TY - JOUR
T1 - Soluble compounds released by hypoxic stroma confer invasive properties to pancreatic ductal adenocarcinoma
AU - Liu, Dajia
AU - Steins, Anne
AU - Klaassen, Remy
AU - van der Zalm, Amber P.
AU - Bennink, Roel J.
AU - van Tienhoven, Geertjan
AU - Besselink, Marc G.
AU - Bijlsma, Maarten F.
AU - van Laarhoven, Hanneke W. M.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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 HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α 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.
AB - 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 HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α 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.
KW - Epithelial-to-mesenchymal transition
KW - Hypoxia
KW - Pancreatic ductal adenocarcinoma
KW - Pancreatic stellate cells
KW - Stroma
UR - http://www.scopus.com/inward/record.url?scp=85094626538&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/biomedicines8110444
DO - https://doi.org/10.3390/biomedicines8110444
M3 - Article
C2 - 33105540
SN - 2227-9059
VL - 8
SP - 1
EP - 23
JO - Biomedicines
JF - Biomedicines
IS - 11
M1 - 444
ER -