Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation
| Autor: | Andrea N. Marcogliese, Hilary J. Selden, Xi Chen, Utpal P. Davé, Kim Cardenas, Guadalupe J. Jasso, Zicheng Hu, Jessica N. Lancaster, LiQi Li, Todd A. Triplett, Sadhana Balasubramanyam, Lauren I.R. Ehrlich, Kathy Chan, Paul E. Love |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Stromal cell Cell Survival medicine.medical_treatment PDGFRB Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Receptor IGF Type 1 Receptor Platelet-Derived Growth Factor beta Mice 03 medical and health sciences 0302 clinical medicine Growth factor receptor Cell Line Tumor Tumor Microenvironment medicine Animals Humans Insulin-like growth factor 1 receptor Tumor microenvironment Multidisciplinary Follicular dendritic cells Growth factor Receptors Somatomedin Dendritic Cells Dendritic cell Neoplasm Proteins Cell biology 030104 developmental biology PNAS Plus 030220 oncology & carcinogenesis Female Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 113 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1520245113 |
| Popis: | Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets. |
| Databáze: | OpenAIRE |
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