Tumor-Infiltrating Myeloid Cells Activate Dll4/Notch/TGF-β Signaling to Drive Malignant Progression
| Autor: | Dunrui Wang, Ombretta Salvucci, Giovanna Tosato, Kan Jiang, Dragan Maric, Hyeongil Kwak, David Sánchez-Martín, Hidetaka Ohnuki |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research Myeloid Notch signaling pathway Article Mice Transforming Growth Factor beta Tumor Microenvironment medicine Animals Myeloid Cells Adaptor Proteins Signal Transducing Cell Proliferation Tumor microenvironment Receptors Notch biology Calcium-Binding Proteins Intracellular Signaling Peptides and Proteins Membrane Proteins Neoplasms Experimental Transforming growth factor beta Squamous carcinoma medicine.anatomical_structure Oncology Tumor progression Hes3 signaling axis Disease Progression biology.protein Cancer research Cyclin-dependent kinase 8 Female Signal Transduction |
| Zdroj: | Cancer Research. 74:2038-2049 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-13-3118 |
| Popis: | Myeloid cells that orchestrate malignant progression in the tumor microenvironment offer targets for a generalized strategy to attack solid tumors. Through an analysis of tumor microenvironments, we explored an experimental model of lung cancer that uncovered a network of Dll4/Notch/TGF-β1 signals that links myeloid cells to cancer progression. Myeloid cells attracted to the tumor microenvironment by the tumor-derived cytokines CCL2 and M-CSF expressed increased levels of the Notch ligand Dll4, thereby activating Notch signaling in the tumor cells and amplifying tumor-intrinsic Notch activation. Heightened Dll4/Notch signaling in tumor cells magnified TGF-β–induced pSMAD2/3 signaling and was required to sustain TGF-β–induced tumor cell growth. Conversely, Notch blockade reduced TGF-β signaling and limited lung carcinoma tumor progression. Corroborating these findings, by interrogating RNAseq results from tumor and adjacent normal tissue in clinical specimens of human head and neck squamous carcinoma, we found evidence that TGF-β/Notch crosstalk contributed to progression. In summary, the myeloid cell-carcinoma signaling network we describe uncovers novel mechanistic links between the tumor microenvironment and tumor growth, highlighting new opportunities to target tumors where this network is active. Cancer Res; 74(7); 2038–49. ©2014 AACR. |
| Databáze: | OpenAIRE |
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