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

Cell Death & Differentiation (2019) | Download Citation

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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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81572813, 81773082, 81702903, 81872423), Guangdong Natural Science Foundation (2017A030310038, 2018B030311036) and Fork Ying Tung Education Foundation (161035).

Author information

Author notes

  1. These authors contributed equally: Rui Li, Rui Zhou, Hui Wang

Affiliations

  1. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    • Rui Li
    • , Rui Zhou
    • , Yanqing Ding
    •  & Liang Zhao
  2. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

    • Rui Li
    • , Rui Zhou
    • , Wanqi Zhan
    • , Lijun Xu
    • , Yanqing Ding
    •  & Liang Zhao
  3. Department of Medical Oncology, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China

    • Hui Wang
    •  & Weidong Li
  4. Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    • Mingxin Pan
  5. Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China

    • Xueqing Yao
  6. Gastrointestinal Surgical Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    • Shibin Yang

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Contributions

LZ led study design and prepared the manuscript; RL, RZ, and HW carried out the experiments; W-DL, L-JX and M-XP performed statistical analysis; X-QY, W-QZ and S-BY assisted in tissue sample collection and clinical analysis; Y-QD performed data analysis and interpretation.

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Yanqing Ding or Liang Zhao.

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DOI

https://doi.org/10.1038/s41418-019-0312-y