Skip to main content

Advertisement

SpringerLink
Log in

Tumor microenvironment-associated gene C3 can predict the prognosis of colorectal adenocarcinoma: a study based on TCGA

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Colorectal cancer is one of the most common malignancies. With continuous exploration of the interaction between tumor cells and the immune system, tumor immunotherapy has become a revolution. However, CRC remains one of the less effective tumors for immunotherapy. The tumor microenvironment plays an important role in tumorigenesis and progression. The aim of this study is to explore tumor microenvironment-related genes that can predict the prognosis of colorectal adenocarcinoma, and also to provide new ideas for the mechanism of tumor development as well as immunotherapy.

Methods

After estimating Stromalscore and Immunescore of colorectal adenocarcinoma tumor samples according to RNA-Seq expression data downloaded from TCGA, we screened for TME-related differential genes. We filtered prognosis-related core genes by constructing protein–protein interaction networks and making one-factor cox analysis for prognosis. Finally, the relative content of 22 immune cells in tumor tissues was evaluated, and then immune cells associated with core genes were identified.

Results

We screened 773 differential genes related to the TME. Then we identified C3 as a core gene associated with prognosis. Single gene analysis showed that C3 expression was significantly higher in tumor tissues than in normal tissues (p < 0.001). High C3 expression was associated with lower overall survival (p = 0.046). Tumor immune cell analysis showed that mast cells resting, mast cells activated, T cells CD4 memory activated, eosinophils, and macrophages M0 were C3-associated immune cells.

Conclusions

C3 has potential as a biomarker for colorectal adenocarcinoma and could provide new research ideas for the diagnosis and treatment of colorectal adenocarcinoma, especially for immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

All relevant data are within the paper.

Code availability

All relevant codes are within the paper.

References

  1. Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  2. Kasi PM, et al. Rising proportion of young individuals with rectal and colon cancer. Clin Colorectal Cancer. 2019;18(1):e87–95.

    Article  PubMed  Google Scholar 

  3. Wolf AMD, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250–81.

    Article  PubMed  Google Scholar 

  4. Ait Ouakrim D, et al. Trends in colorectal cancer mortality in Europe: retrospective analysis of the WHO mortality database. BMJ. 2015;351:h4970.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kirkegaard H, et al. Association of adherence to lifestyle recommendations and risk of colorectal cancer: a prospective Danish cohort study. BMJ. 2010;341:c5504.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Henrikson NB, et al. Family history and the natural history of colorectal cancer: systematic review. Genet Med. 2015;17(9):702–12.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Nguyen LH, Goel A, Chung DC. Pathways of colorectal carcinogenesis. Gastroenterology. 2020;158(2):291–302.

    Article  CAS  PubMed  Google Scholar 

  8. Harada S, Morlote D. Molecular pathology of colorectal cancer. Adv Anat Pathol. 2020;27(1):20–26.

    Article  CAS  PubMed  Google Scholar 

  9. Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol. 2011;5(3):385–99.

    Article  PubMed  Google Scholar 

  10. Bae JM, Kim JH, Kang GH. Epigenetic alterations in colorectal cancer: the CpG island methylator phenotype. Histol Histopathol. 2013;28(5):585–95.

    CAS  PubMed  Google Scholar 

  11. Guinney J, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  13. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401.

    Article  CAS  PubMed  Google Scholar 

  14. Straussman R, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487(7408):500-U118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sato E, et al. Intraepithelial CD8(+) tumor-infiltrating lymphocytes and a high CD8(+)/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102(51):18538–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mlecnik B, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29(6):610–8.

    Article  PubMed  Google Scholar 

  17. Dekker E, et al. Colorectal cancer. Lancet. 2019;394(10207):1467–80.

    Article  PubMed  Google Scholar 

  18. Galon J, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med. 2012;10:205.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Fukunaga A, et al. CD8(+) tumor-infiltrating lymphocytes together with CD4(+) tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28(1):E26–31.

    Article  PubMed  Google Scholar 

  20. Tomsova M, et al. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol. 2008;108(2):415–20.

    Article  CAS  PubMed  Google Scholar 

  21. Kryczek I, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009;114(6):1141–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sharma P, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007;104(10):3967–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pages F, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009;27(35):5944–51.

    Article  CAS  PubMed  Google Scholar 

  24. Ogino S, et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009;15(20):6412–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mlecnik B, et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity. 2016;44(3):698–711.

    Article  CAS  PubMed  Google Scholar 

  26. Le YY, et al. Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. Cell Mol Immunol. 2004;1(2):95–104.

    CAS  PubMed  Google Scholar 

  27. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27(1):109–18.

    Article  CAS  PubMed  Google Scholar 

  28. Plitas G, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity. 2016;45(5):1122–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Peng D, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015;527(7577):249–53.

  30. Karin N, Wildbaum G. The role of chemokines in shaping the balance between CD4(+) T cell subsets and its therapeutic implications in autoimmune and cancer diseases. Front Immunol. 2015;6:609.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Wanninger J, et al. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappa B, and STAT3 signaling pathways. Am J Physiol Gastrointest Liver Physiol. 2009;297(3):611–8.

    Article  CAS  Google Scholar 

  32. Nastase A, et al. Expression of interleukine-8 as an independent prognostic factor for sporadic colon cancer dissemination. J Med Life. 2014;7(2):215–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zumwalt TJ, et al. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB(+) CD8(+) T-cell infiltration. Oncotarget 2015;6(5):2981–91.

    Google Scholar 

  34. Colvin RA, et al. Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function. J Biol Chem. 2004;279(29):30219–27.

    Article  CAS  PubMed  Google Scholar 

  35. Arenberg DA, et al. Improved survival in tumor-bearing SCID mice treated with interferon-gamma-inducible protein 10 (IP-10/CXCL10). Cancer Immunol Immunother. 2001;50(10):533–8.

    Article  CAS  PubMed  Google Scholar 

  36. Toiyama Y, et al. Evaluation of CXCL10 as a novel serum marker for predicting liver metastasis and prognosis in colorectal cancer. Int J Oncol. 2012;40(2):560–6.

    CAS  PubMed  Google Scholar 

  37. Boguslawska J, et al. Expression of genes involved in cellular adhesion and extracellular matrix remodeling correlates with poor survival of patients with renal cancer. J Urol. 2016;195(6):1892–902.

    Article  CAS  PubMed  Google Scholar 

  38. Lyu T, et al. SMYD3 promotes implant metastasis of ovarian cancer via H3K4 trimethylation of integrin promoters. Int J Cancer. 2020;146(6):1553–67.

    Article  CAS  PubMed  Google Scholar 

  39. Sato T, et al. Interleukin 10 production by human melanoma. Clin Cancer Res. 1996;2(8):1383–90.

    CAS  PubMed  Google Scholar 

  40. Li C, et al. TLR4 signaling pathway in mouse Lewis lung cancer cells promotes the expression of TGF-beta1 and IL-10 and tumor cells migration. Biomed Mater Eng. 2014;24(1):869–75.

    CAS  PubMed  Google Scholar 

  41. Boulland ML, et al. Human interleukin-10 expression in T/natural killer-cell lymphomas: association with anaplastic large cell lymphomas and nasal natural killer-cell lymphomas. Am J Pathol. 1998;153(4):1229–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kundu N, et al. Antimetastatic and antitumor activities of interleukin 10 in a murine model of breast cancer. J Natl Cancer Inst. 1996;88(8):536–41.

    Article  CAS  PubMed  Google Scholar 

  43. Zheng LM, et al. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med. 1996;184(2):579–84.

    Article  CAS  PubMed  Google Scholar 

  44. Mannino MH, et al. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 2015;367(2):103–7.

    Article  CAS  PubMed  Google Scholar 

  45. Li BS, et al. Predictive value of IL-18 and IL-10 in the prognosis of patients with colorectal cancer. Oncol Lett. 2019;18(1):713–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ricklin D, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ricklin D, Reis ES, Lambris JD. Complement in disease: a defence system turning offensive. Nat Rev Nephrol. 2016;12(7):383–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kwak JW, et al. Complement activation via a C3a receptor pathway alters CD4(+) T lymphocytes and mediates lung cancer progression. Can Res. 2018;78(1):143–56.

    Article  CAS  Google Scholar 

  49. Janelle V, et al. Transient complement inhibition promotes a tumor-specific immune response through the implication of natural killer cells. Cancer Immunol Res. 2014;2(3):200–6.

    Article  CAS  PubMed  Google Scholar 

  50. Cho MS, et al. Complement component 3 is regulated by TWIST1 and mediates epithelial-mesenchymal transition. J Immunol. 2016;196(3):1412–8.

    Article  CAS  PubMed  Google Scholar 

  51. Downs-Canner S, et al. Complement inhibition: a novel form of immunotherapy for colon cancer. Ann Surg Oncol. 2016;23(2):655–62.

    Article  PubMed  Google Scholar 

  52. Roumenina LT, et al. Context-dependent roles of complement in cancer. Nat Rev Cancer. 2019;19(12):698–715.

    Article  CAS  PubMed  Google Scholar 

  53. Habermann JK, et al. Increased serum levels of complement C3a anaphylatoxin indicate the presence of colorectal tumors. Gastroenterology. 2006;131(4):1020–9.

    Article  CAS  PubMed  Google Scholar 

  54. Mehrabani D, et al. Clinical significance of serum vascular endothelial growth factor and complement 3a levels in patients with colorectal cancer in southern Iran. Asian Pac J Cancer Prev. 2014;15(22):9713–7.

    Article  PubMed  Google Scholar 

  55. Fridman WH, et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717–34.

    Article  CAS  PubMed  Google Scholar 

  56. Bonavita E, et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell. 2015;160(4):700–14.

    Article  CAS  PubMed  Google Scholar 

  57. Crivellato E, Ribatti D. The mast cell: an evolutionary perspective. Biol Rev. 2010;85(2):347–60.

    Article  PubMed  Google Scholar 

  58. Reichman H, et al. Activated eosinophils exert antitumorigenic activities in colorectal cancer. Cancer Immunol Res. 2019;7(3):388–400.

    Article  CAS  PubMed  Google Scholar 

  59. Gangwar RS, et al. Mast cell and eosinophil surface receptors as targets for anti-allergic therapy. Pharmacol Ther. 2017;170:37–63.

    Article  CAS  PubMed  Google Scholar 

  60. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.

    Article  CAS  PubMed  Google Scholar 

  61. Fridman WH, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Y. Liu & X. Wang

Authors
  1. Y. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X. Wang.

Ethics declarations

Conflict of interest

All the authors declared that they have no conflict of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Wang, X. Tumor microenvironment-associated gene C3 can predict the prognosis of colorectal adenocarcinoma: a study based on TCGA. Clin Transl Oncol 23, 1923–1933 (2021). https://doi.org/10.1007/s12094-021-02602-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-021-02602-z

Keywords

Search

Navigation