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.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2271/F1.large.jpg.
©2019 American Association for Cancer Research.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Adult
-
Aged
-
Aged, 80 and over
-
Animals
-
Apoptosis
-
Basic Helix-Loop-Helix Transcription Factors / genetics
-
Basic Helix-Loop-Helix Transcription Factors / metabolism
-
Cell Proliferation
-
Collagen / metabolism*
-
Cystadenocarcinoma, Serous / genetics
-
Cystadenocarcinoma, Serous / metabolism
-
Cystadenocarcinoma, Serous / secondary*
-
Epithelium / physiopathology*
-
Extracellular Matrix / metabolism*
-
Female
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Hypoxia / physiopathology*
-
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
-
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
-
Mice
-
Mice, Inbred NOD
-
Mice, SCID
-
Middle Aged
-
Ovarian Neoplasms / genetics
-
Ovarian Neoplasms / metabolism
-
Ovarian Neoplasms / pathology*
-
Peritoneal Neoplasms / genetics
-
Peritoneal Neoplasms / metabolism
-
Peritoneal Neoplasms / secondary*
-
Prognosis
-
Protein-Lysine 6-Oxidase / genetics
-
Protein-Lysine 6-Oxidase / metabolism
-
Signal Transduction
-
Tumor Cells, Cultured
-
Tumor Microenvironment
-
Xenograft Model Antitumor Assays
Substances
-
Basic Helix-Loop-Helix Transcription Factors
-
HIF1A protein, human
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
endothelial PAS domain-containing protein 1
-
Collagen
-
Protein-Lysine 6-Oxidase