GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment

Yamamichi, Gaku; Kato, Taigo; Arakawa, Noriaki; Ino, Yoko; Ujike, Takeshi; Nakano, Kosuke; Koh, Yoko; Motoyama, Yuichi; Outani, Hidetatsu; Myoba, Shohei; Ishizuya, Yu; Yamamoto, Yoshiyuki; Hatano, Koji; Kawashima, Atsunari; Fukuhara, Shinichiro; Uemura, Hiroji; Okada, Seiji; Morii, Eiichi; Nonomura, Norio; Uemura, Motohide

doi:https://doi.org/10.1186/s40364-024-00695-6

GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment

Yamamichi, Gaku; Kato, Taigo; Arakawa, Noriaki et al.

Biomarker Research, 2024, 12, 147

Number of Access:2,618（2025-07-18 12:26 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/98514

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Title	GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment
Creator	NRID 1000040882262 1000040882262 researchmap permalink urology-osaka-japan urology-osaka-japan CreatorName Yamamichi, Gaku
	NRID 1000070648021 1000070648021 researchmap permalink taigokato taigokato Scopus Author ID 55414697500 55414697500 ORCID 0000-0002-8681-1407 0000-0002-8681-1407 CreatorName Kato, Taigo
	NRID 1000060398394 1000060398394 CreatorName Arakawa, Noriaki
	CreatorName Ino, Yoko
	CreatorName Ujike, Takeshi
	NRID 1000000804410 1000000804410 researchmap permalink uro.med.osaka-u uro.med.osaka-u CreatorName Nakano, Kosuke
	NRID 1000070824754 1000070824754 researchmap permalink uro-koh uro-koh CreatorName Koh, Yoko
	NRID 1000060948074 1000060948074 researchmap permalink y_motoyama y_motoyama Scopus Author ID 57208337832 57208337832 CreatorName Motoyama, Yuichi
	NRID 1000060727965 1000060727965 researchmap permalink h-otani h-otani Scopus Author ID 6506224785 6506224785 CreatorName Outani, Hidetatsu
	CreatorName Myoba, Shohei
	NRID 1000000783854 1000000783854 researchmap permalink okiishi okiishi CreatorName Ishizuya, Yu
	NRID 1000090759557 1000090759557 researchmap permalink yoshi229 yoshi229 CreatorName Yamamoto, Yoshiyuki
	NRID 1000060762234 1000060762234 researchmap permalink koji_hatano koji_hatano Scopus Author ID 14627167600 14627167600 CreatorName Hatano, Koji
	NRID 1000050746568 1000050746568 researchmap permalink akawashima akawashima Scopus Author ID 9846139400 9846139400 CreatorName Kawashima, Atsunari
	NRID 1000020609870 1000020609870 researchmap permalink sf55 sf55 Scopus Author ID 8635237400 8635237400 CreatorName Fukuhara, Shinichiro
	NRID 1000050244439 1000050244439 CreatorName Uemura, Hiroji
	NRID 1000030448435 1000030448435 ORCID 0000-0002-5107-8209 0000-0002-5107-8209 researchmap permalink okadaseiji okadaseiji Scopus Author ID 35079139100 35079139100 CreatorName Okada, Seiji
	NRID 1000010283772 1000010283772 ORCID 0000-0001-8490-3650 0000-0001-8490-3650 researchmap permalink read0046454 read0046454 Scopus Author ID 7003914326 7003914326 CreatorName Morii, Eiichi
	NRID 1000030263263 1000030263263 researchmap permalink read0185096 read0185096 Scopus Author ID 7005880662 7005880662 CreatorName Nonomura, Norio
	NRID 1000040631015 1000040631015 researchmap permalink urourouro urourouro CreatorName Uemura, Motohide
Subject	Castration-resistant prostate cancer
	Bone metastasis
	GDF15
	Biomarker
Description	Yamamichi Gaku, Kato Taigo, Arakawa Noriaki, et al. GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment. Biomarker Research 12, 147 (2024); https://doi.org/10.1186/s40364-024-00695-6.
Abstract	Background: Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC. Methods: We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed. Results: A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16). Conclusions: GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.
Publisher	Springer Science and Business Media LLC
Source Title	Biomarker Research
Volume (Issue)	12
Page	147
Date of Issued	2024-11-25
Language	English
Handle URL	https://hdl.handle.net/11094/98514
eISSN	20507771
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1186/s40364-024-00695-6
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Biomarker Research. 2024, 12, p. 147
DC.title	GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment
DC.creator	Yamamichi, Gaku
	Kato, Taigo
	Arakawa, Noriaki
	Ino, Yoko
	Ujike, Takeshi
	Nakano, Kosuke
	Koh, Yoko
	Motoyama, Yuichi
	Outani, Hidetatsu
	Myoba, Shohei
	Ishizuya, Yu
	Yamamoto, Yoshiyuki
	Hatano, Koji
	Kawashima, Atsunari
	Fukuhara, Shinichiro
	Uemura, Hiroji
	Okada, Seiji
	Morii, Eiichi
	Nonomura, Norio
	Uemura, Motohide
DC.publisher	Springer Science and Business Media LLC
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-11-25
DC.identifier	https://doi.org/10.1186/s40364-024-00695-6
DC.subject	Castration-resistant prostate cancer
	Bone metastasis
	GDF15
	Biomarker
DC.description	Yamamichi Gaku, Kato Taigo, Arakawa Noriaki, et al. GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment. Biomarker Research 12, 147 (2024); https://doi.org/10.1186/s40364-024-00695-6.
DCTERMS.abstract	Background: Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC. Methods: We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed. Results: A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16). Conclusions: GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	98514
citation_title	GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment
citation_author	Yamamichi, Gaku
	Kato, Taigo
	Arakawa, Noriaki
	Ino, Yoko
	Ujike, Takeshi
	Nakano, Kosuke
	Koh, Yoko
	Motoyama, Yuichi
	Outani, Hidetatsu
	Myoba, Shohei
	Ishizuya, Yu
	Yamamoto, Yoshiyuki
	Hatano, Koji
	Kawashima, Atsunari
	Fukuhara, Shinichiro
	Uemura, Hiroji
	Okada, Seiji
	Morii, Eiichi
	Nonomura, Norio
	Uemura, Motohide
citation_publisher	Springer Science and Business Media LLC
citation_language	English
citation_date	2024-11-25
citation_journal_title	Biomarker Research
citation_volume	12
citation_firstpage	147
citation_doi	https://doi.org/10.1186/s40364-024-00695-6
citation_public_url	https://hdl.handle.net/11094/98514

GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment

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