Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Genetics and Genomics

Depiction of the genomic and genetic landscape identifies CCL5 as a protective factor in colorectal neuroendocrine carcinoma

British Journal of Cancer volume 125, pages 994–1002 (2021)Cite this article

Subjects

Abstract

Background

Colorectal neuroendocrine carcinomas (CRNECs) are highly aggressive tumours with poor prognosis and low incidence. To date, the genomic landscape and molecular pathway alterations have not been elucidated.

Methods

Tissue sections and clinical information of CRNEC (n = 35) and CR neuroendocrine tumours (CRNETs) (n = 25) were collected as an in-house cohort (2010–2020). Comprehensive genomic and expression panels (AmoyDx® Master Panel) were applied to identify the genomic and genetic alterations of CRNEC. Through the depiction of the genomic landscape and transcriptome profile, we compared the difference between CRNEC and CRNET. Reverse transcription-polymerase chain reaction and immunofluorescence staining were performed to confirm the genetic alterations.

Results

High tumour mutation load was observed in CRNEC compared with CRNET. CRNECs showed a “cold” immune landscape and increased endothelial cell activity compared with NETs. Importantly, PAX5 was aberrantly expressed in CRNEC and predicted a poor prognosis of CRNECs. CCL5, a factor that is considered an immunosuppressive factor in several tumour types, was strongly expressed in CRNEC patients with long-term survival and correlated with high CD8+ T cell infiltration.

Conclusion

Through the depiction of the genomic landscape and transcriptome profile, we demonstrated alterations in molecular pathways and potential targets for immunotherapy in CRNEC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The genomic landscape of CRNEC and CRNET.
Fig. 2: Comparison of transcriptome profiles between NEC and NET.
Fig. 3: Genetic alterations in CRNEC and potential targets for immunotherapy.
Fig. 4: RT-PCR for targeted genes.
Fig. 5: Immunofluorescence double staining.

Similar content being viewed by others

Data availability

All presented data in this study are available from the corresponding author upon reasonable request.

References

  1. Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020;76:182–8.

    Article  Google Scholar 

  2. Bertani E, Ravizza D, Milione M, Massironi S, Grana CM, Zerini D, et al. Neuroendocrine neoplasms of rectum: a management update. Cancer Treat. Rev. 2018;66:45–55.

    Article  Google Scholar 

  3. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335–42.

    Article  Google Scholar 

  4. Chen L, Liu M, Zhang Y, Guo Y, Chen M-H, Chen J. Genetic characteristics of colorectal neuroendocrine carcinoma: more similar to colorectal adenocarcinoma. Clin Colorectal Cancer. 2021;20:177–85.e13.

    Article  Google Scholar 

  5. Dizdar L, Werner TA, Drusenheimer JC, Möhlendick B, Raba K, Boeck I, et al. BRAFV600E mutation: a promising target in colorectal neuroendocrine carcinoma. Int J Cancer. 2019;144:1379–90.

    Article  CAS  Google Scholar 

  6. Liu L, Zhang R, Deng J, Dai X, Zhu X, Fu Q, et al. Construction of TME and identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma. Cancer Immunol Immunother. 2021:1–16. https://doi.org/10.1007/s00262-021-02967-8. Online ahead of print

  7. Bao X, Zhang H, Wu W, Cheng S, Dai X, Zhu X, et al. Analysis of the molecular nature associated with microsatellite status in colon cancer identifies clinical implications for immunotherapy. J Immunother Cancer. 2020;8:e001437.

    Article  Google Scholar 

  8. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  Google Scholar 

  9. Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 2013;14:7.

    Article  Google Scholar 

  10. Aldinucci D, Borghese C, Casagrande N. The CCL5/CCR5 axis in cancer progression. Cancers 2020;12:1765.

    Article  CAS  Google Scholar 

  11. Walens A, DiMarco AV, Lupo R, Kroger BR, Damrauer JS, Alvarez JV. CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors. Elife 2019;8:e43653.

    Article  Google Scholar 

  12. Huang R, Wang S, Wang N, Zheng Y, Zhou J, Yang B, et al. CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling. Cell Death Dis. 2020;11:1–20.

    Article  Google Scholar 

  13. Zazo S, González-Alonso P, Martin-Aparicio E, Chamizo C, Luque M, Sanz-Alvarez M, et al. Autocrine CCL5 effect mediates trastuzumab resistance by ERK pathway activation in HER2-positive breast cancer. Mol Cancer Ther. 2020;19:1696–707.

    Article  CAS  PubMed  Google Scholar 

  14. García-Suárez O, García B, Fernández-Vega I, Astudillo A, Quirós LM. Neuroendocrine tumors show altered expression of chondroitin sulfate, glypican 1, glypican 5, and syndecan 2 depending on their differentiation grade. Front Oncol. 2014;4:15.

    Article  Google Scholar 

  15. Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, et al. Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J. 2012;279:1177–97.

    Article  CAS  Google Scholar 

  16. Lindahl U, Kjellén L. Pathophysiology of heparan sulphate: many diseases, few drugs. J Intern Med. 2013;273:555–71.

    Article  CAS  Google Scholar 

  17. Iozzo RV, Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med. 2011;15:1013–31.

    Article  CAS  Google Scholar 

  18. Busslinger M. Transcriptional control of early B cell development. Annu Rev Immunol. 2004;22:55–79.

    Article  CAS  Google Scholar 

  19. Souabni A, Jochum W, Busslinger M. Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus. Blood 2007;109:281–9.

    Article  CAS  Google Scholar 

  20. Robichaud GA, Nardini M, Laflamme M, Cuperlovic-Culf M, Ouellette RJ. Human Pax-5 C-terminal isoforms possess distinct transactivation properties and are differentially modulated in normal and malignant B cells. J Biol Chem. 2004;279:49956–63.

    Article  CAS  Google Scholar 

  21. Yan M, Himoudi N, Pule M, Sebire N, Poon E, Blair A, et al. Development of cellular immune responses against PAX5, a novel target for cancer immunotherapy. Cancer Res. 2008;68:8058–65.

    Article  CAS  Google Scholar 

  22. Do HTT, Lee CH, Cho J. Chemokines and their receptors: multifaceted roles in cancer progression and potential value as cancer prognostic markers. Cancers. 2020;12:287.

    Article  CAS  Google Scholar 

  23. Aldinucci D, Borghese C, Casagrande N. Formation of the immunosuppressive microenvironment of classic Hodgkin lymphoma and therapeutic approaches to counter it. Int J Mol Sci. 2019;20:2416.

    Article  Google Scholar 

  24. Chang L-Y, Lin Y-C, Mahalingam J, Huang C-T, Chen T-W, Kang C-W, et al. Tumor-derived chemokine CCL5 enhances TGF-β–mediated killing of CD8+ T cells in colon cancer by T-regulatory cells. Cancer Res. 2012;72:1092–102.

    Article  CAS  Google Scholar 

  25. Jiao X, Velasco-Velázquez MA, Wang M, Li Z, Rui H, Peck AR, et al. CCR5 governs DNA damage repair and breast cancer stem cell expansion. Cancer Res. 2018;78:1657–71.

    Article  CAS  Google Scholar 

  26. Wang S-W, Liu S-C, Sun H-L, Huang T-Y, Chan C-H, Yang C-Y, et al. CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment. Carcinogenesis 2015;36:104–14.

    Article  Google Scholar 

  27. Ban Y, Mai J, Li X, Mitchell-Flack M, Zhang T, Zhang L, et al. Targeting autocrine CCL5–CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity. Cancer Res. 2017;77:2857–68.

    Article  CAS  Google Scholar 

  28. Yang X, Hou J, Han Z, Wang Y, Hao C, Wei L, et al. One cell, multiple roles: contribution of mesenchymal stem cells to tumor development in tumor microenvironment. Cell Biosci. 2013;3:5.

    Article  CAS  Google Scholar 

  29. Casagrande N, Borghese C, Visser L, Mongiat M, Colombatti A, Aldinucci D. CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth. Haematologica 2019;104:564–75.

    Article  CAS  Google Scholar 

  30. Cambien B, Richard-Fiardo P, Karimdjee BF, Martini V, Ferrua B, Pitard B, et al. CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRβ in colorectal carcinoma. PLoS ONE. 2011;6:e28842.

    Article  CAS  Google Scholar 

  31. Üçüncü M, Serilmez M, Sarı M, Bademler S, Karabulut S. The diagnostic significance of PDGF, EphA7, CCR5, and CCL5 levels in colorectal cancer. Biomolecules 2019;9:464.

    Article  Google Scholar 

  32. Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, et al. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell. 2016;29:587–601.

    Article  CAS  Google Scholar 

  33. Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA, et al. Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell. 2019;35:885–900. e10

    Article  CAS  Google Scholar 

  34. de Galarreta MR, Bresnahan E, Molina-Sánchez P, Lindblad KE, Maier B, Sia D, et al. β-Catenin activation promotes immune escape and resistance to anti–PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019;9:1124–41.

    Article  Google Scholar 

  35. Huffman AP, Lin JH, Kim SI, Byrne KT, Vonderheide RH. CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity. JCI Insight. 2020;5:e137263.

    Article  Google Scholar 

  36. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 2018;172:1022–37.e14.

    Article  Google Scholar 

  37. Seo W, Shimizu K, Kojo S, Okeke A, Kohwi-Shigematsu T, Fujii S-I, et al. Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity. Nat Commun. 2020;11:1–16.

    Article  Google Scholar 

  38. Mowat C, Mosley SR, Namdar A, Schiller D, Baker K. Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN–driven CCL5 and CXCL10. J Exp Med. 2021;218:e20210108.

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by grants (nos. 81874143, 31971192) from the National Nature Science Foundation of China and grants (LY21H030005, LQ19H160025, LY19H160040) from the Natural Science Foundation of Zhejiang Province.

Author information

Author notes

  1. These authors contributed equally: Dong Chen, Xuanwen Bao, Ruyi Zhang.

Authors and Affiliations

  1. Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Dong Chen, Benfeng Li, Saisai Wang & Xiaofei Cheng

  2. Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Xuanwen Bao, Ruyi Zhang, Yongfeng Ding, Hangyu Zhang, Zhou Tong, Lulu Liu, Yi Zheng, Jian Ruan, Weijia Fang & Peng Zhao

  3. College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China

    Min Zhang

  4. Department of Emergency, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China

    Xiaolin Li

  5. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China

    Xiaohu Zhou

Authors
  1. Dong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuanwen Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruyi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yongfeng Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Benfeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hangyu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaolin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhou Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lulu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiaohu Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Saisai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiaofei Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yi Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jian Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Weijia Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Peng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DC: investigation, methodology, writing original draft and writing—review and editing. XB: conceptualisation, methodology, data curation, formal analysis, methodology, visualisation, project administration and writing the original draft. RZ: data curation, formal analysis and writing—review and editing. HZ: data curation, formal analysis and writing—review and editing. ZT: data curation, visualisation and writing—review and editing. LL: data curation, validation and writing—review and editing. YZ: data curation, software and writing—review and editing. MZ: data curation, validation and writing—review and editing. XL: validation and writing—review and editing. SW: validation and writing—review and editing. BL: data curation, validation and writing—review and editing. XC: data curation, validation and writing—review and editing. XC: data curation, validation and writing—review and editing. RJ: formal analysis, visualisation, methodology and writing—review and editing. WF: conceptualisation, supervision, funding acquisition and writing—review and editing. PZ: investigation, visualisation, supervision and writing—review and editing.

Corresponding authors

Correspondence to Jian Ruan, Weijia Fang or Peng Zhao.

Ethics declarations

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by the ethics committee of The First Affiliated Hospital, College of Medicine, Zhejiang University. All patients/participants provided informed consent.

Consent for publication

All authors reviewed and approved the manuscript.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, D., Bao, X., Zhang, R. et al. Depiction of the genomic and genetic landscape identifies CCL5 as a protective factor in colorectal neuroendocrine carcinoma. Br J Cancer 125, 994–1002 (2021). https://doi.org/10.1038/s41416-021-01501-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01501-y

Search

Advanced search

Quick links