Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer.

Autor:	Mori Y; Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Okimoto Y; Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan., Sakai H; Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan., Kanda Y; Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan., Ohata H; Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan., Shiokawa D; Ehime University Hospital Translational Research Center, Shitsukawa, Toon, Ehime 791-0295, Japan., Suzuki M; Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo 104-0045, Japan., Yoshida H; Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan., Ueda H; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Sekizuka T; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Tamura R; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Yamawaki K; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Ishiguro T; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Mateos RN; Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo 104-0045, Japan., Shiraishi Y; Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo 104-0045, Japan., Yatabe Y; Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan., Hamada A; Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo 104-0045, Japan., Yoshihara K; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Enomoto T; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan., Okamoto K; Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan. Electronic address: okamoto.kouji.dm@teikyo-u.ac.jp.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 May 21; Vol. 5 (5), pp. 101532. Date of Electronic Publication: 2024 Apr 25.
DOI:	10.1016/j.xcrm.2024.101532
Abstrakt:	Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC. Competing Interests: Declaration of interests Teikyo University has filed for a patent application on CAF inhibition by tyrosine kinase inhibitors, and K.O. and Y.M. are named as inventors on this patent. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu