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.

The pathobiology of mucositis

Key Points

  • Mucositis is a common toxicity of antineoplastic radiation and drug therapies, and is associated with several adverse symptomatic, health and economic outcomes.

  • There is no effective way to prevent or treat mucositis at present.

  • Understanding of the pathobiology of mucositis has increased rapidly during the past decade.

  • Mucositis is a biologically complex process that involves a dynamic, interactive sequence of panmucosal events that ultimately targets epithelial stem cells.

  • Several mechanistically based anti-mucositis agents are in development.

  • It is unlikely that a single drug or biological agent will meet the needs of all patients. Rather, the choice of the interventional agent that is used will depend on a range of factors that are related to the patient and to the particular cancer therapy they are receiving.

Abstract

Oral and gastrointestinal mucositis is a toxicity of many forms of radiotherapy and chemotherapy. It has a significant impact on health, quality of life and economic outcomes that are associated with treatment. It also indirectly affects the success of antineoplastic therapy by limiting the ability of patients to tolerate optimal tumoricidal treatment. The complex pathogenesis of mucositis has only recently been appreciated and reflects the dynamic interactions of all of the cell and tissue types that comprise the epithelium and submucosa. The identification of the molecular events that lead to treatment-induced mucosal injury has provided targets for mechanistically based interventions to prevent and treat mucositis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The oral mucosa.
Figure 2: Primary damage response and signal amplification.
Figure 3: Ulceration and healing.
Figure 4: Signal amplification during mucositis.

References

  1. 1

    Sonis, S. T. & Fey, E. G. Oral complications of cancer therapy. Oncology 16, 680–686 (2002).

    PubMed  Google Scholar 

  2. 2

    Filicko, J., Lazarus, H. M. & Flomenberg, N. Mucosal injury in patients undergoing hematopoietic progenitor cell transplantation: new approaches to prophylaxis and treatment. Bone Marrow Transplant. 31, 1–10 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Vissink, A. et al. Oral sequelae of head and neck radiotherapy. Crit. Rev. Oral Biol. Med. 14, 199–212 (2003).

    CAS  Article  Google Scholar 

  4. 4

    Elting, L. S. et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-based mucositis. Cancer 98, 1531–1539 (2003). The clinical and economic impact of mucositis following myeloablative chemotherapy is significant among patients who are treated for common solid tumours.

    Article  Google Scholar 

  5. 5

    Sonis, S. T. et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem cell transplantation. J. Clin. Oncol. 19, 2201–2205 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Trotti, A. et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother. Oncol. 66, 253–262 (2003).

    Article  Google Scholar 

  7. 7

    Bloomer, W. D. & Hellman, S. Normal tissue responses to radiation therapy. New Engl. J. Med. 293, 80–83 (1975).

    CAS  Article  Google Scholar 

  8. 8

    Lockhart, P. B. & Sonis, S. T. Relationship of oral complications to peripheral blood leukocyte and platelet counts in patients receiving cancer chemotherapy. Oral Surg. Oral Med. Oral Pathol. 48, 21–28 (1971).

    Article  Google Scholar 

  9. 9

    Sonis, S. T. et al. Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor β3. Cancer Res. 54, 1135–1138 (1994).

    CAS  PubMed  Google Scholar 

  10. 10

    Sonis, S. T. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol. 34, 39–43 (1998). The clinical manifestations of mucositis are attributable to a series of interactive biological events that involve all of the cells and tissues of the mucous membrane.

    CAS  Article  Google Scholar 

  11. 11

    Sonis, S. T. et al. Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters. Oral Oncol. 36, 373–381 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Paris, F. et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293, 293–297 (2001). The endothelium, not the epithelium, is the primary initiator of radiation-induced mucosal injury.

    CAS  Article  Google Scholar 

  13. 13

    Jaenke, R. S. et al. Capillary endothelium. Target site for renal radiation injury. Lab. Invest. 68, 396–405.

  14. 14

    Watts, M. E. et al. Effects of novel and conventional anti-cancer agents on human endothelial permeability: influence of tumour secreted factors. Anticancer Res. 17, 71–75 (1997).

    CAS  PubMed  Google Scholar 

  15. 15

    Kinhult, S. et al. Effects of probucol on endothelial damage by 5-fluorouracil. Acta Oncol. 42, 304–308 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Kuenen, B. C. et al. Potential role of platelets in endothelial damage during treatment with cisplatin, gencitabine, and the angiogenesis inhibitor SU5416. J. Clin. Oncol. 21, 2192–2198 (2003).

    CAS  Article  Google Scholar 

  17. 17

    McManus, L. M. et al. Radiation-induced increased platelet-activating factor activity in mixed saliva. Lab. Invest. 68, 118–124 (1993).

    CAS  PubMed  Google Scholar 

  18. 18

    Wang, J. et al. Short-term inhibition of ADP-induced platelet aggregation by clopidogreal ameliorates radiation-induced toxicity in rat small intestine. Thromb. Haemost. 87, 122–128 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Stefanelli, C. et al. Caspase activation in etoposide-treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion. FEBS Lett. 527, 223–228 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Manakova, S. et al. Ara-C induces apoptosis in monkey fibroblast cells. Toxicol. In Vitro 17, 367–373 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Chrzanowski, K. et al. Cytotoxicity and effect of collagen biosynthesis of proline analogue of melphalan as a prolidase-converting prodrug in cultured human skin fibroblasts. Farmaco 56, 701–706 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Handschel, J. et al. Increase in RM3/1-positive macrophages in radiation-induced oral mucositis. J. Pathol. 193, 242–247 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Hall, P. D. et al. The influence of serum tumor necrosis factor-α and interleukin-6 concentrations on nonhematologic toxicity and hematologic recovery in patients with acute myelogenous leukemia. Exp. Hematol. 23, 1256–1260 (1995).

    CAS  PubMed  Google Scholar 

  24. 24

    Remberger, M., Ringden, O. & Markling, L. TNFα levels are increased during bone marrow transplantation conditioning regimens in patients who develop acute GVHD. Bone Marrow Transplant. 15, 99–104 (1995).

    CAS  PubMed  Google Scholar 

  25. 25

    Chen, Y. et al. Radiation pneumonitis and early conditioning cytokine markers. Semin. Radiat. Oncol. 12 (Suppl. 1), 26–33 (2002).

    Article  Google Scholar 

  26. 26

    Billis, W., Fuks, Z. & Kolesnick, R. Signaling in and regulation of ionizing radiation-induced apoptosis of endothelial cells. Recent Prog. Horm. Res. 53, 85–92 (1998).

    CAS  PubMed  Google Scholar 

  27. 27

    Sonis, S. T. et al. Inhibition of ceramide synthase, but not sphingomyelinase attenuates radiation-induced mucositis in hamsters. ASCO Proc. 2003, abstract 3005.

  28. 28

    deSousa, S. et al. Immunolocalization of c-Fos and c-Jun in human oral mucosa and in oral squamous cell carcinoma. J. Oral Pathol. Med. 31, 78–81 (2002).

    Article  Google Scholar 

  29. 29

    Angel, P., Szabowski, A. & Schropp-Kistner, M. Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene 20, 2413–2423 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Maselli, R. et al. Oxidative stress and lung diseases. Monaldi Arch. Chest Dis. 57, 180–181 (2002).

    CAS  PubMed  Google Scholar 

  31. 31

    Guha, A. & Mackman, N. LPS induction of gene expression in human monocytes. Cell Signal. 13, 85–94 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Denham, J. W. & Hauer-Jensen, M. The radiotherapeutic injury — a complex wound. Radiother. Oncol. 63, 129–145 (2002). Radiation-induced normal tissue injury consists of some features that are similar to those seen following traumatic wounds and others that are unique and reflect transient and permanent cellular and tissue alterations.

    Article  Google Scholar 

  33. 33

    Criswell, T. et al. Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation. Oncogene 22, 5813–5827 (2003). Radiation injury is the result of damage to both DNA and non-DNA targets. Signalling from non-DNA targets results in activation of transcription factors that varies with radiation dose.

    CAS  Article  Google Scholar 

  34. 34

    Sonis, S. T. The biologic role of nuclear factor-κB in disease and its potential involvement in mucosal injury associated with antineoplastic therapy. Crit. Rev. Oral Biol. Med. 13, 380–389 (2002).

    Article  Google Scholar 

  35. 35

    Davis, R. J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252 (2000).

    CAS  Article  Google Scholar 

  36. 36

    Braum, S. et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol. Cell. Biol. 22, 5492–5505 (2002).

    Article  Google Scholar 

  37. 37

    Kitada, S. et al. γ-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo. Oncogene 12, 187–192 (1996).

    CAS  PubMed  Google Scholar 

  38. 38

    Chmura, S. J. et al. Loss of ceramide production confers resistance to radiation-induced apoptosis. Cancer Res. 57, 1270–1275 (1997).

    CAS  PubMed  Google Scholar 

  39. 39

    Bamba, S. et al. Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17. J. Gastroenterol. 38, 548–554 (2003).

    CAS  Article  Google Scholar 

  40. 40

    Sesaki, M. et al. Differential regulation of metalloproteinase production, proliferation and chemotaxis of human lung fibroblasts by PDGF, interleukin-1β and TNF-α. Mediators Inflamm. 9, 155–160 (2000).

    Article  Google Scholar 

  41. 41

    Engels-Deutsch, M. A. et al. Insertinal inactivation of pac and rmKB genes reduces the release of tumor necrosis factor α, interleukin-6, and interleukin-8 by Streptococcus mutans in monocytic, dental pulp and periodontal ligament cells. Infect. Immun. 71, 5169–5177 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Alikhani, M. et al. LPS indirectly stimulates apoptosis and global induction of apoptotic genes in fibroblasts. J. Biol. Chem. 278, 52901–52908 (2003).

    CAS  Article  Google Scholar 

  43. 43

    Koukourakis, M. I. Amifostine in clinical oncology: current use and future applications. Anticancer Drugs 13, 181–209 (2002).

    CAS  Article  Google Scholar 

  44. 44

    Mantovani, G. et al. Reactive oxygen species, antioxidant mechanisms, and serum cytokine levels in cancer patients: impact of antioxidant treatment. J. Cell. Mol. Med. 6, 570–582 (2002).

    CAS  Article  Google Scholar 

  45. 45

    Blonder, J. et al. Topical bioadhesive antioxidants reduce the severity of experimental radiation induced oral mucositis. ASCO Proc. 2001, abstract 1606.

  46. 46

    Epstein, J. B. et al. Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo-controlled trial. Cancer 92, 875–885 (2001).

    CAS  Article  Google Scholar 

  47. 47

    Speilberger, R. et al. Use of recombinant human keratinocyte growth factor (rHuKGF) can reduce severe oral mucositis in patients with hematologic malignancies using peripheral blood progenitor transplantation after radiation-based conditioning — results of phase 3 trial. ASCO Proc. 2003, Abstract 3642.

  48. 48

    Farrell, C. L. et al. The effects of keratinocyte growth factor in preclinical models of mucositis. Cell Prolif. 35 (Suppl. 1), 78–85 (2002).

    CAS  Article  Google Scholar 

  49. 49

    Day, R. M. et al. Bleomycin upregulates expression of γ-glutamylcysteine synthase in pulmonary endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L1349–L1357 (2002).

    CAS  Article  Google Scholar 

  50. 50

    Hayashi, A. et al. Transcription factor Nrf2 is required for constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem. Biophys. Res. Commun. 310, 824–329 (2003).

    CAS  Article  Google Scholar 

  51. 51

    Panoskaltsis-Mortari, A. et al. Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of conditioning-induced tissue injury. Blood 96, 4350–4356 (2000).

    CAS  Google Scholar 

  52. 52

    Nemzek, J. A. et al. Keratinocyte growth factor pretreatment is associated with decreased macrophage inflammatory protein-2α concentrations and reduced neutrophil recruitment in acid aspiration lung injury. Shock 18, 501–506 (2002).

    Article  Google Scholar 

  53. 53

    Lappas, M., Permezel, M. & Rice, G. E. N-acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-κB deoxyribonucleic acid-binding activity in human fetal membranes in vitro. J. Clin. Endocrinol. Metab. 88, 1723–1729 (2003).

    CAS  Article  Google Scholar 

  54. 54

    Sironi, M. et al. Benzydamine inhibits the release of tumor necrosis factor-α and monocyte chemotactic protein-1 by Candida albicans-stimulated human peripheral blood cells. Int. J. Clin. Lab. Res. 27, 118–122 (1997).

    CAS  Article  Google Scholar 

  55. 55

    Ziegler, T. R. Glutamine supplementation in cancer patients receiving bone marrow transplantation and high dose chemotherapy. J. Nutr. 131 (Suppl.), 2578S–2584S (2001).

    CAS  Article  Google Scholar 

  56. 56

    Donnelly, J. P. et al. Antimicrobial therapy to prevent or treat oral mucositis. Lancet Infect. Dis. 3, 405–412 (2003).

    Article  Google Scholar 

  57. 57

    Wardley, A. M. et al. A quantitative histometric murine in vivo model of radiation-induced oral mucositis. Arch. Oral Biol. 43, 567–577 (1998).

    CAS  Article  Google Scholar 

  58. 58

    Dorr, W. & Kummermehr, J. Accelerated repopulation of mouse tongue epithelium during fractionated radiation or following single doses. Radiother. Oncol. 17, 249–259 (1990).

    CAS  Article  Google Scholar 

  59. 59

    Sonis, S. T. et al. An animal model for mucositis induced by cancer chemotherapy. Oral Surg. Oral Med. Oral Pathol. 69, 437–443 (1990).

    CAS  Article  Google Scholar 

  60. 60

    Sonis, S. T. et al. The gene expression sequence of radiated mucosa in an animal mucositis model. Cell Prolif. 35 (Suppl. 1), 93–101 (2002).

    CAS  Article  Google Scholar 

  61. 61

    Guo, H. et al. Prevention of radiation-induced oral cavity mucoitis by plasmid/liposome delivery of human manganese superoxide dismutase (SOD2) transgene. Radiat. Res. 159, 361–370 (2003).

    CAS  Article  Google Scholar 

  62. 62

    Ulrich, C. M. et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 98, 231–234 (2001).

    CAS  Article  Google Scholar 

  63. 63

    van Kuilenburg, A. B. et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin. Cancer Res. 6, 4705–4712 (2000).

    CAS  PubMed  Google Scholar 

  64. 64

    Chen, E. Impact of Addison's Disease and Psoriasis on the Frequency of Oral Mucositis. Thesis. Harvard School of Dental Medicine (2003).

    Google Scholar 

Download references

Author information

Affiliations

Authors

Ethics declarations

Competing interests

Stephen T. Sonis is a consultant for Biomodels LLC and its affiliates, which carry out contract research for several pharmaceutical and biotechnology companies.

Related links

Related links

DATABASES

Cancer.gov

nasopharyngeal cancer

oral cavity cancer

oropharyngeal cancer

salivary gland cancer

LocusLink

BAX

BCL2

BCL-XL

caspase 3

c-FOS

c-JUN

FGF10

FGF20

KGF1

IL-1β

IL-6

IL-11

IL-13

JNK

MAPK

MMP1

MMP3

NF-κB

NRF2

p53

PDGF

TGF-β

TNF-α

Glossary

ERYTHEMATOUS

Refers to redness of the oral mucosa that characterizes the early stages of mucositis. Typically, this stage of mucositis is mildly symptomatic, with patients complaining of sensitivity similar to that of a food-induced burn.

PARENTERAL NUTRITION

Intravenous feeding of patients who are unable to eat, providing complete nutrition.

STOMATOTOXIC

Radiation or chemotherapy that results in oral mucositis.

FRACTIONATED DOSING REGIMENS

Therapeutic radiation for head and neck cancer is delivered by multiple (fractionated) small doses given over a long period of time. For example, the conventional radiation plan for tongue cancer might consist of a total dose of 70 Gy administered in 2-Gy fractions 5 days per week for 7 weeks.

NEUTROPENIC

Many forms of chemotherapy have the potential to non-specifically target bone-marrow stem cells. As a consequence, the normal production of neutrophils and platelets is retarded. A significant reduction in peripheral-blood neutrophils renders patients neutropenic.

AMINOTHIOL

A compound that show normal tissue protection from radiation by free-radical scavenging.

ALLOTRANSPLANT

Bone-marrow transplants can be given following aggressive myeloablative radiation and/or chemotherapy. Autologous transplants are those in which marrow harvested from a patient is then treated and reinfused. Allotransplants are those in which marrow is harvested from another individual and than transfused into the recipient.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sonis, S. The pathobiology of mucositis. Nat Rev Cancer 4, 277–284 (2004). https://doi.org/10.1038/nrc1318

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing