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Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis
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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. Significance: This study identifies HIF/LOX signaling as a potential therapeutic target to inhibit collagen remodeling and tumor progression in HGSOC.
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“Moreover, collagen interaction with other ECM molecules including fibronectin, laminin, hyaluronic acid, and MMPs influences cancer cell activity [127].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [127]
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Metadata
- Authors
- Natarajan, S., Foreman, K. M., Soriano, M. I., Rossen, N. S., Shehade, H., Fregoso, D. R., Eggold, J. T., Krishnan, V., Dorigo, O., Krieg, A. J., Heilshorn, S. C., Sinha, S., Fuh, K. C., & Rankin, E. B.
- Affiliations
- Stanford University (US)
- Oregon Health & Science University (US)
- SRI International (US)
- Washington University in St. Louis (US)
- Corresponding author
- Rankin, Erinn B.
- ORCID
- Venue
- Cancer Research
- Published
- 2019-05-01
- Volume
- 79
- Issue
- 9
- Pages
- 2271-2284
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6822898
- OpenAlex
- W2921266140
- Cited by
- 129
- References
- 54
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 15 · 2023: 18 · 2022: 20 · 2021: 20 · 2020: 24 · 2019: 3
- FWCI
- 16.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Defense for Health Affairs (W81XWH-15-1-0097)
- Topics
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- high-grade serous ovarian cancer, peritoneal carcinomatosis, mesothelial cells, hypoxia, collagen remodeling, collagen I deposition, lysyl oxidase, collagen cross-linking, extracellular matrix, tumor invasion, HIF signaling, omental metastases, therapeutic target
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adult, Aged, Aged, 80 and over, Animals, Hypoxia, Collagen, Epithelium, Extracellular Matrix, Female, Humans, Protein-Lysine 6-Oxidase, Middle Aged, Ovarian Neoplasms, Peritoneal Neoplasms, Prognosis, Tumor Cells, Cultured, Signal Transduction, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Inbred NOD, Apoptosis, Cystadenocarcinoma, Serous, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Tumor Microenvironment
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