Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma

Matoba, Daijiro; Noda, Takehiro; Kobayashi, Shogo; Sakano, Yoshihiro; Matsumoto, Kenichi; Yamanaka, Chihiro; Sasaki, Kazuki; Hasegawa, Shinichiro; Iwagami, Yoshifumi; Yamada, Daisaku; Tomimaru, Yoshito; Akita, Hirofumi; Takahashi, Hidenori; Asaoka, Tadafumi; Shimizu, Junzo; Wada, Hisashi; Doki, Yuichiro; Eguchi, Hidetoshi

doi:https://doi.org/10.1111/cas.70179

Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma

Matoba, Daijiro; Noda, Takehiro; Kobayashi, Shogo et al.

Cancer Science, 2025

Number of Access:111（2025-12-10 04:39 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/102952

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Title	Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma
Creator	NRID 1000080966549 1000080966549 ORCID 0009-0002-7155-5452 0009-0002-7155-5452 researchmap permalink dmatobagesurg dmatobagesurg Scopus Author ID 58089081600 58089081600 CreatorName Matoba, Daijiro
	NRID 1000050528594 1000050528594 ORCID 0000-0002-6768-5783 0000-0002-6768-5783 researchmap permalink t-noda t-noda Scopus Author ID 12764559600 12764559600 CreatorName Noda, Takehiro
	NRID 1000030452436 1000030452436 CreatorName Kobayashi, Shogo
	NRID 1000020850267 1000020850267 ORCID 0000-0002-7633-6657 0000-0002-7633-6657 CreatorName Sakano, Yoshihiro
	NRID 1000060781721 1000060781721 CreatorName Matsumoto, Kenichi
	CreatorName Yamanaka, Chihiro
	NRID 1000020745442 1000020745442 researchmap permalink Kazuki_Sasaki Kazuki_Sasaki Scopus Author ID 56087041900 56087041900 CreatorName Sasaki, Kazuki
	NRID 1000060621026 1000060621026 CreatorName Hasegawa, Shinichiro
	NRID 1000060597441 1000060597441 CreatorName Iwagami, Yoshifumi
	NRID 1000060571396 1000060571396 ORCID 0000-0002-6702-3800 0000-0002-6702-3800 researchmap permalink dyamada79222 dyamada79222 Scopus Author ID 37008067700 37008067700 CreatorName Yamada, Daisaku
	NRID 1000070528570 1000070528570 researchmap permalink yoshitotomimaru yoshitotomimaru Scopus Author ID 10240341100 10240341100 CreatorName Tomimaru, Yoshito
	NRID 1000070528463 1000070528463 ORCID 0000-0002-3115-9466 0000-0002-3115-9466 researchmap permalink hirofumi_akita hirofumi_akita Scopus Author ID 12765442200 12765442200 CreatorName Akita, Hirofumi
	NRID 1000090601120 1000090601120 ORCID 0000-0003-4801-3540 0000-0003-4801-3540 researchmap permalink hdnr_tkhs hdnr_tkhs Scopus Author ID 7405468781 7405468781 CreatorName Takahashi, Hidenori
	NRID 1000060528470 1000060528470 CreatorName Asaoka, Tadafumi
	CreatorName Shimizu, Junzo
	NRID 1000070243459 1000070243459 CreatorName Wada, Hisashi
	NRID 1000020291445 1000020291445 researchmap permalink ydoki3251 ydoki3251 Scopus Author ID 7006390687 7006390687 CreatorName Doki, Yuichiro
	NRID 1000090542118 1000090542118 ORCID 0000-0002-2318-1129 0000-0002-2318-1129 researchmap permalink abcdabcdabcd abcdabcdabcd Scopus Author ID 7101627772 7101627772 CreatorName Eguchi, Hidetoshi
Subject	immune suppression
	tumor microenvironment
	tumor vessel
	tumor-associated macrophage
	tumor-endothelial cells
Description	Matoba D., Noda T., Kobayashi S., et al. Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma. Cancer Science (2025); https://doi.org/10.1111/cas.70179.
Abstract	Tumor-associated macrophages (TAMs) and tumor endothelial cells (TECs) are important components in tumor microenvironments. This study examined the interaction between TECs and TAMs in hepatocellular carcinoma (HCC). The aim of this study is to clarify the mechanism of immune suppression and cancer progression mediated by the M2 polarization of TAMs. TECs were isolated from subcutaneous HCC tumors using murine BNL-T cells, and normal endothelial cells (NECs) were isolated from murine liver. M0 macrophages were obtained from bone marrow after incubation with M-CSF. Conditioned medium from TECs (TEC CM) or NECs (NEC CM) was added to M0 macrophages, and the polarization to M2 macrophages was assessed. The percentage of iNOS⁻CD206⁺ cells was increased in the TEC CM group than in the NEC CM group. The subcutaneous tumor model with co-injection of BNL-T and TECs or NECs was applied, and the ratio of M2 macrophages (CD206⁺iNOS−CD45⁺CD11b⁺F4/80⁺ cells) was elevated in the BNL-T + TEC group. IL-4 expression in TECs was upregulated compared to NECs, and the secretion of IL-4 was increased in the TEC CM compared to the NEC CM. After IL-4 down-regulation in TECs, the ratio of iNOS⁻CD206+ cells decreased. The double immunofluorescent staining of CD31 and CD163 was performed in human HCC tissue. The number of CD31+ endothelial cells correlated positively with CD163⁺ TAMs. The high CD163/CD31 group showed poor prognosis in overall and disease-free survival. TECs induce M2 macrophage polarization through IL-4 secretion, leading to immune suppression and cancer progression.
Publisher	John Wiley and Sons Inc
Source Title	Cancer Science
Date of Issued	2025-08-27
Language	English
Handle URL	https://hdl.handle.net/11094/102952
PISSN	13479032
eISSN	13497006
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1111/cas.70179
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 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
DCMI Type	Text
DCTERMS.bibliographicCitation	Cancer Science. 2025
DC.title	Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma
DC.creator	Matoba, Daijiro
	Noda, Takehiro
	Kobayashi, Shogo
	Sakano, Yoshihiro
	Matsumoto, Kenichi
	Yamanaka, Chihiro
	Sasaki, Kazuki
	Hasegawa, Shinichiro
	Iwagami, Yoshifumi
	Yamada, Daisaku
	Tomimaru, Yoshito
	Akita, Hirofumi
	Takahashi, Hidenori
	Asaoka, Tadafumi
	Shimizu, Junzo
	Wada, Hisashi
	Doki, Yuichiro
	Eguchi, Hidetoshi
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-08-27
DC.identifier	https://doi.org/10.1111/cas.70179
DC.subject	immune suppression
	tumor microenvironment
	tumor vessel
	tumor-associated macrophage
	tumor-endothelial cells
DC.description	Matoba D., Noda T., Kobayashi S., et al. Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma. Cancer Science (2025); https://doi.org/10.1111/cas.70179.
DCTERMS.abstract	Tumor-associated macrophages (TAMs) and tumor endothelial cells (TECs) are important components in tumor microenvironments. This study examined the interaction between TECs and TAMs in hepatocellular carcinoma (HCC). The aim of this study is to clarify the mechanism of immune suppression and cancer progression mediated by the M2 polarization of TAMs. TECs were isolated from subcutaneous HCC tumors using murine BNL-T cells, and normal endothelial cells (NECs) were isolated from murine liver. M0 macrophages were obtained from bone marrow after incubation with M-CSF. Conditioned medium from TECs (TEC CM) or NECs (NEC CM) was added to M0 macrophages, and the polarization to M2 macrophages was assessed. The percentage of iNOS⁻CD206⁺ cells was increased in the TEC CM group than in the NEC CM group. The subcutaneous tumor model with co-injection of BNL-T and TECs or NECs was applied, and the ratio of M2 macrophages (CD206⁺iNOS−CD45⁺CD11b⁺F4/80⁺ cells) was elevated in the BNL-T + TEC group. IL-4 expression in TECs was upregulated compared to NECs, and the secretion of IL-4 was increased in the TEC CM compared to the NEC CM. After IL-4 down-regulation in TECs, the ratio of iNOS⁻CD206+ cells decreased. The double immunofluorescent staining of CD31 and CD163 was performed in human HCC tissue. The number of CD31+ endothelial cells correlated positively with CD163⁺ TAMs. The high CD163/CD31 group showed poor prognosis in overall and disease-free survival. TECs induce M2 macrophage polarization through IL-4 secretion, leading to immune suppression and cancer progression.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	102952
citation_title	Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma
citation_author	Matoba, Daijiro
	Noda, Takehiro
	Kobayashi, Shogo
	Sakano, Yoshihiro
	Matsumoto, Kenichi
	Yamanaka, Chihiro
	Sasaki, Kazuki
	Hasegawa, Shinichiro
	Iwagami, Yoshifumi
	Yamada, Daisaku
	Tomimaru, Yoshito
	Akita, Hirofumi
	Takahashi, Hidenori
	Asaoka, Tadafumi
	Shimizu, Junzo
	Wada, Hisashi
	Doki, Yuichiro
	Eguchi, Hidetoshi
citation_publisher	John Wiley and Sons Inc
citation_language	English
citation_date	2025-08-27
citation_journal_title	Cancer Science
citation_doi	https://doi.org/10.1111/cas.70179
citation_public_url	https://hdl.handle.net/11094/102952

Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma

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