Soluble Compounds Released by Hypoxic Stroma Confer Invasive Properties to Pancreatic Ductal Adenocarcinoma
| Autor: | Hanneke W. M. van Laarhoven, Geertjan van Tienhoven, Maarten F. Bijlsma, Dajia Liu, Remy Klaassen, Amber P. van der Zalm, Anne Steins, Marc G. Besselink, Roel J. Bennink |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Stromal cell endocrine system diseases pancreatic ductal adenocarcinoma Medicine (miscellaneous) pancreatic stellate cells Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Paracrine signalling 0302 clinical medicine Stroma stroma medicine Epithelial–mesenchymal transition lcsh:QH301-705.5 Tumor hypoxia hypoxia business.industry Mesenchymal stem cell Hypoxia (medical) digestive system diseases Desmoplasia 030104 developmental biology lcsh:Biology (General) 030220 oncology & carcinogenesis Cancer research epithelial-to-mesenchymal transition medicine.symptom business |
| Zdroj: | Biomedicines Volume 8 Issue 11 Biomedicines, Vol 8, Iss 444, p 444 (2020) |
| ISSN: | 2227-9059 |
| DOI: | 10.3390/biomedicines8110444 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and a hypoxic microenvironment. Pancreatic stellate cells (PSC) are activated by hypoxia and promote excessive desmoplasia, further contributing to the development of hypoxia. We aimed to explore how hypoxia and stroma interact to contribute to invasive growth in PDAC. [18F]HX4 PET/CT was found to be a feasible non-invasive method to assess tumor hypoxia in 42 patients and correlated with HIF1&alpha immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1&alpha were strong prognostic markers for overall survival. Co-culture and medium transfer experiments demonstrated that hypoxic PSCs and their supernatant induce upregulation of mesenchymal markers in tumor cells, and that hypoxia-induced stromal factors drive invasive growth in hypoxic PDACs. Through stepwise selection, stromal MMP10 was identified as the most likely candidate responsible for this. In conclusion, hypoxia-activated PSCs promote the invasiveness of PDAC through paracrine signaling. The identification of PSC-derived MMP10 may provide a lead to develop novel stroma-targeting therapies. |
| Databáze: | OpenAIRE |
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