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Journal of Molecular Medicine

, Volume 98, Issue 1, pp 149–159 | Cite as

Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea

  • Andreas U. Lindner
  • Alexa J. Resler
  • Steven Carberry
  • Kasia Oficjalska
  • Orna Bacon
  • Chun Seng Lee
  • Abdurehman Choudhry
  • John P. Burke
  • Kieran Sheahan
  • Mattia Cremona
  • Bryan T Hennessy
  • Deborah McNamara
  • Glen Doherty
  • Elizabeth J. Ryan
  • Jochen H.M. PrehnEmail author
Original Article

Abstract

Chemotherapy-induced diarrhoea (CID) is a common dose-limiting adverse event in patients with cancer. Here, we hypothesise that chemotherapy evokes apoptosis in normal gut epithelium, contributes to CID and that patients with increased risk of CID can be identified using a systems model of BCL-2 protein interactions (DR_MOMP) that calculates the sensitivity of cells to undergo apoptosis. Normal adjacent gut epithelium tissue was collected during resection surgery from a cohort of 35 patients with stage II–III colorectal cancer (CRC) who were subsequently treated with capecitabine, XELOX or FOLFOX. Clinical follow-up, type and grade of adverse events during adjuvant chemotherapy were recorded. The level of five BCL-2 proteins required for the calculation of the DR_MOMP score was quantified together with 62 additional signalling proteins related to apoptotic pathways. Odds ratios for the occurrence of diarrhoea were determined using multinomial logistic regression (MLR). Patients treated with capecitabine who had a DR_MOMP score equal or higher than the mean had a significantly lower frequency of diarrhoea significantly compared to patients below the mean. High DR_MOMP scores indicate high apoptosis resistance. No statistical difference was observed in patients treated with XELOX or FOLFOX. Using MLR, we found that levels of apoptosis-related proteins caspase-8, p53 and XIAP statistically interacted with the DR_MOMP stress dose. Markers of MAPK signalling were prognostic for diarrhoea independently of DR_MOMP. In conclusion, apoptosis sensitivity and MAPK signalling status of the adjacent normal gut epithelium of chemotherapy-naïve patients represent promising biomarkers to identify patients with CRC with increased risk of CID.

Keywords

BCL-2 Systems biology Adverse effect Apoptosis Colorectal Cancer 

Abbreviations

a.U.

arbitrary unit

BAK

BCL2 antagonist/killer 1 (BAK1)

BAX

BCL2 associated X, apoptosis regulator (BCL2L4)

BCL2

B cell lymphoma 2

BCL(X)L

B cell lymphoma-extra large (BCL2L1)

CED

cycle with episodes of diarrhoea

CI

confidence interval

CID

chemotherapy-induced diarrhoea

MCL1

Myeloid cell leukaemia sequence 1 (BCL2L3)

MLR

multinomial logistic regression

MOMP

mitochondrial outer membrane permeabilisation

nM

nanomolar (10^–9 mol/L)

RPPA

reverse protein phase array

TNM

tumour/lymph node/metastasis staging system

Tukey HSD

Tukey honest significant differences post hoc test

Notes

Authors’ contributions

AUL and JHMP wrote the manuscript and prepared figures. AUL and AJR conducted the computational and statistical analysis. CSL, KO, OB, AC, JPB, DMN, KS and GD performed acquisition and processing of data. SC conducted protein quantification. DMN, GD, ER and JHMP supervised the project. All authors read, reviewed and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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References

  1. 1.
    Tilson L, Sharp L, Usher C, Walsh C, Whyte S, O’Ceilleachair A, Stuart C, Mehigan B, John Kennedy M, Tappenden P, Chilcott J, Staines A, Comber H, Barry M (2012) Cost of care for colorectal cancer in Ireland: a health care payer perspective. Eur J Health Econ 13(4):511–524PubMedGoogle Scholar
  2. 2.
    Zalcberg J, Kerr D, Seymour L, Palmer M (1998) Haematological and non-haematological toxicity after 5-fluorouracil and leucovorin in patients with advanced colorectal cancer is significantly associated with gender, increasing age and cycle number. Tomudex International Study Group. Eur J Cancer 34(12):1871–1875PubMedGoogle Scholar
  3. 3.
    Ibrahim A, Hirschfeld S, Cohen MH, Griebel DJ, Williams GA, Pazdur R (2004) FDA drug approval summaries: oxaliplatin. Oncologist 9(1):8–12PubMedGoogle Scholar
  4. 4.
    Arbuckle RB, Huber SL, Zacker C (2000) The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist 5(3):250–259PubMedGoogle Scholar
  5. 5.
    National Cancer Institute USDoHaHS (2017) Common Terminology Criteria for Adverse Events (CTCAE). 5.0:146Google Scholar
  6. 6.
    Sharif S, O'Connell MJ, Yothers G, Lopa S, Wolmark N (2008) FOLFOX and FLOX regimens for the adjuvant treatment of resected stage II and III colon cancer. Cancer Investig 26(9):956–963Google Scholar
  7. 7.
    Gibson RJ, Keefe DM (2006) Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies. Support Care Cancer 14(9):890–900PubMedGoogle Scholar
  8. 8.
    Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, McCallum R, Mitchell EP, O'Dorisio TM, Vokes EE, Wadler S (2004) Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22(14):2918–2926PubMedGoogle Scholar
  9. 9.
    Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ (1995) Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer 75(1):11–17PubMedGoogle Scholar
  10. 10.
    Sloan JA, Goldberg RM, Sargent DJ, Vargas-Chanes D, Nair S, Cha SS, Novotny PJ, Poon MA, O'Connell MJ, Loprinzi CL (2002) Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 20(6):1491–1498PubMedGoogle Scholar
  11. 11.
    Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M, German FUTSG (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26(13):2131–2138PubMedGoogle Scholar
  12. 12.
    Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256(1):42–49PubMedGoogle Scholar
  13. 13.
    Lindner AU, Concannon CG, Boukes GJ, Cannon MD, Llambi F, Ryan D, Boland K, Kehoe J, McNamara DA, Murray F, Kay EW, Hector S, Green DR, Huber HJ, Prehn JH (2013) Systems analysis of BCL2 protein family interactions establishes a model to predict responses to chemotherapy. Cancer Res 73(2):519–528PubMedGoogle Scholar
  14. 14.
    Flanagan L, Lindner AU, de Chaumont C, Kehoe J, Fay J, Bacon O, Toomey S, Huber HJ, Hennessy BT, Kay EW, McNamara DA, Prehn JH (2015) BCL2 protein signalling determines acute responses to neoadjuvant chemoradiotherapy in rectal cancer. J Mol Med (Berl) 93(3):315–326Google Scholar
  15. 15.
    Lindner AU, Salvucci M, Morgan C, Monsefi N, Resler AJ, Cremona M, Curry S, Toomey S, O'Byrne R, Bacon O, Stuhler M, Flanagan L, Wilson R, Johnston PG, Salto-Tellez M, Camilleri-Broet S, McNamara DA, Kay EW, Hennessy BT, Laurent-Puig P, Van Schaeybroeck S, Prehn JHM (2017) BCL-2 system analysis identifies high-risk colorectal cancer patients. Gut 66(12):2141–2148PubMedGoogle Scholar
  16. 16.
    Lucantoni F, Lindner AU, O'Donovan N, Dussmann H, Prehn JHM (2018) Systems modeling accurately predicts responses to genotoxic agents and their synergism with BCL-2 inhibitors in triple negative breast cancer cells. Cell Death Dis 9(2):42PubMedPubMedCentralGoogle Scholar
  17. 17.
    Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G, Deng J, Anderson KC, Richardson P, Tai YT, Mitsiades CS, Matulonis UA, Drapkin R, Stone R, Deangelo DJ, McConkey DJ, Sallan SE, Silverman L, Hirsch MS, Carrasco DR, Letai A (2011) Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334(6059):1129–1133PubMedGoogle Scholar
  18. 18.
    Gao J, Gao J, Qian L, Wang X, Wu M, Zhang Y, Ye H, Zhu S, Yu Y, Han W (2014) Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil. Cancer Biol Ther 15(8):982–991PubMedPubMedCentralGoogle Scholar
  19. 19.
    Ribeiro RA, Wanderley CW, Wong DV, Mota JM, Leite CA, Souza MH, Cunha FQ, Lima-Junior RC (2016) Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives. Cancer Chemother Pharmacol 78(5):881–893PubMedGoogle Scholar
  20. 20.
    Bowen JM, Gibson RJ, Keefe DM, Cummins AG (2005) Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans. Pathology 37(1):56–62PubMedGoogle Scholar
  21. 21.
    Guo H, Liu W, Ju Z, Tamboli P, Jonasch E, Mills GB, Lu Y, Hennessy BT, Tsavachidou D (2012) An efficient procedure for protein extraction from formalin-fixed, paraffin-embedded tissues for reverse phase protein arrays. Proteome Sci 10(1):56PubMedPubMedCentralGoogle Scholar
  22. 22.
    Meropol NJ (1998) Oral fluoropyrimidines in the treatment of colorectal cancer. Eur J Cancer 34(10):1509–1513PubMedGoogle Scholar
  23. 23.
    Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kroning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schuller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352(26):2696–2704PubMedGoogle Scholar
  24. 24.
    Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388(6639):300–304PubMedGoogle Scholar
  25. 25.
    Cregan SP, Arbour NA, Maclaurin JG, Callaghan SM, Fortin A, Cheung EC, Guberman DS, Park DS, Slack RS (2004) p53 activation domain 1 is essential for PUMA upregulation and p53-mediated neuronal cell death. J Neurosci 24(44):10003–10012PubMedPubMedCentralGoogle Scholar
  26. 26.
    Muller PA, Vousden KH (2013) p53 mutations in cancer. Nat Cell Biol 15(1):2–8PubMedGoogle Scholar
  27. 27.
    Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, Liu X, Wu H (2003) PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3(2):117–130PubMedGoogle Scholar
  28. 28.
    Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100(4):387–390PubMedGoogle Scholar
  29. 29.
    Avruch J, Zhang XF, Kyriakis JM (1994) Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci 19(7):279–283PubMedGoogle Scholar
  30. 30.
    King AJ, Sun H, Diaz B, Barnard D, Miao W, Bagrodia S, Marshall MS (1998) The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 396(6707):180–183PubMedGoogle Scholar
  31. 31.
    Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Tan BK, Sethi G, Bishayee A (2014) Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta 1845(2):136–154PubMedGoogle Scholar
  32. 32.
    Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y, Kim JD (2000) Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A 97(8):4227–4232PubMedPubMedCentralGoogle Scholar
  33. 33.
    Lovato P, Brender C, Agnholt J, Kelsen J, Kaltoft K, Svejgaard A, Eriksen KW, Woetmann A, Odum N (2003) Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease. J Biol Chem 278(19):16777–16781PubMedGoogle Scholar
  34. 34.
    Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41(16):2502–2512PubMedGoogle Scholar
  35. 35.
    Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, Lehr HA, Hirth S, Weigmann B, Wirtz S, Ouyang W, Neurath MF, Becker C (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206(7):1465–1472PubMedPubMedCentralGoogle Scholar
  36. 36.
    Hruz P, Dann SM, Eckmann L (2010) STAT3 and its activators in intestinal defense and mucosal homeostasis. Curr Opin Gastroenterol 26(2):109–115PubMedGoogle Scholar
  37. 37.
    Sonis ST (2004) The pathobiology of mucositis. Nat Rev Cancer 4(4):277–284PubMedGoogle Scholar
  38. 38.
    Barnard D, Diaz B, Clawson D, Marshall M (1998) Oncogenes, growth factors and phorbol esters regulate Raf-1 through common mechanisms. Oncogene 17(12):1539–1547PubMedGoogle Scholar
  39. 39.
    Chen G, Porter MD, Bristol JR, Fitzgibbon MJ, Pazhanisamy S (2000) Kinetic mechanism of the p38-alpha MAP kinase: phosphoryl transfer to synthetic peptides. Biochemistry 39(8):2079–2087PubMedGoogle Scholar
  40. 40.
    Yang SH, Sharrocks AD, Whitmarsh AJ (2013) MAP kinase signalling cascades and transcriptional regulation. Gene 513(1):1–13PubMedGoogle Scholar
  41. 41.
    Hauge C, Frodin M (2006) RSK and MSK in MAP kinase signalling. J Cell Sci 119(Pt 15):3021–3023PubMedGoogle Scholar
  42. 42.
    Richardson CJ, Schalm SS, Blenis J (2004) PI3-kinase and TOR: PIKTORing cell growth. Semin Cell Dev Biol 15(2):147–159PubMedGoogle Scholar
  43. 43.
    Oda K, Matsuoka Y, Funahashi A, Kitano H (2005) A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 1(2005):0010PubMedGoogle Scholar
  44. 44.
    Hirsh V (2011) Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol 18(3):126–138PubMedPubMedCentralGoogle Scholar
  45. 45.
    Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31(27):3327–3334PubMedGoogle Scholar
  46. 46.
    Opleta-Madsen K, Hardin J, Gall DG (1991) Epidermal growth factor upregulates intestinal electrolyte and nutrient transport. Am J Phys 260(6 Pt 1):G807–G814Google Scholar
  47. 47.
    Harandi A, Zaidi AS, Stocker AM, Laber DA (2009) Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Oncol 2009:567486PubMedPubMedCentralGoogle Scholar
  48. 48.
    Loriot Y, Perlemuter G, Malka D, Penault-Llorca F, Boige V, Deutsch E, Massard C, Armand JP, Soria JC (2008) Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Nat Clin Pract Oncol 5(5):268–278PubMedGoogle Scholar
  49. 49.
    Berlanga-Acosta J, Playford RJ, Mandir N, Goodlad RA (2001) Gastrointestinal cell proliferation and crypt fission are separate but complementary means of increasing tissue mass following infusion of epidermal growth factor in rats. Gut 48(6):803–807PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Andreas U. Lindner
    • 1
    • 2
  • Alexa J. Resler
    • 1
    • 2
  • Steven Carberry
    • 1
    • 2
  • Kasia Oficjalska
    • 3
  • Orna Bacon
    • 1
    • 2
    • 4
  • Chun Seng Lee
    • 3
  • Abdurehman Choudhry
    • 1
    • 2
  • John P. Burke
    • 4
  • Kieran Sheahan
    • 3
    • 5
  • Mattia Cremona
    • 6
  • Bryan T Hennessy
    • 6
  • Deborah McNamara
    • 4
  • Glen Doherty
    • 3
    • 7
  • Elizabeth J. Ryan
    • 3
    • 7
    • 8
  • Jochen H.M. Prehn
    • 1
    • 2
    Email author
  1. 1.Centre for Systems Medicine and Department of Physiology and Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland
  2. 2.Department of Physiology and Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland
  3. 3.Centre for Colorectal DiseaseSt. Vincent’s University HospitalDublinIreland
  4. 4.Department of SurgeryBeaumont HospitalDublin 9Ireland
  5. 5.Department of PathologySt. Vincent’s University HospitalDublinIreland
  6. 6.Department of Medical OncologyBeaumont HospitalDublin 9Ireland
  7. 7.School of Medicine & Medical ScienceUniversity College DublinDublinIreland
  8. 8.Health Research InstituteUniversity of LimerickLimerickIreland

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