Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma

Kimura, Toru; Akazawa, Takashi; Mizote, Yu; Nakamura, Harumi; Sakaue, Miki; Maniwa, Tomohiro; Shintani, Yasushi; Honma, Keiichiro; Tahara, Hideaki; Okami, Jiro

doi:https://doi.org/10.1007/s10147-024-02507-1

Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma

Kimura, Toru; Akazawa, Takashi; Mizote, Yu et al.

International Journal of Clinical Oncology, 2024, 99, 102237

Number of Access:1,137（2025-08-21 16:01 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/95021

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Title	Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma
Creator	NRID 1000090580796 1000090580796 ORCID 0000-0003-4504-232X 0000-0003-4504-232X researchmap permalink toru_kimura toru_kimura CreatorName Kimura, Toru
	NRID 1000080359299 1000080359299 CreatorName Akazawa, Takashi
	NRID 1000070801497 1000070801497 CreatorName Mizote, Yu
	NRID 1000080164325 1000080164325 CreatorName Nakamura, Harumi
	CreatorName Sakaue, Miki
	CreatorName Maniwa, Tomohiro
	NRID 1000090572983 1000090572983 researchmap permalink shintani6384 shintani6384 Scopus Author ID 7103142734 7103142734 CreatorName Shintani, Yasushi
	NRID 1000020505945 1000020505945 CreatorName Honma, Keiichiro
	NRID 1000070322071 1000070322071 CreatorName Tahara, Hideaki
	NRID 1000040538857 1000040538857 CreatorName Okami, Jiro
Subject	Cancer-associated fibroblast
	Fibroblast-activation protein
	Lepidic growth
	Lung adenocarcinoma
	Tumor stroma
Description	This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s10147-024-02507-1.
Abstract	Background: Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. Methods: We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. Results: Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. Conclusions: FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.
Publisher	Springer Science and Business Media LLC
Source Title	International Journal of Clinical Oncology
Volume (Issue)	99
Page	102237
Date of Issued	2024-04-11
Language	English
Handle URL	https://hdl.handle.net/11094/95021
PISSN	13419625
eISSN	14377772
Relation.isVersionOf	DOI (Publisher Version) https://doi.org/10.1007/s10147-024-02507-1
Access Rights	open access
oaire:version	Accepted Manuscript
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	International Journal of Clinical Oncology. 2024, 99, p. 102237
DC.title	Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma
DC.creator	Kimura, Toru
	Akazawa, Takashi
	Mizote, Yu
	Nakamura, Harumi
	Sakaue, Miki
	Maniwa, Tomohiro
	Shintani, Yasushi
	Honma, Keiichiro
	Tahara, Hideaki
	Okami, Jiro
DC.publisher	Springer Science and Business Media LLC
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-04-11
DC.identifier	https://doi.org/10.1007/s10147-024-02507-1
DC.subject	Cancer-associated fibroblast
	Fibroblast-activation protein
	Lepidic growth
	Lung adenocarcinoma
	Tumor stroma
DC.description	This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s10147-024-02507-1.
DCTERMS.abstract	Background: Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. Methods: We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. Results: Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. Conclusions: FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.
DC.format	95021
citation_title	Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma
citation_author	Kimura, Toru
	Akazawa, Takashi
	Mizote, Yu
	Nakamura, Harumi
	Sakaue, Miki
	Maniwa, Tomohiro
	Shintani, Yasushi
	Honma, Keiichiro
	Tahara, Hideaki
	Okami, Jiro
citation_publisher	Springer Science and Business Media LLC
citation_language	English
citation_date	2024-04-11
citation_journal_title	International Journal of Clinical Oncology
citation_volume	99
citation_firstpage	102237
citation_doi	https://doi.org/10.1007/s10147-024-02507-1
citation_public_url	https://hdl.handle.net/11094/95021

Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma

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