Top

Journal of Hematology & Oncology

Published in:

Open Access 01-12-2017 | Research

Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein

Authors: Yulei Chen, Siyuan Zhang, Qizhi Wang, Xiaobo Zhang

Published in: Journal of Hematology & Oncology | Issue 1/2017

Abstract

Background

The macrophage, one of the several key immune cell types, is believed to be involved in tumorigenesis. However, the mechanism of macrophages promoting tumor progression is largely unknown.

Methods

The differentially secreted proteins of M1 and M2 macrophages were analyzed by mass spectrometry. We performed GST pull-down assay for the identification of cell-membrane receptors that interact with chitinase 3-like protein 1 (CHI3L1) protein. The mouse model was used to validate the function of CHI3L1 in cancer metastasis in vivo. Protein phosphorylation and gene expression were performed to study the signaling pathway activation of cancer cells after CHI3L1 treatment.

Results

M2 macrophage-secreted CHI3L1 promoted the metastasis of gastric and breast cancer cells in vitro and in vivo. The CHI3L1 protein functioned by interacting with interleukin-13 receptor α2 chain (IL-13Rα2) molecules on the plasma membranes of cancer cells. Activation of IL-13Rα2 by CHI3L1 triggered the activation of the mitogen-activated protein kinase signaling pathway, leading to the upregulated expression of matrix metalloproteinase genes, which promoted tumor metastasis. The results of this study indicated that the level of CHI3L1 protein in the sera of patients with gastric or breast cancer was significantly elevated compared with those of healthy donors.

Conclusions

Our study revealed a novel aspect of macrophages with respect to cancer metastasis and showed that CHI3L1 could be a marker of metastatic gastric and breast cancer in patients.

Available only for authorised users

Legler DF, Uetz-von Allmen E, Hauser MA. CCR7: Roles in cancer cell dissemination, migration and metastasis formation. Int J Biochem Cell Bio. 2014;54:78–82.CrossRef

Bravo-Cordero JJ, Hodgson L, Condeelis J. Directed cell invasion and migration during metastasis. Curr Opin Cell Bio. 2012;24:277–83.CrossRef

Whiteside T. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27:5904–12.CrossRefPubMedPubMedCentral

Cho HJ, Jung JI, Lim DY, Kwon GT, Her S, et al. Bone marrow-derived, alternatively activated macrophages enhance solid tumor growth and lung metastasis of mammary carcinoma cells in a Balb/C mouse orthotopic model. Breast Cancer Res. 2012;14:R81.CrossRefPubMedPubMedCentral

Kawata M, Koinuma D, Ogami T, Umezawa K, Iwata C, et al. TGF-β-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by pro-inflammatory cytokines derived from RAW 264.7 macrophage cells. J Biochem. 2012;151:205–16.CrossRefPubMed

Chen J, Yao Y, Gong C, Yu F, Su S, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541–55.CrossRefPubMedPubMedCentral

Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood. 2010;116:829–40.CrossRefPubMedPubMedCentral

Balkwill F. TNF-α in promotion and progression of cancer. Cancer Metast Rev. 2006;25:409–16.CrossRef

Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, et al. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell. 2010;140:268–79.CrossRefPubMed

10.

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.CrossRefPubMedPubMedCentral

11.

Liu W, Han F, Zhang X. Ran GTPase regulates hemocytic phagocytosis of shrimp by interaction with myosin. J Proteome Res. 2009;8:1198–206.CrossRefPubMed

12.

Ye T, Tang W, Zhang X. Involvement of Rab6 in the regulation of phagocytosis against virus infection in invertebrates. J Proteome Res. 2012;11:4834–46.CrossRefPubMed

13.

Chen Y, Jiang C, Jin M, Gong Y, Zhang X. The role of Rab6 GTPase in the maturation of phagosome against Staphylococcus aureus. Int J Biochem Cell Bio. 2015;61:35–44.CrossRef

14.

Wu W, Zong R, Xu J, Zhang X. Antiviral phagocytosis is regulated by a novel Rab-dependent complex in shrimp Penaeus japonicus. J Proteome Res. 2008;7:424–31.CrossRefPubMed

15.

Gong Y, He T, Yang L, Yang G, Chen Y, et al. The role of miR-100 in regulating apoptosis of breast cancer cells. Sci Rep. 2015;5:11650.CrossRefPubMedPubMedCentral

16.

Yang G, Gong Y, Wang Q, Wang L, Zhang X. miR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation. Oncogene. 2016;1–15 doi:10.1038/onc.2016.270

17.

Zhao Z, Wang L, Xu W. IL-13Rα2 mediates PNR-induced migration and metastasis in ERα-negative breast cancer. Oncogene. 2015;34:1596–607.CrossRefPubMed

18.

Barderas R, Bartolomé RA, Fernandez-Aceñero MJ, Torres S, Casal JI. High expression of IL-13 receptor α2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis. Cancer Res. 2012;72:2780–90.CrossRefPubMed

19.

Fujisawa T, Joshi B, Nakajima A, Puri RK. A novel role of interleukin-13 receptor α2 in pancreatic cancer invasion and metastasis. Cancer Res. 2009;69:8678–85.CrossRefPubMed

20.

Fujisawa T, Joshi BH, Puri RK. IL‐13 regulates cancer invasion and metastasis through IL-13Rα2 via ERK/AP-1 pathway in mouse model of human ovarian cancer. Int J Cancer. 2012;131:344–56.CrossRefPubMed

21.

Kim JH, Kim JH, Kim SC, Yi Y-S, Yang WS, et al. Adenosine dialdehyde suppresses MMP-9-mediated invasion of cancer cells by blocking the Ras/Raf-1/ERK/AP-1 signaling pathway. Biochem Pharmacol. 2013;86:1285–300.CrossRefPubMed

22.

Tuveson DA, Neoptolemos JP. Understanding metastasis in pancreatic cancer: a call for new clinical approaches. Cell. 2012;148:21–3.CrossRefPubMed

23.

Chen Q, Zhang XH-F, Massagué J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell. 2011;20:538–49.CrossRefPubMedPubMedCentral

24.

Qian B-Z, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.CrossRefPubMedPubMedCentral

25.

Yeo E-J, Cassetta L, Qian B-Z, Lewkowich I, Li J-f, et al. Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res. 2014;74:2962–73.CrossRefPubMedPubMedCentral

26.

Hou Z, Falcone DJ, Subbaramaiah K, Dannenberg AJ. Macrophages induce COX-2 expression in breast cancer cells: role of IL-1β autoamplification. Carcinogenesis. 2011;32:695–702.CrossRefPubMedPubMedCentral

27.

Massague J. TGFβ in cancer. Cell. 2008;134:215–30.CrossRefPubMedPubMedCentral

28.

Kaler P, Augenlicht L, Klampfer L. Macrophage-derived IL-1β stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene. 2009;28:3892–902.CrossRefPubMedPubMedCentral

29.

Yang J, Liao D, Chen C, Liu Y, Chuang TH, et al. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells. 2013;31:248–58.CrossRefPubMed

30.

Zhong L, Roybal J, Chaerkady R, Zhang W, Choi K, et al. Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment. Cancer Res. 2008;68:7237–45.CrossRefPubMedPubMedCentral

31.

Su S, Liu Q, Chen J, Chen J, Chen F, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25:605–20.CrossRefPubMed

32.

Jeet V, Tevz G, Lehman M, Hollier B, Nelson C. Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells. Endocr Relat Cancer. 2014;21:723–37.CrossRefPubMedPubMedCentral

33.

Ngernyuang N, Francescone RA, Jearanaikoon P, Daduang J, Supoken A, et al. Chitinase 3 like 1 is associated with tumor angiogenesis in cervical cancer. Int J Biochem Cell Bio. 2014;51:45–52.CrossRef

34.

He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, et al. Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2. Cell Rep. 2013;4:830–41.CrossRefPubMedPubMedCentral

35.

Lee C-M, He CH, Nour AM, Zhou Y, Ma B, et al. IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses. Nat Commun. 2016;7:12752.CrossRefPubMedPubMedCentral

36.

Kook S-H, Jang Y-S, Lee J-C. Involvement of JNK-AP-1 and ERK-NF-κB signaling in tension-stimulated expression of type I collagen and MMP-1 in human periodontal ligament fibroblasts. J Appl Physiol. 2011;111:1575–83.CrossRefPubMed

37.

Lin C-M, Chen Y-H, Ma H-P, Wang B-W, Chiu J-H, et al. Silibinin inhibits the invasion of IL-6-stimulated colon cancer cells via selective JNK/AP-1/MMP-2 modulation in vitro. J Agr Food Chem. 2012;60:12451–7.CrossRef

38.

Nguyen P, Tsunematsu T, Yanagisawa S, Kudo Y, Miyauchi M, et al. The FGFR1 inhibitor PD173074 induces mesenchymal–epithelial transition through the transcription factor AP-1. Brit J Cancer. 2013;109:2248–58.CrossRefPubMedPubMedCentral

39.

Chiang AC, Massagué J. Molecular basis of metastasis. N Engl J Med. 2008;359:2814–23.CrossRefPubMedPubMedCentral

Title: Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein
Authors: Yulei Chen
Siyuan Zhang
Qizhi Wang
Xiaobo Zhang
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-017-0408-0

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

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients

Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways

Drug-induced amino acid deprivation as strategy for cancer therapy

Ongoing clinical trials of PD-1 and PD-L1 inhibitors for lung cancer in China

Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways

Pterostilbene prevents AKT-ERK axis-mediated polymerization of surface fibronectin on suspended lung cancer cells independently of apoptosis and suppresses metastasis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer