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
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

Open Access 01-12-2020 | Metastasis | Research

C3a-C3aR signaling promotes breast cancer lung metastasis via modulating carcinoma associated fibroblasts

Authors: Chi Shu, Haoran Zha, Haixia Long, Xinxin Wang, Fei Yang, Jianbao Gao, Chunyan Hu, Li Zhou, Bo Guo, Bo Zhu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

Login to get access

Abstract

Background

Mounting evidence suggests that complement components promote tumor progression via modulating immune suppression, angiogenesis, or tumor cell proliferation. However, the role of C3a-C3aR signaling in regulating lung metastasis of breast cancer remains unknown.

Methods

We performed various ex-vivo and in-vivo assays. Genetic and pharmacological C3aR blockade models were applied to investigate the role of C3a-C3aR in metastasis of breast cancer.

Results

C3a-C3aR signaling in CAFs facilitates the metastasis of breast cancer. Mechanically, C3a-C3aR signaling augments pro-metastatic cytokine secretion and extracellular matrix components expression of CAFs via the activation of PI3K-AKT signaling. Genetic or pharmacological blockade of C3aR signaling effectively inhibited lung metastasis of breast cancer in mouse models.

Conclusions

C3a-C3aR signaling in CAFs facilitates the metastasis of breast cancer. Targeting C3aR signaling is a potential anti-metastasis strategy for breast cancer therapy.
Appendix
Available only for authorised users
Literature
1.
2.
Ren W, Liu Y, Wang X, Piao C, Ma Y, Qiu S, Jia L, Chen B, Wang Y, Jiang W, et al. The complement C3a-C3aR Axis promotes development of thoracic aortic dissection via regulation of MMP2 expression. J Immunol. 2018;200(5):1829–38.PubMed
3.
4.
Cho MS, Rupaimoole R, Choi HJ, Noh K, Chen J, Hu Q, Sood AK, Afshar-Kharghan V. Complement Component 3 Is Regulated by TWIST1 and Mediates Epithelial-Mesenchymal Transition. J Immunol (Baltimore, Md : 1950). 2016;196(3):1412–8.CrossRef
5.
Bulla R, Tripodo C, Rami D, Ling GS, Agostinis C, Guarnotta C, Zorzet S, Durigutto P, Botto M, Tedesco F. C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat Commun. 2016;7:10346.PubMedPubMedCentralCrossRef
6.
Wang Y, Sun SN, Liu Q, Yu YY, Guo J, Wang K, Xing BC, Zheng QF, Campa MJ, Patz EF Jr, et al. Autocrine complement inhibits IL10-dependent T-cell-mediated antitumor immunity to promote tumor progression. Cancer Discov. 2016;6(9):1022–35.PubMedPubMedCentralCrossRef
7.
Kwak JW, Laskowski J, Li HY, McSharry MV, Sippel TR, Bullock BL, Johnson AM, Poczobutt JM, Neuwelt AJ, Malkoski SP, et al. Complement activation via a C3a receptor pathway alters CD4(+) T lymphocytes and mediates lung Cancer progression. Cancer Res. 2018;78(1):143–56.PubMedCrossRef
8.
9.
Cho MS, Vasquez HG, Rupaimoole R, Pradeep S, Wu S, Zand B, Han HD, Rodriguez-Aguayo C, Bottsford-Miller J, Huang J, et al. Autocrine effects of tumor-derived complement. Cell Rep. 2014;6(6):1085–95.PubMedPubMedCentralCrossRef
10.
Zha H, Wang X, Zhu Y, Chen D, Han X, Yang F, Gao J, Hu C, Shu C, Feng Y, et al. Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages. Cancer Immunol Res. 2019;7(2):193–207.PubMedCrossRef
11.
Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat Immunol. 2013;14(2):162–71.PubMedCrossRef
12.
Boire A, Zou Y, Shieh J, Macalinao DG, Pentsova E, Massague J. Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis. Cell. 2017;168(6):1101–1113.e1113.PubMedPubMedCentralCrossRef
13.
Ye J, Qian Z, Xue M, Liu Y, Zhu S, Li Y, Liu X, Cai D, Rui J, Zhang L. Aristolochic acid I aggravates renal injury by activating the C3a/C3aR complement system. Toxicol Lett. 2019;312:118–24.PubMedCrossRef
14.
Nabizadeh JA, Manthey HD, Steyn FJ, Chen W, Widiapradja A, Md Akhir FN, Boyle GM, Taylor SM, Woodruff TM, Rolfe BE. The complement C3a receptor contributes to melanoma tumorigenesis by inhibiting neutrophil and CD4+ T cell responses. J Immunol. 2016;196(11):4783–92.PubMedCrossRef
15.
Gu H, Fisher AJ, Mickler EA, Duerson F 3rd, Cummings OW, Peters-Golden M, Twigg HL 3rd, Woodruff TM, Wilkes DS, Vittal R. Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB J : official publication of the Federation of American Societies for Experimental Biology. 2016;30(6):2336–50.CrossRef
16.
Liu Y, Wang K, Liang X, Li Y, Zhang Y, Zhang C, Wei H, Luo R, Ge S, Xu G. Complement C3 produced by macrophages promotes renal fibrosis via IL-17A secretion. Front Immunol. 2018;9:2385.PubMedPubMedCentralCrossRef
17.
Zhang Y, Yang P, Wang XF. Microenvironmental regulation of cancer metastasis by miRNAs. Trends Cell Biol. 2014;24(3):153–60.PubMedCrossRef
18.
19.
Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC. Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res : BCR. 2016;18(1):84.PubMedCrossRefPubMedCentral
20.
Dumont N, Liu B, DeFilippis RA, Chang H, Rabban JT, Karnezis AN, Tjoe JA, Marx J, Parvin B, Tlsty TD. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia. 2013;15(3):249–IN247.PubMedPubMedCentralCrossRef
21.
Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, Shi X. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. J Exp Clin Cancer Res. 2018;37(1):324.PubMedPubMedCentralCrossRef
22.
Yan L, Xu F, Dai CL. Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. J Exp Clin Cancer Res. 2018;37(1):203.PubMedPubMedCentralCrossRef
23.
Djurec M, Grana O, Lee A, Troule K, Espinet E, Cabras L, Navas C, Blasco MT, Martin-Diaz L, Burdiel M, et al. Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc Natl Acad Sci U S A. 2018;115(6):E1147–56.PubMedPubMedCentralCrossRef
24.
Houthuijzen JM, Jonkers J. Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment. Cancer Metastasis Rev. 2018;37(4):577–97.PubMedCrossRef
25.
Zhu Y, Zhang L, Zha H, Yang F, Hu C, Chen L, Guo B, Zhu B. Stroma-derived fibrinogen-like protein 2 activates Cancer-associated fibroblasts to promote tumor growth in lung Cancer. Int J Biol Sci. 2017;13(6):804–14.PubMedPubMedCentralCrossRef
26.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25(4):402–8.CrossRefPubMed
27.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.PubMedCrossRef
28.
Cancer Genome Atlas N: Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.
29.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013, 6(269):pl1.PubMedPubMedCentralCrossRef
30.
Chen Y, Zeng C, Zhan Y, Wang H, Jiang X, Li W. Aberrant low expression of p85alpha in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b. Oncogene. 2017;36(33):4692–705.PubMedPubMedCentralCrossRef
31.
32.
Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol. 2015;15:669–82.PubMedCrossRef
33.
Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C, Coukos G, Lambris JD. Modulation of the antitumor immune response by complement. Nat Immunol. 2008;9(11):1225–35.PubMedPubMedCentralCrossRef
34.
Mizutani N, Nabe T, Yoshino S. Complement C3a regulates late asthmatic response and airway hyperresponsiveness in mice. J Immunol. 2009;183(6):4039–46.PubMedCrossRef
35.
Weigelt B, Peterse JL, van 't Veer LJ: Breast cancer metastasis: markers and models. Nat Rev Cancer 2005, 5(8):591–602.PubMedCrossRef
36.
Nissen NI, Karsdal M, Willumsen N. Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology. J Exp Clin Cancer Res. 2019;38(1):115.PubMedPubMedCentralCrossRef
37.
Santolla MF, Lappano R, Cirillo F, Rigiracciolo DC, Sebastiani A, Abonante S, Tassone P, Tagliaferri P, Di Martino MT, Maggiolini M, et al. miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling. J Exp Clin Cancer Res. 2018;37(1):94.PubMedPubMedCentralCrossRef
38.
39.
Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239–52.PubMedCrossRef
40.
Arnold JN, Magiera L, Kraman M, Fearon DT. Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1. Cancer Immunol Res. 2014;2:121–6.PubMedPubMedCentralCrossRef
41.
Cirillo F, Lappano R, Bruno L, Rizzuti B, Grande F, Guzzi R, Briguori S, Miglietta AM, Nakajima M, Di Martino MT, et al. AHR and GPER mediate the stimulatory effects induced by 3-methylcholanthrene in breast cancer cells and cancer-associated fibroblasts (CAFs). J Exp Clin Cancer Res. 2019;38(1):335.PubMedPubMedCentralCrossRef
42.
43.
Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.PubMedCrossRef
44.
Vadrevu SK, Chintala NK, Sharma SK, Sharma P, Cleveland C, Riediger L, Manne S, Fairlie DP, Gorczyca W, Almanza O, et al. Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res. 2014;74(13):3454–65.CrossRefPubMed
45.
Yamamura Y, Asai N, Enomoto A, Kato T, Mii S, Kondo Y, Ushida K, Niimi K, Tsunoda N, Nagino M, et al. Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression. Cancer Res. 2015;75(5):813–23.PubMedCrossRef
Metadata
Title
C3a-C3aR signaling promotes breast cancer lung metastasis via modulating carcinoma associated fibroblasts
Authors
Chi Shu
Haoran Zha
Haixia Long
Xinxin Wang
Fei Yang
Jianbao Gao
Chunyan Hu
Li Zhou
Bo Guo
Bo Zhu
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1515-2

Other articles of this Issue 1/2020

Journal of Experimental & Clinical Cancer Research 1/2020 Go to the issue

Review

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Research

Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

Research

WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway

Research

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

Correction

Correction to: IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2

Research

Tubulin Tyrosine Ligase Like 4 (TTLL4) overexpression in breast cancer cells is associated with brain metastasis and alters exosome biogenesis
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