Challenges (2024) · cites this paper as [134]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Hanahan, D., & Coussens, L. M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.022 · Cited by 4,632 · cited 3×
“, cancerassociated fibroblasts (CAF), immune cells, endothelial cells, pericytes, neurons, adipocytes] in the tumor microenvironment (TME) has gained attention as a promising target for cancer therapy (1).”
BackgroundIL-6 as a keystone cytokine in health and disease
Hunter, C. A., & Jones, S. A. (2015) · Nature Immunology · doi:10.1038/ni.3153 · Cited by 2,511
Imaging individual mRNA molecules using multiple singly labeled probes
Raj, A., van den Bogaard, P., Rifkin, S. A., van Oudenaarden, A., & Tyagi, S. (2008) · Nature Methods · doi:10.1038/nmeth.1253 · Cited by 2,028
Self-citationTumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation
Deschênes-Simard, X., Gaumont-Leclerc, M.-F., Bourdeau, V., Lessard, F., Moiseeva, O., Forest, V., Igelmann, S., Mallette, F. A., Saba-El-Leil, M. K., Meloche, S., et al. (2013) · Genes & Development · doi:10.1101/gad.203984.112 · Cited by 194
Verification and Unmasking of Widely Used Human Esophageal Adenocarcinoma Cell Lines
Boonstra, J. J., van Marion, R., Beer, D. G., Lin, L., Chaves, P., Ribeiro, C., Pereira, A. D., Roque, L., Darnton, S. J., Altorki, N. K., et al. (2010) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djp499 · Cited by 127
Khan, M. W., Saadalla, A., Ewida, A. H., Al-Katranji, K., Al-Saoudi, G., Giaccone, Z. T., Gounari, F., Zhang, M., Frank, D. A., & Khazaie, K. (2018) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-017-2057-0 · Cited by 103
Self-citation
Research works printed but not linked: 35
- Kalluri, 2016, The biology and function of fibroblasts in cancer, Nat Rev Cancer, 16, 10.1038/nrc.2016.73 · DOI · Paper page
- Alderton, 2015, Therapeutic resistance: fibroblasts restrain drug sensitivity, Nat Rev Cancer, 15, 318, 10.1038/nrc3965 · DOI
- Torre, 2015, Global cancer statistics, 2012, CA Cancer J Clin, 65, 87, 10.3322/caac.21262 · DOI
- Rustgi, 2014, Esophageal carcinoma, N Engl J Med, 371, 2499, 10.1056/NEJMra1314530 · DOI
- Howlader, Cancer statistics review, 1975-2013 - SEER Statistics [Internet]
- Sato, 2015, EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition, Cancer Biol Ther, 16, 933, 10.1080/15384047.2015.1040959 · DOI
- Lin, 2016, The tumor microenvironment in esophageal cancer, Oncogene, 35, 5337, 10.1038/onc.2016.34 · DOI
- Ilson, 2008, Esophageal cancer chemotherapy: recent advances, Gastrointest Cancer Res, 85
- Zhang, 2015, STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma, Tumour Biol, 36, 2135, 10.1007/s13277-014-2823-y · DOI
- Yamasaki, 1988, Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor, Science, 241, 825, 10.1126/science.3136546 · DOI
- Karakasheva, 2015, CD38-expressing myeloid-derived suppressor cells promote tumor growth in a murine model of esophageal cancer, Cancer Res, 75, 4074, 10.1158/0008-5472.CAN-14-3639 · DOI
- Chen, 2014, IL-6-stimulated CD11b+ CD14+ HLA-DR- myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus, Oncotarget, 5, 8716, 10.18632/oncotarget.2368 · DOI
- Dotto, 2016, Squamous cell cancers: a unified perspective on biology and genetics, Cancer Cell, 29, 622, 10.1016/j.ccell.2016.04.004 · DOI
- Okano, 2000, Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation, J Biol Chem, 275, 30934, 10.1074/jbc.M004112200 · DOI
- Park, 1990, Characteristics of cell lines established from human gastric carcinoma, Cancer Res, 50, 2773
- Okawa, 2007, The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation, Genes Dev, 21, 2788, 10.1101/gad.1544507 · DOI
- Kalabis, 2012, Isolation and characterization of mouse and human esophageal epithelial cells in 3D organotypic culture, Nat Protoc, 7, 235, 10.1038/nprot.2011.437 · DOI
- Facompre, 2016, JARID1B enables transit between distinct states of the stem-like cell population in oral cancers, Cancer Res, 76, 5538, 10.1158/0008-5472.CAN-15-3377 · DOI
- Basu, 2013, EGFR inhibition promotes an aggressive invasion pattern mediated by mesenchymal-like tumor cells within squamous cell carcinomas, Mol Cancer Ther, 12, 10.1158/1535-7163.MCT-12-1210 · DOI
- Babicki, 2016, Heatmapper: web-enabled heat mapping for all, Nucleic Acids Res, 44, W147, 10.1093/nar/gkw419 · DOI
- Natsuizaka, 2014, IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment, Am J Cancer Res, 4, 29
- Kent, 2002, The human genome browser at UCSC, Genome Res, 12, 996, 10.1101/gr.229102 · DOI · Paper page
- Lo, 2015, Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells, Cancer Res, 75, 2800, 10.1158/0008-5472.CAN-14-3041 · DOI · Paper page
- Özdemir, 2014, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell, 25, 719, 10.1016/j.ccr.2014.04.005 · DOI · Paper page
- Sumida, 2012, Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses, Eur J Immunol, 42, 2060, 10.1002/eji.201142335 · DOI
- Ying, 2015, The effectiveness of an anti-human IL-6 receptor monoclonal antibody combined with chemotherapy to target colon cancer stem-like cells, Int J Oncol, 46, 1551, 10.3892/ijo.2015.2851 · DOI
- Chopra, 2015, Trametinib in metastatic melanoma, Expert Rev Anticancer Ther, 15, 749, 10.1586/14737140.2015.1060127 · DOI
- Takakura, 2011, Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways, Hum Mol Genet, 20, 4143, 10.1093/hmg/ddr338 · DOI · Paper page
- Ling, 2006, The multiple roles of Id-1 in cancer progression, Differentiation, 74, 481, 10.1111/j.1432-0436.2006.00083.x · DOI
- Weiskopf, 2017, Cancer immunotherapy targeting the CD47/SIRPα axis, Eur J Cancer, 76, 100, 10.1016/j.ejca.2017.02.013 · DOI
- Derks, 2015, Epithelial PD-L2 expression marks Barrett's esophagus and esophageal adenocarcinoma, Cancer Immunol Res, 3, 1123, 10.1158/2326-6066.CIR-15-0046 · DOI
- De Luca, 2012, Mesenchymal stem cell-derived interleukin-6 and vascular endothelial growth factor promote breast cancer cell migration, J Cell Biochem, 113, 3363, 10.1002/jcb.24212 · DOI
- Ara, 2010, Interleukin-6 in bone metastasis and cancer progression, Eur J Cancer, 46, 1223, 10.1016/j.ejca.2010.02.026 · DOI
- Neiva, 2014, Endothelial cell-derived interleukin-6 regulates tumor growth, BMC Cancer, 14, 99, 10.1186/1471-2407-14-99 · DOI
- Bochet, 2011, Cancer-associated adipocytes promotes breast tumor radioresistance, Biochem Biophys Res Commun, 411, 102, 10.1016/j.bbrc.2011.06.101 · DOI
Cited by
Yuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., Zhang, Z., Yang, S., & Xiao, M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01744-8 · Cited by 977
Wei, C., Yang, C., Wang, S., Shi, D., Zhang, C., Lin, X., Liu, Q., Dou, R., & Xiong, B. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0976-4 · Cited by 833
Zhang, R., Qi, F., Zhao, F., Li, G., Shao, S., Zhang, X., Yuan, L., & Feng, Y. (2019) · Cell Death & Disease · doi:10.1038/s41419-019-1435-2 · Cited by 343
Chalak, M., Hesaraki, M., Mirbahari, S. N., Yeganeh, M., Abdi, S., Rajabi, S., & Hemmatzadeh, F. (2024) · Life · doi:10.3390/life14030417 · Cited by 66
Metadata
- Authors
- Karakasheva, T. A., Lin, E. W., Tang, Q., Qiao, E., Waldron, T. J., Soni, M., Klein-Szanto, A. J., Sahu, V., Basu, D., Ohashi, S., Baba, K., Giaccone, Z. T., Walker, S. R., Frank, D. A., Wileyto, E. P., Long, Q., Dunagin, M. C., Raj, A., Diehl, J. A., Wong, K. K., Bass, A. J., & Rustgi, A. K.
- Affiliations
- 1Division of Gastroenterology, Department of Medicine, Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
- 3Fox Chase Cancer Center, Philadelphia, Pennsylvania.
- 2Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
- 6Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- 7Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
- 8Department of Biostatistics, Epidemiology and Bioinformatics, University of Pennsylvania, Philadelphia, Pennsylvania.
- 9Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.
- 10Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.
- Venue
- Cancer Research
- Published
- 2018-09-01
- Volume
- 78
- Issue
- 17
- Pages
- 4957-4970
- ISSN
- 0008-5472
- 1538-7445
- PMC
- PMC6125177
- Cited by
- 250
- References
- 7
- Language
- en
- Funders
- NCI (P01-CA14305603)
- National Institutes of Health Center (P30-DK050306)
- NIH (K08-DE02284, R21-DE024396, R01-CA196932 02)
- NIEHS (P30-ES013508)
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
