A unique model for SDH-deficient GIST: an endocrine-related cancer
| Autor: | Xue Zhang, Troy F. Langford, James D. Baleja, Hadley D. Sikes, Inna Lomakin, James F. Powers, Arthur S. Tischler, Kassi T. Stein, Brent H. Cochran |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Chemical Engineering |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research Programmed cell death Gastrointestinal Stromal Tumors SDHB Endocrinology Diabetes and Metabolism Biology medicine.disease_cause Article 03 medical and health sciences Endocrinology Endocrine Gland Neoplasms medicine Humans Stromal tumor GiST Cancer medicine.disease Primary tumor 030104 developmental biology Oncology Cancer research Female KRAS Oxidative stress |
| Zdroj: | PMC |
| ISSN: | 1479-6821 1351-0088 |
| DOI: | 10.1530/erc-18-0115 |
| Popis: | We describe a unique patient-derived xenograft (PDX) and cell culture model of succinate dehydrogenase-deficient gastrointestinal stromal tumor (SDH-deficient GIST), a rare mesenchymal tumor that can occur in association with paragangliomas in hereditary and non-hereditary syndromes. This model is potentially important for what it might reveal specifically pertinent to this rare tumor type and, more broadly, to other types of SDH-deficient tumors. The primary tumor and xenografts show a very high proliferative fraction, and distinctive morphology characterized by tiny cells with marked autophagic activity. It is likely that these characteristics resulted from the combination of the germline SDHB mutation and a somatic KRAS G12D mutation. The most broadly relevant findings to date concern oxygen and oxidative stress. In paragangliomas harboring SDHx mutations, both hypoxic signaling and oxidative stress are putative drivers of tumor growth. However, there are no models for SDH-deficient paragangliomas. This related model is the first from a SDHB-mutated human tumor that can be experimentally manipulated to study mechanisms of oxygen effects and novel treatment strategies. Our data suggest that tumor growth and survival require a balance between protective effects of hypoxic signaling vs deleterious effects of oxidative stress. While reduced oxygen concentration promotes tumor cell survival, a further survival benefit is achieved with antioxidants. This suggests potential use of drugs that increase oxidative stress as novel therapies. In addition, autophagy, which has not been reported as a major finding in any type of SDH-deficient tumor, is a potential target of agents that might trigger autophagic cell death. National Institutes of Health (U.S.). Shared Instrumentation Grant Program (S10OD020073) |
| Databáze: | OpenAIRE |
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