Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Breast Cancer | Research

CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3

Authors: Chongru Zhao, Ning Zeng, Xiaomei Zhou, Yufang Tan, Yichen Wang, Jun Zhang, Yiping Wu, Qi Zhang

Published in: BMC Cancer | Issue 1/2023

Login to get access

Abstract

Background

Tumor-associated macrophages (TAMs) are the most abundant types of immune cells in the tumor microenvironment (TME) of breast cancer (BC). TAMs usually exhibit an M2 phenotype and promote tumor progression by facilitating immunosuppression. This study aimed to investigate the effect of CAA-derived IL-6 on macrophage polarization in promoting BC progression.

Methods

Human BC samples and adipocytes co-cultured with 4T1 BC cells were employed to explore the properties of CAAs. The co-implantation of adipocytes and 4T1 cells in mouse tumor-bearing model and tail vein pulmonary metastasis model were constructed to investigate the impact of CAAs on BC malignant progression in vivo. The functional assays, qRT-PCR, western blotting assay and ELISA assay were employed to explore the effect of CAA-derived IL-6 on macrophage polarization and programmed cell death protein ligand 1 (PD-L1) expression.

Results

CAAs were located at the invasive front of BC and possessed a de-differentiated fibroblast phenotype. CAAs facilitated the malignant behaviors of 4T1 cells in vitro, and promoted 4T1 tumor growth and pulmonary metastasis in vivo. The IHC staining of both human BC specimens and xenograft and the in vitro experiment indicated that CAAs could enhance infiltration of M2 macrophages in the TME of 4T1 BC. Furthermore, CAA-educated macrophages could enhance malignant behaviors of 4T1 cells in vitro. More importantly, CAAs could secret abundant IL-6 and thus induce M2 macrophage polarization by activating STAT3. In addition, CAAs could upregulate PD-L1 expression in macrophages.

Conclusions

Our study revealed that CAAs and CAA-educated macrophages enhanced the malignant behaviors of BC. Specifically, CAA-derived IL-6 induced migration and M2 polarization of macrophages via activation STAT3 and promoted macrophage PD-L1 expression, thereby leading to BC progression.
Appendix
Available only for authorised users
Literature
1.
Gok Yavuz B, Gunaydin G, Gedik ME, et al. Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs. Sci Rep. 2019;9(1):3172.CrossRefPubMedPubMedCentral
2.
Santander A, Lopez-Ocejo O, Casas O, et al. Paracrine interactions between adipocytes and tumor cells recruit and modify macrophages to the mammary tumor microenvironment: the role of obesity and inflammation in breast adipose tissue. Cancers (Basel). 2015;7(1):143–78.CrossRefPubMed
3.
Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196(3):254–65.CrossRefPubMed
4.
Tu D, Dou J, Wang M, et al. M2 macrophages contribute to cell proliferation and migration of breast cancer. Cell Biol Int. 2021;45(4):831–8.CrossRefPubMed
5.
Cho H, Seo Y, Loke KM, et al. Cancer-stimulated CAFs enhance monocyte differentiation and protumoral TAM activation via IL6 and GM-CSF secretion. Clin Cancer Res. 2018;24(21):5407–21.CrossRefPubMed
6.
7.
Comito G, Giannoni E, Segura CP, et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2014;33(19):2423–31.CrossRefPubMed
8.
Cha YJ, Kim ES, Koo JS. Tumor-associated macrophages and crown-like structures in adipose tissue in breast cancer. Breast Cancer Res Treat. 2018;170(1):15–25.CrossRefPubMed
9.
10.
11.
Montalbán Del Barrio I, Penski C, Schlahsa L, et al. Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages – a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape. J Immunother Cancer. 2016;4(1):49.CrossRefPubMedPubMedCentral
12.
Mu X, Shi W, Xu Y, et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018;17(4):428–38.CrossRefPubMedPubMedCentral
13.
Dethlefsen C, Højfeldt G, Hojman P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat. 2013;138(3):657–64.CrossRefPubMed
14.
Weng Y, Tseng H, Chen YA, et al. MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer. Mol Cancer. 2019;18(1):42.CrossRefPubMedPubMedCentral
15.
Lee J, Kim HJ, Yang CS, et al. A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway effectively suppresses non-small cell lung cancer. Mol Ther. 2014;22(7):1254–65.CrossRefPubMedPubMedCentral
16.
Takaishi K, Komohara Y, Tashiro H, et al. Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci. 2010;101(10):2128–36.CrossRefPubMed
17.
Fu XL, Duan W, Su CY, et al. Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression. Cancer Immunol Immunother. 2017;66(12):1597–608.CrossRefPubMed
18.
Wei X, Li S, He J, et al. Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling. Cell Commun Signal. 2019;17(1):1–18.CrossRef
19.
Lee J, Hong BS, Ryu HS, et al. Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism. PLoS One. 2017;12(3):e0174126.CrossRefPubMedPubMedCentral
20.
Liu L, Wu Y, Zhang C, et al. Cancer-associated adipocyte-derived G-CSF promotes breast cancer malignancy via Stat3 signaling. J Mol Cell Biol. 2020;12(9):723–37.CrossRefPubMedPubMedCentral
21.
Takehara M, Sato Y, Kimura T, et al. Cancer-associated adipocytes promote pancreatic cancer progression through SAA1 expression. Cancer Sci. 2020;111(8):2883–94.CrossRefPubMedPubMedCentral
22.
Dirat B, Bochet L, Dabek M, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71(7):2455–65.CrossRefPubMed
23.
Fujisaki K, Fujimoto H, Sangai T, et al. Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP-1[J]. Breast Cancer Res Treat. 2015;150(2):255–63.
24.
Suárez-Nájera LE, Chanona-Pérez JJ, Valdivia-Flores A, et al. Morphometric study of adipocytes on breast cancer by means of photonic microscopy and image analysis. Microsc Res Tech. 2018;81(2):240–9.CrossRefPubMed
25.
Chin AR, Wang SE. Cytokines driving breast cancer stemness. Mol Cell Endocrinol. 2014;382(1):598–602.CrossRefPubMed
26.
Masjedi A, Hashemi V, Hojjat-Farsangi M, et al. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 2018;108:1415–24.CrossRefPubMed
27.
Manore SG, Doheny DL, Wong GL, et al. IL-6/JAK/STAT3 signaling in breast cancer metastasis: biology and treatment. Front Oncol. 2022;12:1–17.CrossRef
28.
Chen X, Fu E, Lou H, et al. IL-6 induced M1 type macrophage polarization increases radiosensitivity in HPV positive head and neck cancer. Cancer Lett. 2019;456:69–79.CrossRefPubMed
29.
Braune J, Weyer U, Hobusch C, et al. IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity. J Immunol. 2017;198(7):2927–34.CrossRefPubMed
30.
Santoni M, Romagnoli E, Saladino T, et al. Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1/PD-L1 agents. Biochim Biophys Acta Rev Cancer. 2018;1869(1):78–84.CrossRefPubMed
31.
Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889–96.CrossRefPubMed
32.
Koru-Sengul T, Santander AM, Miao F, et al. Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians. Breast Cancer Res Treat. 2016;158(1):113–26.CrossRefPubMedPubMedCentral
33.
34.
35.
Olmes G, Büttner-Herold M, Ferrazzi F, et al. CD163+ M2c-like macrophages predominate in renal biopsies from patients with lupus nephritis. Arthritis Res Ther. 2016;18(1):90.CrossRefPubMedPubMedCentral
36.
Ohlsson SM, Linge CP, Gullstrand B, et al. Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization. Clin Immunol. 2014;152(1–2):10–9.CrossRefPubMed
37.
Mantovani A, Sica A, Sozzani S, et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.CrossRefPubMed
38.
Zhang W, Liu Y, Yan Z, et al. IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J Immunother Cancer. 2020;8(1):e000285.CrossRefPubMedPubMedCentral
Metadata
Title
CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3
Authors
Chongru Zhao
Ning Zeng
Xiaomei Zhou
Yufang Tan
Yichen Wang
Jun Zhang
Yiping Wu
Qi Zhang
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10826-1

Other articles of this Issue 1/2023

BMC Cancer 1/2023 Go to the issue

Research

Peripheral blood lymphocytes differentiation patterns in responses / outcomes to immune checkpoint blockade therapies in non-small cell lung cancer: a retrospective study

Research

Delay in diagnosis and associated factors among children with cancer admitted at pediatric oncology ward, University of Gondar comprehensive specialized hospital, Ethiopia: a retrospective cross-sectional study

Research

Developing a predictive nomogram for colposcopists: a retrospective, multicenter study of cervical precancer identification in China

Research

A novel PEGylated form of granulocyte colony-stimulating factor, mecapegfilgrastim, for peripheral blood stem cell mobilization in patients with hematologic malignancies

Study protocol

The QUILT study: quilting sutures in patients undergoing breast cancer surgery: a stepped wedge cluster randomized trial study

Study Protocol

Effects of sleep disturbances and circadian rhythms modifications on cognition in breast cancer women before and after adjuvant chemotherapy: the ICANSLEEP-1 protocol
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits