Elsevier

Matrix Biology

Volume 109, May 2022, Pages 70-90
Matrix Biology

Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis

https://doi.org/10.1016/j.matbio.2022.03.003Get rights and content
Under a Creative Commons license
open access

Highlights

  • In patients with ovarian cancer, peritoneal mesothelial cells are transformed into cancer-associated mesothelial cells via mesenchymal transition and form a favorable microenvironment for tumors to promote metastasis.

  • Vitamin D inhibits mesenchymal transition of mesothelial cells and suppressed thrombospondin-1 (THBS1) expression, a key molecule promoting cancer cell adhesion, via vitamin D receptor/Smad3 competition in TGF-β signaling, resulting in marked reduction in peritoneal dissemination.

  • Vitamin D restores cancer-associated mesothelial cells to an epithelial state with normalization of THBS1 expression in preclinical models that mimic cancerous peritonitis in vivo.

  • This study suggests that peritoneal restoration and normalization of THBS1 expression may be a novel strategy for preventing ovarian cancer dissemination.

Abstract

Ovarian cancer (OvCa), a lethal gynecological malignancy, disseminates to the peritoneum. Mesothelial cells (MCs) act as barriers in the abdominal cavity, preventing the adhesion of cancer cells. However, in patients with OvCa, they are transformed into cancer-associated mesothelial cells (CAMs) via mesenchymal transition and form a favorable microenvironment for tumors to promote metastasis. However, attempts for restoring CAMs to their original state have been limited. Here, we investigated whether inhibition of mesenchymal transition and restoration of MCs by vitamin D suppressed the OvCa dissemination in vitro and in vivo. The effect of vitamin D on the mutual association of MCs and OvCa cells was evaluated using in vitro coculture models and in vivo using a xenograft model. Vitamin D restored the CAMs, and thrombospondin-1 (component of the extracellular matrix that is clinically associated with poor prognosis and is highly expressed in peritoneally metastasized OvCa) was found to promote OvCa cell adhesion and proliferation. Mechanistically, TGF-β1 secreted from OvCa cells enhanced thrombospondin-1 expression in CAMs via Smad-dependent TGF-β signaling. Vitamin D inhibited mesenchymal transition in MCs and suppressed thrombospondin-1 expression via vitamin D receptor/Smad3 competition, contributing to the marked reduction in peritoneal dissemination in vivo. Importantly, vitamin D restored CAMs from a stabilized mesenchymal state to the epithelial state and normalized thrombospondin-1 expression in preclinical models that mimic cancerous peritonitis in vivo. MCs are key players in OvCa dissemination and peritoneal restoration and normalization of thrombospondin-1 expression by vitamin D may be a novel strategy for preventing OvCa dissemination.

Keywords

Ovarian cancer
Peritoneum
Metastasis
Thrombospondin-1
Vitamin D
Epithelial-mesenchymal transition (EMT)

Abbreviations

OvCa
ovarian cancer
MC
mesothelial cell
CAM
cancer-associated mesothelial cell
CAF
cancer-associated fibroblasts
TGF-β1
transforming growth factor beta 1
TGFβ-RI
TGF-β1 receptor inhibitor
EMT
epithelial-mesenchymal transition
MET
mesenchymal-epithelial transition
ECM
extracellular matrix
VD
vitamin D
VDR
vitamin D receptor
THBS1
thrombospondin-1
FACS
fluorescence-activated cell sorting
GSEA
Gene Set Enrichment Analysis
TCGA
The Cancer Genome Atlas
DAVID
Database for Annotation, Visualization and Integrated Discovery
FBS
fetal bovine serum

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