Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Kitami, Kazuhisa ; Yoshihara, Masato ; Tamauchi, Satoshi ; Sugiyama, Mai ; Koya, Yoshihiro ; Yamakita, Yoshihiko ; Fujimoto, Hiroki ; Iyoshi, Shohei ; Uno, Kaname LU orcid and Mogi, Kazumasa , et al. (2022) In Matrix Biology 109. p.70-90
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Epithelial-mesenchymal transition (EMT), Metastasis, Ovarian cancer, Peritoneum, Thrombospondin-1, Vitamin D
in
Matrix Biology
volume
109
pages
21 pages
publisher
Elsevier
external identifiers
  • scopus:85127754024
  • pmid:35339636
ISSN
0945-053X
DOI
10.1016/j.matbio.2022.03.003
language
English
LU publication?
yes
id
8ef726b3-29be-4f75-a739-35302a6ea086
date added to LUP
2022-06-13 14:57:17
date last changed
2024-04-16 01:28:02
@article{8ef726b3-29be-4f75-a739-35302a6ea086,
  abstract     = {{<p>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.</p>}},
  author       = {{Kitami, Kazuhisa and Yoshihara, Masato and Tamauchi, Satoshi and Sugiyama, Mai and Koya, Yoshihiro and Yamakita, Yoshihiko and Fujimoto, Hiroki and Iyoshi, Shohei and Uno, Kaname and Mogi, Kazumasa and Ikeda, Yoshiki and Yokoi, Akira and Yoshikawa, Nobuhisa and Nishino, Kimihiro and Niimi, Kaoru and Nawa, Akihiro and Enomoto, Atsushi and Kajiyama, Hiroaki}},
  issn         = {{0945-053X}},
  keywords     = {{Epithelial-mesenchymal transition (EMT); Metastasis; Ovarian cancer; Peritoneum; Thrombospondin-1; Vitamin D}},
  language     = {{eng}},
  pages        = {{70--90}},
  publisher    = {{Elsevier}},
  series       = {{Matrix Biology}},
  title        = {{Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis}},
  url          = {{http://dx.doi.org/10.1016/j.matbio.2022.03.003}},
  doi          = {{10.1016/j.matbio.2022.03.003}},
  volume       = {{109}},
  year         = {{2022}},
}