Skip to main content

Advertisement

SpringerLink
Log in

Colorectal cancer-derived exosomes and modulation KRAS signaling

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

Abstract

Colorectal cancer (CRC) is one of the most common cancers worldwide and one of the main causes of cancer-associated mortality. At the period of diagnosis, metastases to other tissues will be present in around 30% of CRC individuals. Individuals with CRC continue to have a poor prognosis despite advances in medication. There is a growing body of literature that CRC develops as a result of the aggregation of various mutations in tumor oncogenes or suppressor genes and that diagnosing cancer in its initial phases may assist in increasing the overall lifespan of individuals with the illness. On the other hand, tumor cells may discharge exosomes in response to oncogenic mutations. By Inhibiting signaling pathways, including the Kirsten rat sarcoma virus (KRAS) mechanism, which is important in a variety of cell activities, exosomes have been shown to cause colorectal cancer in animal studies. The purpose of this review was to summarize the latest discoveries on the modulation of KRAS signaling by exosomes extracted from colorectal cancer.

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

Similar content being viewed by others

Data availability

It is not applicable.

References

  1. Hofsli E, Sjursen W, Prestvik W, Johansen J, Rye M, Tranø G, et al. Identification of serum microRNA profiles in colon cancer. Br J Cancer. 2013;108(8):1712–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gao Y, Wang J, Zhou Y, Sheng S, Qian SY, Huo X. Evaluation of serum CEA, CA19-9, CA72-4, CA125 and ferritin as diagnostic markers and factors of clinical parameters for colorectal cancer. Sci Rep. 2018;8(1):2732.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Taylor DP, Burt RW, Williams MS, Haug PJ, Cannon-Albright LA. Population-based family history–specific risks for colorectal cancer: a constellation approach. Gastroenterology. 2010;138(3):877–85.

    Article  PubMed  Google Scholar 

  4. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507.

    Article  CAS  PubMed  Google Scholar 

  5. Iranshahi N, Zafari P, Yari KH, Alizadeh E. The most common genes involved in epigenetics modifications among Iranian patients with breast cancer: a systematic review. Cell Mole biol (Noisy-le-Grand, France). 2016;62(12):116–22.

    CAS  Google Scholar 

  6. Simanshu DK, Nissley DV, McCormick F. RAS Proteins and their regulators in human disease. Cell. 2017;170(1):17–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mustachio LM, Chelariu-Raicu A, Szekvolgyi L, Roszik J. Targeting KRAS in cancer: promising therapeutic strategies. Cancers (Basel). 2021;13(6):1204.

    Article  CAS  Google Scholar 

  8. Hao Y-X, Li Y-M, Ye M, Guo Y-Y, Li Q-W, Peng X-M, et al. KRAS and BRAF mutations in serum exosomes from patients with colorectal cancer in a Chinese population. Oncol Lett. 2017;13(5):3608–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Singh A, Sweeney MF, Yu M, Burger A, Greninger P, Benes C, et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell. 2012;148(4):639–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Vermeulen L, De Sousa EMF, Van Der Heijden M, Cameron K, De Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat cell biol. 2010;12(5):468–76.

    Article  CAS  PubMed  Google Scholar 

  11. Kobayashi M, Salomon C, Tapia J, Illanes SE, Mitchell MD, Rice GE. Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200. J Transl Med. 2014;12(1):1–12.

    Article  Google Scholar 

  12. Hejrati A, Hasani B, Esmaili M, Bashash D, Tavakolinia N, Zafari P. Role of exosome in autoimmunity, with a particular emphasis on rheumatoid arthritis. Int J Rheum Dis. 2021;24(2):159–69.

    Article  CAS  PubMed  Google Scholar 

  13. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325(7):669–85.

    Article  CAS  PubMed  Google Scholar 

  14. Mosquera-Heredia MI, Morales LC, Vidal OM, Barceló E, Silvera-Redondo C, Vélez JI, et al. Exosomes: potential disease biomarkers and new therapeutic targets. Biomedicines. 2021;9(8):1061.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Narang P, Shah M, Beljanski V. Exosomal RNAs in diagnosis and therapies. Non-coding RNA Res. 2022;7(1):7–15.

    Article  CAS  Google Scholar 

  16. Yuana Y, Sturk A, Nieuwland R. Extracellular vesicles in physiological and pathological conditions. Blood Rev. 2013;27(1):31–9.

    Article  CAS  PubMed  Google Scholar 

  17. De Toro J, Herschlik L, Waldner C, Mongini C. Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol. 2015;6:203.

    PubMed  PubMed Central  Google Scholar 

  18. Nicolini A, Ferrari P, Biava PM. Exosomes and cell communication: from tumour-derived exosomes and their role in tumour progression to the use of exosomal cargo for cancer treatment. Cancers (Basel). 2021;13(4):822.

    Article  CAS  Google Scholar 

  19. Bahrami A, Moradi Binabaj MA, Ferns G. Exosomes: Emerging modulators of signal transduction in colorectal cancer from molecular understanding to clinical application. Biomed Pharmacother. 2021;141:182.

    Article  Google Scholar 

  20. Campanella C, Rappa F, Sciumè C, Marino Gammazza A, Barone R, Bucchieri F, et al. Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery. Cancer. 2015;121(18):3230–9.

    Article  CAS  PubMed  Google Scholar 

  21. Vafaei S, Fattahi F, Ebrahimi M, Janani L, Shariftabrizi A, Madjd Z. Common molecular markers between circulating tumor cells and blood exosomes in colorectal cancer: a systematic and analytical review. Cancer Manag Res. 2019;11:8669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: small particle, big player. J Hematol Oncol. 2015;8(1):1–13.

    Article  PubMed Central  Google Scholar 

  23. Lugini L, Valtieri M, Federici C, Cecchetti S, Meschini S, Condello M, et al. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells. Oncotarget. 2016;7(31):50086.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Beckler MD, Higginbotham JN, Franklin JL, Ham A-J, Halvey PJ, Imasuen IE, et al. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics. 2013;12(2):343–55.

    Article  CAS  Google Scholar 

  25. Wood K, Hensing T, Malik R, Salgia R. Prognostic and predictive value in KRAS in non–small-cell lung cancer: a review. JAMA Oncol. 2016;2(6):805–12.

    Article  PubMed  Google Scholar 

  26. Dearden S, Stevens J, Wu Y-L, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24(9):2371–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dogan S, Shen R, Ang DC, Johnson ML, D’Angelo SP, Paik PK, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012;18(22):6169–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Carvalho PD, Guimaraes CF, Cardoso AP, Mendonça S, Costa ÂM, Oliveira MJ, et al. KRAS oncogenic signaling extends beyond cancer cells to orchestrate the microenvironment. Can Res. 2018;78(1):7–14.

    Article  Google Scholar 

  29. Pereira F, Ferreira A, Reis CA, Sousa MJ, Oliveira MJ, Preto A. KRAS as a modulator of the inflammatory tumor microenvironment: therapeutic implications. Cells. 2022;11(3):398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sumimoto H, Takano A, Teramoto K, Daigo Y. RAS–mitogen-activated protein kinase signal is required for enhanced PD-L1 expression in human lung cancers. PLoS ONE. 2016;11(11): e0166626.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chen N, Fang W, Lin Z, Peng P, Wang J, Zhan J, et al. KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunol Immunother. 2017;66(9):1175–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zdanov S, Mandapathil M, Eid RA, Adamson-Fadeyi S, Wilson W, Qian J, et al. Mutant KRAS conversion of conventional T cells into regulatory T cells. Cancer Immunol Res. 2016;4(4):354–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Petanidis S, Anestakis D, Argyraki M, Hadzopoulou-Cladaras M, Salifoglou A. Differential expression of IL-17, 22 and 23 in the progression of colorectal cancer in patients with K-ras mutation: ras signal inhibition and crosstalk with GM-CSF and IFN-γ. PLoS ONE. 2013;8(9): e73616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gurtner K, Kryzmien Z, Koi L, Wang M, Benes CH, Hering S, et al. Radioresistance of KRAS/TP53-mutated lung cancer can be overcome by radiation dose escalation or EGFR tyrosine kinase inhibition in vivo. Int J Cancer. 2020;147(2):472–7.

    Article  CAS  PubMed  Google Scholar 

  35. Bahrami A, Hassanian SM, ShahidSales S, Farjami Z, Hasanzadeh M, Anvari K, et al. Targeting RAS signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. J Cell Physiol. 2018;233(3):2058–66.

    Article  CAS  PubMed  Google Scholar 

  36. Ayatollahi H, Tavassoli A, Jafarian AH, Alavi A, Shakeri S, Shams SF, et al. KRAS codon 12 and 13 mutations in gastric cancer in the Northeast Iran. Iran J Pathol. 2018;13(2):167.

    Article  PubMed  PubMed Central  Google Scholar 

  37. McCormick F. KRAS as a therapeutic target. Clin Cancer Res. 2015;21(8):1797–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Garcia-Carbonero N, Martinez-Useros J, Li W, Orta A, Perez N, Carames C, et al. KRAS and BRAF mutations as prognostic and predictive biomarkers for standard chemotherapy response in metastatic colorectal cancer: a single institutional study. Cells. 2020;9(1):219.

    Article  CAS  PubMed Central  Google Scholar 

  39. Higginbotham JN, Beckler MD, Gephart JD, Franklin JL, Bogatcheva G, Kremers G-J, et al. Amphiregulin exosomes increase cancer cell invasion. Curr Biol. 2011;21(9):779–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lucchetti D, Calapà F, Palmieri V, Fanali C, Carbone F, Papa A, et al. Differentiation affects the release of exosomes from colon cancer cells and their ability to modulate the behavior of recipient cells. Am J Pathol. 2017;187(7):1633–47.

    Article  CAS  PubMed  Google Scholar 

  41. Cha DJ, Franklin JL, Dou Y, Liu Q, Higginbotham JN, Beckler MD, et al. KRAS-dependent sorting of miRNA to exosomes. Elife. 2015;4: e07197.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dou Y, Cha DJ, Franklin JL, Higginbotham JN, Jeppesen DK, Weaver AM, et al. Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes. Sci Rep. 2016;6(1):1–11.

    Article  Google Scholar 

  43. Bahrami A, Hesari A, Khazaei M, Hassanian SM, Ferns GA, Avan A. The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer. J Cell Physiol. 2018;233(3):2162–9.

    Article  CAS  PubMed  Google Scholar 

  44. Ragusa M, Statello L, Maugeri M, Barbagallo C, Passanisi R, Alhamdani MS, et al. Highly skewed distribution of miRNAs and proteins between colorectal cancer cells and their exosomes following Cetuximab treatment: biomolecular, genetic and translational implications. Oncoscience. 2014;1(2):132–57.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ragusa M, Statello L, Maugeri M, Barbagallo C, Passanisi R, Alhamdani MS, et al. Highly skewed distribution of miRNAs and proteins between colorectal cancer cells and their exosomes following cetuximab treatment: biomolecular, genetic and translational implications. Oncoscience. 2014;1(2):132.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Bigagli E, Luceri C, Guasti D, Cinci L. Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: role of microRNA-210. Cancer Biol Ther. 2016;17(10):1062–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bahrami A, Majeed M, Sahebkar A. Curcumin: a potent agent to reverse epithelial-to-mesenchymal transition. Cell Oncol. 2019;42(4):405–21.

    Article  CAS  Google Scholar 

  48. Shang A, Gu C, Zhou C, Yang Y, Chen C, Zeng B, et al. Exosomal KRAS mutation promotes the formation of tumor-associated neutrophil extracellular traps and causes deterioration of colorectal cancer by inducing IL-8 expression. Cell Commun Signal. 2020;18(1):1–14.

    Article  Google Scholar 

  49. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205(12):858–62.

    Article  CAS  PubMed  Google Scholar 

  50. Román M, Baraibar I, López I, Nadal E, Rolfo C, Vicent S, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer. 2018;17(1):33.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, et al. Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer. J Med Chem. 2020;63(13):6679–93.

    Article  CAS  PubMed  Google Scholar 

  52. Fakih M, O’Neil B, Price TJ, Falchook GS, Desai J, Kuo J, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. Am Soc Clin Oncol. 2019;37:3003.

    Article  Google Scholar 

  53. Kargbo RB. Inhibitors of G12C mutant ras proteins for the treatment of cancers. ACS Med Chem Lett. 2018;10(1):10–1.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Xie C, Li Y, Li L-L, Fan X-X, Wang Y-W, Wei C-L, et al. Identification of a new potent inhibitor targeting KRAS in non-small cell lung cancer cells. Front Pharmacol. 2017;8:823.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Patricelli MP, Janes MR, Li L-S, Hansen R, Peters U, Kessler LV, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 2016;6(3):316–29.

    Article  CAS  PubMed  Google Scholar 

  57. Lito P, Solomon M, Li L-S, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cao Z, Liao Q, Su M, Huang K, Jin J, Cao D. AKT and ERK dual inhibitors: the way forward? Cancer Lett. 2019;459:30–40.

    Article  CAS  PubMed  Google Scholar 

  59. Roskoski R Jr. Targeting ERK1/2 protein-serine/threonine kinases in human cancers. Pharmacol Res. 2019;142:151–68.

    Article  CAS  PubMed  Google Scholar 

  60. Sullivan RJ, Hollebecque A, Flaherty KT, Shapiro GI, Ahnert JR, Millward MJ, et al. A phase I study of LY3009120, a pan-RAF inhibitor, in patients with advanced or metastatic cancer. Mol Cancer Ther. 2020;19(2):460–7.

    Article  CAS  PubMed  Google Scholar 

  61. Tignanelli CJ, Herrera Loeza SG, Yeh JJ. KRAS and PIK3CA mutation frequencies in patient-derived xenograft models of pancreatic and colorectal cancer are reflective of patient tumors and stable across passages. Am Surg. 2014;80(9):873–7.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Stefani C, Miricescu D, Stanescu-Spinu I-I, Nica RI, Greabu M, Totan AR, et al. Growth factors, PI3K/AKT/mTOR and MAPK signaling pathways in colorectal cancer pathogenesis: where are we now? Int J Mol Sci. 2021;22(19):10260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6(1):425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Janes MR, Zhang J, Li L-S, Hansen R, Peters U, Guo X, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172(3):578-89. e17.

    Article  CAS  PubMed  Google Scholar 

  65. Saiki AY, Gaida K, Rex K, Achanta P, San Miguel T, Koppada N, et al. Discovery and in vitro characterization of AMG 510–a potent and selective covalent small-molecule inhibitor of KRASG12C. AACR. 2019;79:4484–4484.

    Google Scholar 

  66. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23.

    Article  CAS  PubMed  Google Scholar 

  67. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54–71.

    Article  CAS  PubMed  Google Scholar 

  68. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang C, Fakih M. Targeting KRAS in colorectal cancer. Curr Oncol Rep. 2021;23(3):1–10.

    Article  Google Scholar 

Download references

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

  1. Three Branches of General Surgery, JiuJiang First People’s Hospital, Jiujiang, Jiangxi, China

    Yan Hua Wan, Qi Sheng Liu & Ri Wei Wang

  2. Endoscopy Room, JiuJiang First People’s Hospital, Jiujiang, Jiangxi, China

    Sha Sha Wan

Authors
  1. Yan Hua Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qi Sheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sha Sha Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ri Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SV and FA contributed to the idea design and literature search. HT and YH wrote parts of the manuscript. AF contributed to designing the figures.

Corresponding author

Correspondence to Ri Wei Wang.

Ethics declarations

Conflict of interest

None.

Ethical approval

It is not applicable.

Informed consent

It is 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

Wan, Y.H., Liu, Q.S., Wan, S.S. et al. Colorectal cancer-derived exosomes and modulation KRAS signaling. Clin Transl Oncol 24, 2074–2080 (2022). https://doi.org/10.1007/s12094-022-02877-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-022-02877-w

Keywords

Search

Navigation