Soluble Compounds Released by Hypoxic Stroma Confer Invasive Properties to Pancreatic Ductal Adenocarcinoma

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2020 Oct 27

PMID 33105540

Citations 5

Authors

Dajia Liu

Anne Steins

Remy Klaassen

Amber P van der Zalm

Roel J Bennink

Geertjan van Tienhoven

Marc G Besselink

Maarten F Bijlsma

Hanneke W M van Laarhoven

Affiliations

Soon will be listed here.

Abstract

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. [F]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. [F]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.

Citing Articles

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