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Cancer Res. 2019 Mar 12. pii: canres.2616.2018. doi: 10.1158/0008-5472.CAN-18-2616. [Epub ahead of print]

Collagen remodeling in the hypoxic tumor-mesothelial niche promotes ovarian cancer metastasis.

Author information

1
Radiation Oncology, Stanford University.
2
Obstetrics and Gynecology, Stanford University.
3
Obstetrics and Gynecology/Gynecologic Oncology, Stanford University.
4
Obstetrics and Gynecology, Oregon Health and Science University.
5
Materials Science and Engineering, Stanford University.
6
Biosciences Division, Stanford Research Institute.
7
Obstetrics and Gynecology, Washington University.
8
Radiation Oncology and Obstetrics & Gynecology, Stanford University erankin@stanford.edu.

Abstract

Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here we report that the HGSOC tumor-mesothelial niche was hypoxic and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion. The mesothelial niche was enriched with fibrillar collagen in human and murine omental metastases. Pharmacologic inhibition of LOX reduced tumor burden and collagen remodeling in murine omental metastases. These findings highlight an important role for hypoxia and mesothelial cells in the modification of the extracellular matrix and tumor invasion in HGSOC.

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