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Cited by 386Immune cells in cancerProtease and Inhibitor MechanismsGut microbiota and health

Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer

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Li, Rui, Zhou, Rui, Wang, Hui, Li, Weidong, Pan, Mingxin, Yao, Xueqing, Zhan, Wanqi, Yang, Shibin +3 more·2019·Cell Death & Differentiation
DOI 10.1038/s41418-019-0312-yPMC PMC6889446
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Abstract

Metastasis is a complex process that requires the interaction between tumor cells and their microenvironment. As an important regulator of intestinal microenvironment, gut microbiota plays a significant role in the initiation and progression of colorectal cancer (CRC), but the underlying mechanisms remain elusive. In this study, a metastasis-related secretory protein cathepsin K (CTSK) was identified as a vital mediator between the imbalance of intestinal microbiota and CRC metastasis. We implanted MC38 cells into the cecal mesentry of antibiotic-treated mice with intragastrically administration of E. coli to mimic gut microbiota imbalance. The bigger primary tumors and more liver metastatic foci were detected in the E. coli group accompanied with high LPS secretion and CTSK overexpression compared with that in the control group. CTSK contributes to the aggressive phenotype of CRC cells both in vitro and in vivo. Silencing CTSK or administration of Odanacatib, a CTSK-specific inhibitor, totally abolished the CTSK-enhanced migration and motility of CRC cells. Interestingly, the tumor-secreted CTSK could bind to toll-like receptor 4 (TLR4) to stimulate the M2 polarization of tumor-associated macrophages (TAMs) via an mTOR-dependent pathway. Recombinant CTSK could neither stimulate CRC growth and metastasis, nor induce M2 macrophage polarization in TRL4-/- mice. Meanwhile, CTSK could stimulate the secretion of cytokines by M2 TAMs including IL10 and IL17, which, in turn, promote the invasion and metastasis of CRC cells through NFκB pathway. Clinically, overexpression of CTSK in human CRC tissues is always accompanied with high M2 TAMs in the stroma, and correlated with CRC metastasis and poor prognosis. Our current research identified CTSK as a mediator between the imbalance of gut microbiota and CRC metastasis. More importantly, we illustrated a CTSK-mediated-positive feedback loop between CRC cells and TAMs during metastasis, prompting CTSK as a novel predictive biomarker and feasible therapeutic target for CRC.

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  • Disruption of microbiota resulted in immunosuppression via inducing M2-like tumor-associated macrophages (TAM).

    “Emerging evidence demonstrated that the disruption of microbiota resulted in immunosuppression via inducing M2-like TAM.”

    From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [17]

  • CRC-secreted CTSK activated the mTOR pathway via interaction with Toll-like receptor 4 (TLR4) on the macrophage membrane, inducing M2 polarization and production of cytokines, such as IL-4 and IL-10.

    “Further investigation showed that CRC-secreted CTSK activated mTOR pathway via interaction with Toll-like receptor 4 (TLR4) on the macrophage membrane, inducing M2 polarization and production of cytokines, such as IL-4, IL-10 [17].”

    From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [17]

  • Intestinal dysbiosis increased the release of lipopolysaccharide (LPS), which contributed to the expression of cathepsin K (CTSK) in CRC cells.

    “Li et al. found that intestinal dysbiosis increased the release of lipopolysaccharide (LPS), which contributed to the expression of CTSK in CRC cells [17].”

    From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [17]

  • Overexpression of CTSK was associated with aggressive phenotypes of CRC cells as well as poor prognosis in patients.

    “Overexpression of CTSK was associated with aggressive phenotypes of CRC cells as well as poor prognosis in patients [17].”

    From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [17]

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References 42 · Cited by 386

Research works printed but not linked: 35

  1. De Rosa M, Pace U, Rega D, Costabile V, Duraturo F, Izzo P, et al. Genetics, diagnosis and management of colorectal cancer (Review). Oncol Rep. 2015;34:1087-96.
  2. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348:74-80.
  3. Chung L, Orberg ET, Geis AL, Chan JL, Fu K, DeStefano Shields CE, et al. Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe. 2018;23:421.
  4. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, et al. Activation of Gpr109a, receptor for niacin and the com- mensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40:128-39.
  5. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16:341-52.
  6. Novinec M, Lenarcic B. Cathepsin K: a unique collagenolytic cysteine peptidase. Biol Chem. 2013;394:1163-79.
  7. Aguda AH, Panwar P, Du X, Nguyen NT, Brayer GD, Bromme D. Structural basis of collagen fiber degradation by cathepsin K. Proc Natl Acad Sci USA. 2014;111:17474-9.
  8. Leusink FK, Koudounarakis E, Frank MH, Koole R, van Diest PJ, Willems SM. Cathepsin K associates with lymph node metastasis and poor prognosis in oral squamous cell carcinoma. Bmc Cancer. 2018;18:385.
  9. Duong LT, Wesolowski GA, Leung P, Oballa R, Pickarski M. Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis. Mol Cancer Ther. 2014;13:2898-909.
  10. Xu H, Ma Y, Zhang Y, Pan Z, Lu Y, Liu P, et al. Identification of cathepsin K in the peritoneal metastasis of ovarian carcinoma using in-silico, gene expression analysis. J Cancer. 2016;7:722-9.
  11. Verbovsek U, Motaln H, Rotter A, Atai NA, Gruden K, Van Noorden CJ, et al. Expression analysis of all protease genes reveals cathepsin K to be overexpressed in glioblastoma. PLoS ONE. 2014;9:e111819.
  12. Christensen J, Shastri VP. Matrix-metalloproteinase-9 is cleaved and activated by cathepsin K. BMC Res Notes. 2015;8:322.
  13. Kleer CG, Bloushtain-Qimron N, Chen YH, Carrasco D, Hu M, Yao J, et al. Epithelial and stromal cathepsin K and CXCL14 expression in breast tumor progression. Clin Cancer Res. 2008;14:5357-67.
  14. Zhao L, Wang H, Liu C, Liu Y, Wang X, Wang S, et al. Pro- motion of colorectal cancer growth and metastasis by the LIM and SH3 domain protein 1. Gut. 2010;59:1226-35.
  15. Cummins J, Cronin M, van Pijkeren JP, Gahan CG, Tangney M. Bacterial systems for gene delivery to systemic tumors. Methods Mol Biol. 2014;1141:201-9.
  16. Nimri L, Spivak O, Tal D, Schalling D, Peri I, Graeve L, et al. A recombinant fungal compound induces anti-proliferative and pro-apoptotic effects on colon cancer cells. Oncotarget. 2017;8:28854-64.
  17. Zhang X, Goncalves R, Mosser DM. The isolation and char- acterization of murine macrophages. Curr Protoc Immunol. 2008; Chapter 14: Unit 14.1.
  18. Liao Q, Li R, Zhou R, Pan Z, Xu L, Ding Y, et al. LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes color- ectal cancer progression. Br J Cancer. 2017;117:563-71.
  19. Hirabara S, Kojima T, Takahashi N, Hanabayashi M, Ishiguro N. Hyaluronan inhibits TLR-4 dependent cathepsin K and matrix metalloproteinase 1 expression in human fibroblasts. Biochem Biophys Res Commun. 2013;430:519-22.
  20. Caronni N, Savino B, Bonecchi R. Myeloid cells in cancer-related inflammation. Immunobiology. 2015;220:249-53.
  21. Schulz MD, Atay C, Heringer J, Romrig FK, Schwitalla S, Aydin B, et al. High-fat-diet-mediated dysbiosis promotes intestinal car- cinogenesis independently of obesity. Nature. 2014;514:508-12.
  22. Jorgensen SF, Troseid M, Kummen M, Anmarkrud JA, Michelsen AE, Osnes LT, et al. Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopoly- saccharide and markers of systemic immune activation. Mucosal Immunol. 2016;9:1455-65.
  23. Cordes C, Bartling B, Simm A, Afar D, Lautenschlager C, Hansen G, et al. Simultaneous expression of Cathepsins B and K in pul- monary adenocarcinomas and squamous cell carcinomas predicts poor recurrence-free and overall survival. Lung Cancer. 2009;64:79-85.
  24. Herroon MK, Rajagurubandara E, Rudy DL, Chalasani A, Hardaway AL, Podgorski I. Macrophage cathepsin K promotes prostate tumor progression in bone. Oncogene. 2013;32:1580-93.
  25. Kos J, Sekirnik A, Premzl A, Zavasnik Bergant V, Langerholc T, Turk B, et al. Carboxypeptidases cathepsins X and B display distinct protein profile in human cells and tissues. Exp Cell Res. 2005;306:103-13.
  26. Guiet R, Van Goethem E, Cougoule C, Balor S, Valette A, Al Saati T, et al. The process of macrophage migration promotes matrix metalloproteinase-independent invasion by tumor cells. J Immunol. 2011;187:3806-14.
  27. Tan SY, Fan Y, Luo HS, Shen ZX, Guo Y, Zhao LJ. Prognostic significance of cell infiltrations of immunosurveillance in color- ectal cancer. World J Gastroenterol. 2005;11:1210-4.
  28. Cui YL, Li HK, Zhou HY, Zhang T, Li Q. Correlations of tumor-associated macrophage subtypes with liver metastases of colorectal cancer. Asian Pac J Cancer Prev. 2013;14:1003-7.
  29. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. Activation of a metabolic gene regulatory network down- stream of mTOR complex 1. Mol Cell. 2010;39:171-83.
  30. Salmiheimo AN, Mustonen HK, Vainionpaa SA, Shen Z, Kemppainen EA, Seppanen HE, et al. Increasing the inflammatory competence of macrophages with IL-6 or with combination of IL- 4 and LPS restrains the invasiveness of pancreatic cancer cells. J Cancer. 2016;7:42-9.
  31. Fan Y, Liu B. Expression of toll-like receptors in the mucosa of patients with ulcerative colitis. Exp Ther Med. 2015;9:1455-9.
  32. Watanabe T, Takahashi N, Hirabara S, Ishiguro N, Kojima T. Hyaluronan inhibits Tlr-4-dependent RANKL expression in human rheumatoid arthritis synovial fibroblasts. PLoS ONE. 2016;11:e0153142.
  33. Donners MM, Bai L, Lutgens SP, Wijnands E, Johnson J, Schurgers LJ, et al. Cathepsin K deficiency prevents the aggra- vated vascular remodeling response to flow cessation in ApoE-/- mice. PLoS ONE. 2016;11:e0162595.
  34. Sun Y, Ishibashi M, Seimon T, Lee M, Sharma SM, Fitzgerald KA, et al. Free cholesterol accumulation in macrophage mem- branes activates Toll-like receptors and p38 mitogen-activated protein kinase and induces cathepsin K. Circ Res. 2009;104:455- 65.
  35. Popena I, Abols A, Saulite L, Pleiko K, Zandberga E, Jekabsons K, et al. Effect of colorectal cancer-derived extracellular vesicles on the immunophenotype and cytokine secretion profile of monocytes and macrophages. Cell Commun Signal. 2018;16:17.

Authors
Li, R., Zhou, R., Wang, H., Li, W., Pan, M., Yao, X., Zhan, W., Yang, S., Xu, L., Ding, Y., & Zhao, L.
Affiliations
  • Nanfang Hospital (CN)
  • Guangzhou Medical University Cancer Hospital (CN)
  • Zhujiang Hospital (CN)
  • Guangdong General Hospital (CN)
  • Southern Medical University (CN)
  • The First Affiliated Hospital, Sun Yat-sen University (CN)
Corresponding author
  • Ding, Yanqing
  • Zhao, Liang
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2019-03-08
Volume
26
Issue
11
Pages
2447-2463
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/s41418-019-0312-y
PMC
PMC6889446
OpenAlex
W2921846932
Cited by
386
References
42
Citations by year
2026: 34 · 2025: 86 · 2024: 80 · 2023: 69 · 2022: 51 · 2021: 37 · 2020: 24 · 2019: 5
FWCI
11.61
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cell Death and Differentiation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81702903, 81773082, 81572813, 81872423)
  • Natural Science Foundation of Guangdong Province (2017A030310038, 2018B030311036, 2017A030310038, 2018B030311036)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
cathepsin K, colorectal cancer metastasis, gut microbiota imbalance, M2 macrophage polarization, tumor-associated macrophages, TLR4, mTOR signaling, NF-κB signaling, IL-10, IL-17, tumor microenvironment, odanacatib, tumor cell migration and invasion, predictive biomarkers, therapeutic target
MeSH terms
Gastrointestinal Microbiome, Animals, Escherichia coli, Female, Humans, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Prognosis, Colorectal Neoplasms, HT29 Cells, HCT116 Cells, Cell Line, Tumor, Toll-Like Receptor 4, Mice, Cathepsin K, Tumor Microenvironment, Heterografts

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