中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 40 Issue 6
Jun.  2024
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(6): 1183-1190

Impact of cancer-associated fibroblasts on immunotherapy and liver metastasis in colorectal cancer

DOI: 10.12449/JCH240618
  • 1.

    School of Medicine，South China University of Technology，Guangzhou 510006，China

  • 2.

    Guangdong Cardiovascular Institute，Guangdong Provincial People’s Hospital，Guangzhou 510080，China

Research funding:

Young Scientists Fund of the National Natural Science Foundation of China (82303785);

Young Scientists Fund of the National Natural Science Foundation of China (32100720)

More Information
  • Corresponding author: LIAN Zhexiong， zxlian@gdph.org.cn （ORCID： 0000-0002-9525-1421）
  • Received Date: 2023-12-27
  • Accepted Date: 2024-01-19
  • Published Date: 2024-06-25
    Abstract
  •   Objective  To investigate the impact of cancer-associated fibroblasts （CAFs） on immunotherapy and liver metastasis in colorectal cancer （CRC）.  Methods  The single-cell sequencing data （GSE205506） of CRC patients with mismatch repair deficiency （MMRd） were downloaded from the gene expression omnibus database， and R software was used to preprocess the original sequencing data and establish the umap of fibroblast subpopulations， with each subpopulation named based on signature genes. GraphPad was used for the statistical analysis of the proportion of each fibroblast subpopulation， and the key subpopulations with significant differences were analyzed among CRC patients before and after PD-1 immunotherapy， as well as between the patients with pathological complete response （pCR） and those without pCR （non-pCR） after treatment. The analysis of differentially expressed genes and the gene pathway enrichment analysis were performed for the key subpopulations. The TCGA database was used to perform a prognostic and survival analysis of the signature genes of key CAF subpopulations， and RNA sequencing data were used to score and calculate the proportion of key CAF subpopulations in the primary lesions of CRC patients with liver metastasis. The independent-samples t test was used for comparison of normally distributed continuous data between two groups； the Kaplan-Meier method was used to plot survival curves， and the log-rank test was used to calculate survival rates. CellPhoneDB software was used to analyze the receptor-ligand interaction between fibroblast subpopulations and tumor cells， and in vitro cell experiments were used to validate the effect of NRG1， a key ligand molecule， on the migration and invasion abilities of CRC cells.  Results  After PD-1 immunotherapy for CRC patients， there was a significant reduction in the proportion of F6_MMP1+CAFs （P<0.001）， which was only observed in patients achieving complete remission after immunotherapy. F6_MMP1+CAFs were upregulated， as well as the genes and signaling pathways associated with tumor migration and invasion， and in addition， there was a significant increase in F6_MMP1+CAFs in the tumor tissue of CRC patients with liver metastasis （P<0.000 1）. As a ligand， NRG1 expressed by F6_MMP1+CAFs interacted with ERBB3 receptor expressed by tumor cells， and the in vitro experiments confirmed that NRG1 promoted the migration and invasion abilities of tumor cells by activating the ERBB signaling pathway （P<0.05）.  Conclusion  F6_MMP1+CAFs may affect the efficacy of PD-1 immunotherapy in CRC patients and play an important role in promoting liver metastasis in CRC. F6_MMP1+CAFs， along with NRG1 that is produced by them and can promote tumor metastasis， can be used as potential therapeutic targets and prognostic markers for CRC.

     

    • FullText(HTML)
  • loading
    • References(32)
  • [1]
    DEKKER E, TANIS PJ, VLEUGELS JLA, et al. Colorectal cancer[J]. Lancet, 2019, 394( 10207): 1467- 1480. DOI: 10.1016/S0140-6736(19)32319-0.
    [2]
    HUANG XY, SHI GM, ZHOU J. Opportunities and challenges for the treatment of malignant hepatobiliary tumors in the new era of immunotherapy[J]. J Clin Hepatol, 2022, 38( 5): 977- 979. DOI: 10.3969/j.issn.1001-5256.2022.05.001.

    黄晓勇, 施国明, 周俭. 免疫治疗新时代下肝胆恶性肿瘤治疗的机遇和挑战[J]. 临床肝胆病杂志, 2022, 38( 5): 977- 979. DOI: 10.3969/j.issn.1001-5256.2022.05.001.
    [3]
    LE DT, URAM JN, WANG H, et al. PD-1 blockade in tumors with mismatch-repair deficiency[J]. N Engl J Med, 2015, 372( 26): 2509- 2520. DOI: 10.1056/NEJMoa1500596.
    [4]
    ZHOU H, LIU ZT, WANG YX, et al. Colorectal liver metastasis: Molecular mechanism and interventional therapy[J]. Signal Transduct Target Ther, 2022, 7( 1): 70. DOI: 10.1038/s41392-022-00922-2.
    [5]
    MAO XQ, XU J, WANG W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: New findings and future perspectives[J]. Mol Cancer, 2021, 20( 1): 131. DOI: 10.1186/s12943-021-01428-1.
    [6]
    LI C, TEIXEIRA AF, ZHU HJ, et al. Cancer associated-fibroblast-derived exosomes in cancer progression[J]. Mol Cancer, 2021, 20( 1): 154. DOI: 10.1186/s12943-021-01463-y.
    [7]
    MANTOVANI A, MARCHESI F, JAILLON S, et al. Tumor-associated myeloid cells: Diversity and therapeutic targeting[J]. Cell Mol Immunol, 2021, 18( 3): 566- 578. DOI: 10.1038/s41423-020-00613-4.
    [8]
    TANAKA R, KIMURA K, EGUCHI S, et al. Interleukin-8 produced from cancer-associated fibroblasts suppresses proliferation of the OCUCh-LM1 cancer cell line[J]. BMC Cancer, 2022, 22( 1): 748. DOI: 10.1186/s12885-022-09847-z.
    [9]
    BARRETT T, WILHITE SE, LEDOUX P, et al. NCBI GEO: Archive for functional genomics data sets: Update[J]. Nucleic Acids Res, 2013, 41( Database issue): D991- D995. DOI: 10.1093/nar/gks1193.
    [10]
    LI JX, WU C, HU HB, et al. Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer[J]. Cancer Cell, 2023, 41( 6): 1152- 1169. e 7. DOI: 10.1016/j.ccell.2023.04.011.
    [11]
    FOLEY CJ, LUO C, O'CALLAGHAN K, et al. Matrix metalloprotease-1a promotes tumorigenesis and metastasis[J]. J Biol Chem, 2012, 287( 29): 24330- 24338. DOI: 10.1074/jbc.M112.356303.
    [12]
    WAN XY, GUAN SD, HOU YX, et al. FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts[J]. Theranostics, 2021, 11( 10): 4975- 4991. DOI: 10.7150/thno.55074.
    [13]
    MA ZK, LI XD, MAO YZ, et al. Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer[J]. Cancer Cell, 2022, 40( 12): 1550- 1565. e 7. DOI: 10.1016/j.ccell.2022.11.005.
    [14]
    KUMAR V, RAMNARAYANAN K, SUNDAR R, et al. Single-cell atlas of lineage states, tumor microenvironment, and subtype-specific expression programs in gastric cancer[J]. Cancer Discov, 2022, 12( 3): 670- 691. DOI: 10.1158/2159-8290.CD-21-0683.
    [15]
    DONATO C, KUNZ L, CASTRO-GINER F, et al. Hypoxia triggers the intravasation of clustered circulating tumor cells[J]. Cell Rep, 2020, 32( 10): 108105. DOI: 10.1016/j.celrep.2020.108105.
    [16]
    LEQUEUX A, NOMAN MZ, XIAO M, et al. Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy[J]. Oncogene, 2021, 40( 28): 4725- 4735. DOI: 10.1038/s41388-021-01846-x.
    [17]
    ZHONG BP, CHENG B, HUANG XM, et al. Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling[J]. Cell Death Dis, 2021, 13( 1): 16. DOI: 10.1038/s41419-021-04461-6.
    [18]
    KALLURI R. The biology and function of fibroblasts in cancer[J]. Nat Rev Cancer, 2016, 16( 9): 582- 598. DOI: 10.1038/nrc.2016.73.
    [19]
    LI XQ, XU K. Mechanism of cancer-associated fibroblasts promoting tumor metastasis and invasion[J]. Chin J Biochem Mol Biol, 2019, 35( 4): 386- 392. DOI: 10.13865/j.cnki.cjbmb.2019.04.06.

    李学勤, 徐克. 肿瘤相关成纤维细胞促进肿瘤侵袭转移的作用机制[J]. 中国生物化学与分子生物学报, 2019, 35( 4): 386- 392. DOI: 10.13865/j.cnki.cjbmb.2019.04.06.
    [20]
    ZHANG W, WANG HS, SUN MY, et al. CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target[J]. Cancer Commun, 2020, 40( 2-3): 69- 80. DOI: 10.1002/cac2.12010.
    [21]
    ZHOU SL, DAI Z, ZHOU ZJ, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma[J]. Hepatology, 2012, 56( 6): 2242- 2254. DOI: 10.1002/hep.25907.
    [22]
    ZHAO JK, OU BC, HAN DP, et al. Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways[J]. Mol Cancer, 2017, 16( 1): 70. DOI: 10.1186/s12943-017-0629-4.
    [23]
    SUN XT, HE XK, ZHANG Y, et al. Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism[J]. Gut, 2022, 71( 1): 129- 147. DOI: 10.1136/gutjnl-2020-322744.
    [24]
    XIONG XY, LIAO XY, QIU S, et al. CXCL8 in tumor biology and its implications for clinical translation[J]. Front Mol Biosci, 2022, 9: 723846. DOI: 10.3389/fmolb.2022.723846.
    [25]
    JONES SA, JENKINS BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer[J]. Nat Rev Immunol, 2018, 18( 12): 773- 789. DOI: 10.1038/s41577-018-0066-7.
    [26]
    MCANDREWS KM, CHEN Y, DARPOLOR JK, et al. Identification of functional heterogeneity of carcinoma-associated fibroblasts with distinct IL6-mediated therapy resistance in pancreatic cancer[J]. Cancer Discov, 2022, 12( 6): 1580- 1597. DOI: 10.1158/2159-8290.CD-20-1484.
    [27]
    HAN Y, ZHANG YY, PAN YQ, et al. IL-1β-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance[J]. Mol Cell, 2023, 83( 11): 1887- 1902. e 8. DOI: 10.1016/j.molcel.2023.05.011.
    [28]
    ZHANG ZD, KARTHAUS WR, LEE YS, et al. Tumor microenvironment-derived NRG1 promotes antiandrogen resistance in prostate cancer[J]. Cancer Cell, 2020, 38( 2): 279- 296. e 9. DOI: 10.1016/j.ccell.2020.06.005.
    [29]
    WEI DY, GENG F, LIANG SM, et al. CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells[J]. Biosci Rep, 2017, 37( 2): BSR20160470. DOI: 10.1042/BSR20160470.
    [30]
    XU QX, CHIAO P, SUN Y. Amphiregulin in cancer: New insights for translational medicine[J]. Trends Cancer, 2016, 2( 3): 111- 113. DOI: 10.1016/j.trecan.2016.02.002.
    [31]
    EREZ N, TRUITT M, OLSON P, et al. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner[J]. Cancer Cell, 2010, 17( 2): 135- 147. DOI: 10.1016/j.ccr.2009.12.041.
    [32]
    QI JJ, SUN HX, ZHANG Y, et al. Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer[J]. Nat Commun, 2022, 13( 1): 1742. DOI: 10.1038/s41467-022-29366-6.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(4)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (472) PDF downloads(53) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return