Potential oncogenic roles of mutant-p53-derived exosomes in the tumor–host interaction of head and neck cancers

Abstract

The wide-ranging collection of malignancies arising at the upper aerodigestive tract is categorized as head and neck cancer (HNC), the sixth most prevalent cancer worldwide. Infection with human papillomavirus (HPV) or exposure to carcinogens is the leading causes of HPV+ and HPV− HNCs development, respectively. HPV+ and HPV− HNCs are different in clinical and molecular aspects. Specifically, HPV− HNCs tightly associate with missense mutants of the TP53 gene (encoding for the p53 protein), suggesting a central role for mutant p53 gain-of-function (GOF) in driving tumorigenesis. In contrast, in HPV + HNC, the sequence of TP53 typically remains intact, while the protein is degraded. In tumor cells, the status of the TP53 gene affects the cargo of secreted exosomes. In this review, we describe the accumulated knowledge regarding the involvement of exosomes and p53 on cellular interactions between HPV+ and HPV− HNC cells, and the surrounding tumor microenvironment (TME). Moreover, we envision how TP53 status may determine exosomes cargo in HNC, and, consequently, modify the TME. The potential roles of exosomes described herein are based on both our studies and the studies of others on mutant p53-derived exosomes. Specifically, we showed how exosomes are shed by cancer cells harboring mutant p53 communicate with tumor-associated macrophages in the colon as well as with cancer-associated fibroblasts in the lung, creating immunosuppressive conditions and promoting invasiveness. Altogether, exosomes in HNC in the context of TP53 status are understudied and extensive research is required to shed light on the biology of HPV+ and HPV− HNC.

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

Fig. 1
Fig. 2
Fig. 3

Abbreviations

AACR:

American Association for Cancer Research

CAFs:

Cancer-associated fibroblasts

COX2:

Cyclooxygenase-2

CRC:

Colorectal cancer

CTLA-4:

Cytolytic T lymphocyte-associated antigen 4

EBV:

Epstein–Barr virus

ECM:

Extracellular matrix

GENIE:

Genomics Evidence Neoplasia Information Exchange [AACR Project]

GOF:

Gain-of-function

HNC:

Head and neck cancer

HPV−:

HPV negative

HPV:

Human papillomavirus

HPV+:

HPV positive

IARC:

International Agency for Research on Cancer

miR:

microRNA

mutp53:

Mutant protein 53

PD-1:

Programmed death 1

Rb:

Retinoblastoma

TAMs:

Tumor-associated macrophages

TCGA:

The Cancer Genome Atlas Program

TME:

Tumor microenvironment

TP53:

Tumor protein 53 gene

WT:

Wild type

WTp53:

Wild-type protein 53

References

  1. 1.

    Parkin DM, Bray F, Ferlay J, Pisani P (2002) Global cancer statistics. CA Cancer J Clin 55:74–108

    Article  Google Scholar 

  2. 2.

    Warnakulasuriya S (2009) Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 45:309–316. https://doi.org/10.1016/j.oraloncology.2008.06.002

    Article  PubMed  Google Scholar 

  3. 3.

    Deng Z, Uehara T, Maeda H et al (2014) Epstein-barr virus and human papillomavirus infections and genotype distribution in head and neck cancers. PLoS One 9:e113702. https://doi.org/10.1371/journal.pone.0113702

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Ritchie JM, Smith EM, Summersgill KF et al (2003) Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 104:336–344. https://doi.org/10.1002/ijc.10960

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Khalid MB, Ting P, Pai A et al (2019) Initial presentation of human papillomavirus-related head and neck cancer: a retrospective review. Laryngoscope 129:877–882. https://doi.org/10.1002/lary.27296

    Article  PubMed  Google Scholar 

  6. 6.

    Forman D, de Martel C, Lacey CJ et al (2012) Global burden of human papillomavirus and related diseases. Vaccine 30:F12–F23. https://doi.org/10.1016/J.VACCINE.2012.07.055

    Article  PubMed  Google Scholar 

  7. 7.

    Marur S, D’Souza G, Westra WH, Forastiere AA (2010) HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 11:781–789. https://doi.org/10.1016/S1470-2045(10)70017-6

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Madeo M, Colbert PL, Vermeer DW et al (2018) Cancer exosomes induce tumor innervation. Nat Commun 9:4284. https://doi.org/10.1038/s41467-018-06640-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Parfenov M, Pedamallu CS, Gehlenborg N et al (2014) Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci 111:15544–15549. https://doi.org/10.1073/pnas.1416074111

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Hollstein M, Sidransky D, Vogelstein B, Harris C (1991) p53 mutations in human cancers. Science (80-) 253:49–53. https://doi.org/10.1126/science.1905840

    CAS  Article  Google Scholar 

  11. 11.

    Liu C, Mann D, Sinha UK, Kokot NC (2018) The molecular mechanisms of increased radiosensitivity of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC): an extensive review. J Otolaryngol Head Neck Surg 47:59. https://doi.org/10.1186/s40463-018-0302-y

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Sabapathy K, Lane DP (2018) Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol 15:13–30. https://doi.org/10.1038/nrclinonc.2017.151

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Liu Y, Zhang X, Han C et al (2015) TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 520:697–701. https://doi.org/10.1038/nature14418

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Greathouse KL, White JR, Vargas AJ et al (2018) Interaction between the microbiome and TP53 in human lung cancer. Genome Biol 19:123. https://doi.org/10.1186/s13059-018-1501-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Kim MP, Lozano G (2018) Mutant p53 partners in crime. Cell Death Differ 25:161–168. https://doi.org/10.1038/cdd.2017.185

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Pfister NT, Prives C (2017) Transcriptional regulation by wild-type and cancer-related mutant forms of p53. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a026054

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Oren M, Rotter V (2010) Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol 2:a001107. https://doi.org/10.1101/cshperspect.a001107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Li Y, Zhang M-C, Xu X-K et al (2019) Functional diversity of p53 in human and wild animals. Front Endocrinol (Lausanne) 10:152. https://doi.org/10.3389/fendo.2019.00152

    Article  Google Scholar 

  19. 19.

    Cooks T, Pateras IS, Jenkins LM et al (2018) Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun 9:771. https://doi.org/10.1038/s41467-018-03224-w

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Peltanova B, Raudenska M, Masarik M (2019) Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review. Mol Cancer 18:63. https://doi.org/10.1186/s12943-019-0983-5

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wolf P (1967) The nature and significance of platelet products in human plasma. Br J Haematol 13:269–288. https://doi.org/10.1111/j.1365-2141.1967.tb08741.x

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Skog J, Würdinger T, van Rijn S et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476. https://doi.org/10.1038/ncb1800

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Valadi H, Ekström K, Bossios A et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. https://doi.org/10.1038/ncb1596

    CAS  Article  Google Scholar 

  24. 24.

    Zhang X, Yuan X, Shi H et al (2015) Exosomes in cancer: small particle, big player. J Hematol Oncol 8:83. https://doi.org/10.1186/s13045-015-0181-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Xie C, Ji N, Tang Z et al (2019) The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers. Mol Cancer 18:83. https://doi.org/10.1186/s12943-019-0985-3

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Theodoraki M-N, Yerneni S, Gooding WE et al (2019) Circulating exosomes measure responses to therapy in head and neck cancer patients treated with cetuximab, ipilimumab, and IMRT. Oncoimmunology 8:1593805. https://doi.org/10.1080/2162402X.2019.1593805

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ludwig N, Yerneni SS, Razzo BM, Whiteside TL (2018) Exosomes from HNSCC promote angiogenesis through reprogramming of endothelial cells. Mol Cancer Res 16:1798–1808. https://doi.org/10.1158/1541-7786.MCR-18-0358

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Whiteside TL (2016) Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem 74:103–141. https://doi.org/10.1016/bs.acc.2015.12.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Fong MY, Zhou W, Liu L et al (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17:183–194. https://doi.org/10.1038/ncb3094

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Kannan A, Hertweck KL, Philley JV et al (2017) Genetic mutation and exosome signature of human papilloma virus associated oropharyngeal cancer. Sci Rep 7:46102. https://doi.org/10.1038/srep46102

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Rivera F, García-Castaño A, Vega N et al (2009) Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial. Expert Rev Anticancer Ther 9:1421–1428. https://doi.org/10.1586/era.09.113

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Muratori L, La Salvia A, Sperone P, Di Maio M (2019) Target therapies in recurrent or metastatic head and neck cancer: state of the art and novel perspectives. A systematic review. Crit Rev Oncol Hematol 139:41–52. https://doi.org/10.1016/J.CRITREVONC.2019.05.002

    Article  PubMed  Google Scholar 

  33. 33.

    Marongiu L, Godi A, Parry JV, Beddows S (2014) Human Papillomavirus 16, 18, 31 and 45 viral load, integration and methylation status stratified by cervical disease stage. BMC Cancer 14:384. https://doi.org/10.1186/1471-2407-14-384

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Yim E-K, Park J-S (2005) The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer Res Treat 37:319. https://doi.org/10.4143/CRT.2005.37.6.319

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Bernard X, Robinson P, Nominé Y et al (2011) Proteasomal degradation of p53 by human papillomavirus E6 oncoprotein relies on the structural integrity of p53 core domain. PLoS One 6:e25981. https://doi.org/10.1371/journal.pone.0025981

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Tanaka N, Zhao M, Tang L et al (2018) Gain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1. Oncogene 37:1279–1292. https://doi.org/10.1038/s41388-017-0032-z

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Zhou G, Liu Z, Myers JN (2016) TP53 mutations in head and neck squamous cell carcinoma and their impact on disease progression and treatment response. J Cell Biochem 117:2682–2692. https://doi.org/10.1002/jcb.25592

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    cBioPortal for GENIE. http://genie.cbioportal.org/. Accessed 10 Jul 2019

  39. 39.

    Atay S, Godwin AK (2014) Tumor-derived exosomes. Commun Integr Biol 7:e28231. https://doi.org/10.4161/cib.28231

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Principe S, Hui AB-Y, Bruce J et al (2013) Tumor-derived exosomes and microvesicles in head and neck cancer: implications for tumor biology and biomarker discovery. Proteomics 13:1608–1623. https://doi.org/10.1002/pmic.201200533

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Theodoraki M-N, Yerneni SS, Hoffmann TK et al (2018) Clinical significance of PD-L1 + exosomes in plasma of head and neck cancer patients. Clin Cancer Res 24:896–905. https://doi.org/10.1158/1078-0432.CCR-17-2664

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Horton JD, Knochelmann HM, Day TA et al (2019) Immune evasion by head and neck cancer: foundations for combination therapy. Trends in Cancer 5:208–232. https://doi.org/10.1016/J.TRECAN.2019.02.007

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Ferris RL (2015) Immunology and immunotherapy of head and neck cancer. J Clin Oncol 33:3293–3304. https://doi.org/10.1200/JCO.2015.61.1509

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Ludwig S, Floros T, Theodoraki M-N et al (2017) Suppression of lymphocyte functions by plasma exosomes correlates with disease activity in patients with head and neck cancer. Clin Cancer Res 23:4843–4854. https://doi.org/10.1158/1078-0432.CCR-16-2819

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Honegger A, Schilling D, Sültmann H et al (2018) Identification of E6/E7-dependent microRNAs in HPV-positive cancer cells. In: Methods in molecular biology (Clifton, N.J.). pp 119–134

  46. 46.

    Ludwig S, Sharma P, Theodoraki M-N et al (2018) Molecular and functional profiles of exosomes From HPV(+) and HPV(−) head and neck cancer cell lines. Front Oncol 8:445. https://doi.org/10.3389/fonc.2018.00445

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Raulf N, Lucarelli P, Thavaraj S et al (2018) Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers. Eur J Cancer 102:52–68. https://doi.org/10.1016/j.ejca.2018.07.123

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Ludwig S, Marczak L, Sharma P et al (2019) Proteomes of exosomes from HPV(+) or HPV(−) head and neck cancer cells: differential enrichment in immunoregulatory proteins. Oncoimmunology 8:1593808. https://doi.org/10.1080/2162402X.2019.1593808

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Dias Carvalho P, Guimarães CF, Cardoso AP et al (2018) KRAS oncogenic signaling extends beyond cancer cells to orchestrate the microenvironment. Cancer Res 78:7–14. https://doi.org/10.1158/0008-5472.CAN-17-2084

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Bedognetti D, Hendrickx W, Ceccarelli M et al (2016) Disentangling the relationship between tumor genetic programs and immune responsiveness. Curr Opin Immunol 39:150–158. https://doi.org/10.1016/j.coi.2016.02.001

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Demory Beckler M, Higginbotham JN, Franklin JL et al (2013) Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics 12:343–355. https://doi.org/10.1074/mcp.M112.022806

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Fonseka P, Liem M, Ozcitti C et al (2019) Exosomes from N-Myc amplified neuroblastoma cells induce migration and confer chemoresistance to non-N-Myc amplified cells: implications of intra-tumour heterogeneity. J Extracell vesicles 8:1597614. https://doi.org/10.1080/20013078.2019.1597614

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Lesnik J, Antes T, Kim J et al (2016) Registered report: melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Elife 5:e07383. https://doi.org/10.7554/eLife.07383

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Li X-L, Zhou J, Chen Z-R, Chng W-J (2015) p53 mutations in colorectal cancer-molecular pathogenesis and pharmacological reactivation. World J Gastroenterol 21:84. https://doi.org/10.3748/WJG.V21.I1.84

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Wortzel I, Dror S, Kenific CM, Lyden D (2019) Exosome-mediated metastasis: communication from a distance. Dev Cell 49:347–360. https://doi.org/10.1016/j.devcel.2019.04.011

    CAS  Article  Google Scholar 

  56. 56.

    Wang J, Zhao Y, Qi R et al (2017) Prognostic role of podocalyxin-like protein expression in various cancers: a systematic review and meta-analysis. Oncotarget 8:52457–52464. https://doi.org/10.18632/oncotarget.14199

    Article  PubMed  Google Scholar 

  57. 57.

    Novo D, Heath N, Mitchell L et al (2018) Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nat Commun 9:5069. https://doi.org/10.1038/s41467-018-07339-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Mantovani F, Collavin L, Del Sal G (2019) Mutant p53 as a guardian of the cancer cell. Cell Death Differ 26:199–212. https://doi.org/10.1038/s41418-018-0246-9

    Article  PubMed  Google Scholar 

  59. 59.

    Solomon H, Dinowitz N, Pateras IS et al (2018) Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers. Oncogene 37:1669–1684. https://doi.org/10.1038/s41388-017-0060-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Cooks T, Pateras IS, Tarcic O et al (2013) Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 23:634–646. https://doi.org/10.1016/j.ccr.2013.03.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Muller PAJ, Caswell PT, Doyle B et al (2009) Mutant p53 drives invasion by promoting integrin recycling. Cell 139:1327–1341. https://doi.org/10.1016/j.cell.2009.11.026

    Article  PubMed  Google Scholar 

  62. 62.

    Freed-Pastor WA, Mizuno H, Zhao X et al (2012) Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148:244–258. https://doi.org/10.1016/j.cell.2011.12.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Seiwert TY, Zuo Z, Keck MK et al (2015) Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 21:632–641. https://doi.org/10.1158/1078-0432.CCR-13-3310

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Zhou G, Wang J, Zhao M et al (2014) Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol Cell 54:960–974. https://doi.org/10.1016/j.molcel.2014.04.024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was funded by the Israel Science Foundation (ISF, 700/16), the Concern Foundation (#7895), the United States—Israel Binational Science Foundation (BSF, #2017323), and the Israel Cancer Research Foundation (ICRF, 17-1693-RCDA) to Moshe Elkabets. Moshe Elkabets is supported by an Alon Fellowship for outstanding young researchers.

Author information

Affiliations

Authors

Contributions

EEA surveyed the literature, summarized the published data, and wrote the backbone of the manuscript as well as performed the analysis displayed in Fig. 1, and created all figures presented in this review. TC and ME outlined the sections, edited the text, and finalized it.

Corresponding authors

Correspondence to Tomer Cooks or Moshe Elkabets.

Ethics declarations

Conflict of interest

The authors declare that no potential conflicts of interest exist.

Additional information

Publisher's Note

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

This paper is a Focussed Research Review based on a presentation given at the Sixth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2019), held in Tbilisi, Georgia, 29th April–2nd May 2019. It is part of a series of CITIM 2019 papers in Cancer Immunology, Immunotherapy.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Azulay, E.E., Cooks, T. & Elkabets, M. Potential oncogenic roles of mutant-p53-derived exosomes in the tumor–host interaction of head and neck cancers. Cancer Immunol Immunother 69, 285–292 (2020). https://doi.org/10.1007/s00262-019-02450-5

Download citation

Keywords

  • Head and neck
  • Exosomes
  • Mutant p53
  • Human papillomavirus
  • Tumor microenvironment
  • CITIM 2019