Background: Information about chemotherapy-induced intestinal gene expression may provide insight into the mechanisms underlying gut toxicity and help identify biomarkers and targets for intervention. Methods: We analyzed jejunal tissue from piglets subjected to two different, clinically relevant chemotherapy regimens: (1) busulfan plus cyclophosphamide (BUCY) and (2) doxorubicin (DOX). Results: Gene expression analysis identified 1,328 differentially expressed genes in the BUCY piglets and 594 in the DOX piglets, compared to controls. Similar changes in expression were found for 137 genes across the BUCY and DOX piglets. Selected genes of potential biological significance with a similar change in expression across the treatments were controlled by real-time polymerase chain reaction. Key innate defense molecules, including surfactant protein-D and deleted in malignant brain tumors 1, were among the upregulated genes for both treatments. Conclusion: In the developing intestine, chemotherapy increases the expression of genes related to innate immune functions involved in surveillance, protection, and homeostasis of mucosal surfaces.

1.
Kuiken NS, Rings EH, Tissing WJ: Risk analysis, diagnosis and management of gastrointestinal mucositis in pediatric cancer patients. Crit Rev Oncol Hematol 2015;94:87-97.
2.
Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB; Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology: Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004;100:1995-2025.
3.
Al-Dasooqi N, Sonis ST, Bowen JM, Bateman E, Blijlevens N, Gibson RJ, Logan RM, Nair RG, Stringer AM, Yazbeck R, Elad S, Lalla RV: Emerging evidence on the pathobiology of mucositis. Support Care Cancer 2013;21:3233-3241.
4.
Melichar B, Dvorak J, Hyspler R, Zadak Z: Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents. Chemotherapy 2005;51:336-338.
5.
Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, Hayden V, Eilers J, Epstein JB, LeVeque FG, Miller C, Peterson DE, Schubert MM, Spijkervet FK, Horowitz M: Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001;19:2201-2205.
6.
Sonis ST: Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 2007;5:3-11.
7.
Stringer AM, Gibson RJ, Bowen JM, Logan RM, Ashton K, Yeoh AS, Al-Dasooqi N, Keefe DM: Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol 2009;90:489-499.
8.
Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh AS, Laurence J, Keefe DM: Irinotecan-induced mucositis is associated with changes in intestinal mucins. Cancer Chemother Pharmacol 2009;64:123-132.
9.
Pontoppidan PE, Shen RL, Cilieborg MS, Jiang P, Kissow H, Petersen BL, Thymann T, Heilmann C, Muller K, Sangild PT: Bovine colostrum modulates myeloablative chemotherapy-induced gut toxicity in piglets. J Nutr 2015;145:1472-1480.
10.
Kaczmarek A, Brinkman BM, Heyndrickx L, Vandenabeele P, Krysko DV: Severity of doxorubicin-induced small intestinal mucositis is regulated by the TLR-2 and TLR-9 pathways. J Pathol 2012;226:598-608.
11.
Sukhotnik I, Pollak Y, Coran AG, Pilatov J, Bejar J, Mogilner JG, Berkowitz D: Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat. Nutr Metab (Lond) 2014;11:17.
12.
Frank M, Hennenberg EM, Eyking A, Runzi M, Gerken G, Scott P, Parkhill J, Walker AW, Cario E: TLR signaling modulates side effects of anticancer therapy in the small intestine. J Immunol 2015;194:1983-1995.
13.
Beutheu Youmba S, Belmonte L, Galas L, Boukhettala N, Bole-Feysot C, Dechelotte P, Coeffier M: Methotrexate modulates tight junctions through NF-κB, MEK, and JNK pathways. J Pediatr Gastroenterol Nutr 2012;54:463-470.
14.
Hamada K, Kakigawa N, Sekine S, Shitara Y, Horie T: Disruption of ZO-1/claudin-4 interaction in relation to inflammatory responses in methotrexate-induced intestinal mucositis. Cancer Chemother Pharmacol 2013;72:757-765.
15.
Al-Dasooqi N, Gibson RJ, Bowen JM, Logan RM, Stringer AM, Keefe DM: Matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the dark agouti rat. Exp Biol Med 2010;235:1244-1256.
16.
Al-Azri AR, Gibson RJ, Bowen JM, Stringer AM, Keefe DM, Logan RM: Involvement of matrix metalloproteinases (MMP-3 and MMP-9) in the pathogenesis of irinotecan-induced oral mucositis. J Oral Pathol 2015;44:459-467.
17.
Bowen JM, Gibson RJ, Tsykin A, Stringer AM, Logan RM, Keefe DM: Gene expression analysis of multiple gastrointestinal regions reveals activation of common cell regulatory pathways following cytotoxic chemotherapy. Int J Cancer 2007;121:1847-1856.
18.
Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM: Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Cancer Chemother Pharmacol 2009;63:239-251.
19.
Logan RM, Gibson RJ, Bowen JM, Stringer AM, Sonis ST, Keefe DM: Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Cancer Chemother Pharmacol 2008;62:33-41.
20.
Han X, Wu Z, Di J, Pan Y, Zhang H, Du Y, Cheng Z, Jin Z, Wang Z, Zheng Q, Zhang P, Wang Y: CXCL9 attenuated chemotherapy-induced intestinal mucositis by inhibiting proliferation and reducing apoptosis. Biomed Pharmacother 2011;65:547-554.
21.
Lu H, Liu H, Wang J, Shen J, Weng S, Han L, Sun T, Qian L, Wu M, Zhu S, Yu Y, Han W, Zhu J, Moldenhauer A: The chemokine CXCL9 exacerbates chemotherapy-induced acute intestinal damage through inhibition of mucosal restitution. J Cancer Res Clin Oncol 2014;141:683-692.
22.
Mougeot JL, Bahrani-Mougeot FK, Lockhart PB, Brennan MT: Microarray analyses of oral punch biopsies from acute myeloid leukemia (AML) patients treated with chemotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:446-452.
23.
de Koning BA, Lindenbergh-Kortleve DJ, Pieters R, Buller HA, Renes IB, Einerhand AW: Alterations in epithelial and mesenchymal intestinal gene expression during doxorubicin-induced mucositis in mice. Dig Dis Sci 2007;52:1814-1825.
24.
Pontoppidan PL, Shen RL, Petersen BL, Thymann T, Heilmann C, Muller K, Sangild PT: Intestinal response to myeloablative chemotherapy in piglets. Exp Biol Med 2014;239:94-104.
25.
Martin J, Howard SC, Pillai A, Vogel P, Naren AP, Davis S, Ringwald-Smith K, Buddington K, Buddington RK: The weaned pig as a model for doxorubicin-induced mucositis. Chemotherapy 2014;60:24-36.
26.
Manzano M, Bueno P, Rueda R, Ramirez-Tortosa CL, Prieto PA, Lopez-Pedrosa JM: Intestinal toxicity induced by 5-fluorouracil in pigs: a new preclinical model. Chemotherapy 2007;53:344-355.
27.
Ballen KK, Joffe S, Brazauskas R, Wang Z, Aljurf MD, Akpek G, Dandoy C, Frangoul HA, Freytes CO, Khera N, Lazarus HM, LeMaistre CF, Mehta P, Parsons SK, Szwajcer D, Ustun C, Wood WA, Majhail NS: Hospital length of stay in the first 100 days after allogeneic hematopoietic cell transplantation for acute leukemia in remission: comparison among alternative graft sources. Biol Blood Marrow Transplant 2014;20:1819-1827.
28.
Toft N, Birgens H, Abrahamsson J, Bernell P, Griskevicius L, Hallbook H, Heyman M, Holm MS, Hulegardh E, Klausen TW, Marquart HV, Jonsson OG, Nielsen OJ, Quist-Paulsen P, Taskinen M, Vaitkeviciene G, Vettenranta K, Asberg A, Schmiegelow K: Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol. Eur J Haematol 2013;90:404-412.
29.
Sung L, Tomlinson GA, Greenberg ML, Koren G, Judd P, Ota S, Feldman BM: Validation of the oral mucositis assessment scale in pediatric cancer. Pediatr Blood Cancer 2007;49:149-153.
30.
Shen RL, Pontoppidan PL, Jiang P, Thymann T, Buddington RK, Müller K, Sangild PT: Chemotherapy-induced gastrointestinal toxicity in milk-fed piglets. London, European Society for Pediatric Gastroenterology Hepatology and Nutrition, 2013, p 163.
31.
Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A, Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J: TM4: a free, open-source system for microarray data management and analysis. Biotechniques 2003;34:374-378.
32.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci 2005;102:15545-15550.
33.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2[-delta delta C(T)] method. Methods 2001;25:402-408.
34.
Yuan JS, Reed A, Chen F, Stewart CN Jr: Statistical analysis of real-time PCR data. BMC Bioinformatics 2006;7:85.
35.
Peterson LW, Artis D: Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 2014;14:141-153.
36.
McConnell BB, Yang VW: Mammalian Krüppel-like factors in health and diseases. Physiol Rev 2010;90:1337-1381.
37.
Jensen SB, Mouridsen HT, Reibel J, Brunner N, Nauntofte B: Adjuvant chemotherapy in breast cancer patients induces temporary salivary gland hypofunction. Oral Oncol 2008;44:162-173.
38.
Karolewska E, Konopka T, Pupek M, Chybicka A, Mendak M: Antibacterial potential of saliva in children with leukemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:739-744.
39.
Madsen J, Kliem A, Tornoe I, Skjodt K, Koch C, Holmskov U: Localization of lung surfactant protein D on mucosal surfaces in human tissues. J Immunol 2000;164:5866-5870.
40.
Soerensen CM, Nielsen OL, Willis A, Heegaard PM, Holmskov U: Purification, characterization and immunolocalization of porcine surfactant protein D. Immunology 2005;114:72-82.
41.
Madsen J, Mollenhauer J, Holmskov U: Review: Gp-340/DMBT1 in mucosal innate immunity. Innate immun 2010;16:160-167.
42.
End C, Bikker F, Renner M, Bergmann G, Lyer S, Blaich S, Hudler M, Helmke B, Gassler N, Autschbach F, Ligtenberg AJ, Benner A, Holmskov U, Schirmacher P, Nieuw Amerongen AV, Rosenstiel P, Sina C, Franke A, Hafner M, Kioschis P, Schreiber S, Poustka A, Mollenhauer J: DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands. Eur J Immunol 2009;39:833-842.
43.
Dziarski R, Gupta D: Review: mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity. Innate Immun 2010;16:168-174.
44.
Saha S, Jing X, Park SY, Wang S, Li X, Gupta D, Dziarski R: Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma. Cell Host Microb 2010;8:147-162.
45.
Herbers AH, de Haan AF, van der Velden WJ, Donnelly JP, Blijlevens NM: Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients. Transpl Infect Dis 2014;16:279-285.
46.
Pontoppidan PL, Jordan K, Carlsen AL, Uhlving HH, Kielsen K, Christensen M, Ifversen M, Nielsen CH, Sangild P, Heegaard NH, Heilmann C, Sengelov H, Muller K: Associations between gastrointestinal toxicity, micro RNA and cytokine production in patients undergoing myeloablative allogeneic stem cell transplantation. Int Immunopharmacol 2015;25:180-188.
47.
Wardill HR, Gibson RJ, Logan RM, Bowen JM: TLR4/PKC-mediated tight junction modulation: a clinical marker of chemotherapy-induced gut toxicity? Int J Cancer 2014;135:2483-2492.
48.
Al-Dasooqi N, Wardill HR, Gibson RJ: Gastrointestinal mucositis: the role of MMP-tight junction interactions in tissue injury. Pathol Oncol Res 2014;20:485-491.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.