Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2018

01-04-2018 | Original Article

Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice

Authors: Concetta Panebianco, Kaarel Adamberg, Madis Jaagura, Massimiliano Copetti, Andrea Fontana, Signe Adamberg, Kaia Kolk, Raivo Vilu, Angelo Andriulli, Valerio Pazienza

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2018

Login to get access

Abstract

Background and aims

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-related death. We aimed to evaluate whether gemcitabine treatment shapes the gut microbiota in a model of PDAC xenografted mice.

Materials and methods

Pancreatic cancer xenograft mice were subjected to gemcitabine injection once per week for 3 weeks to assess the tumor volume as compared to control mice injected with normal saline solution. The composition of fecal microbiota, the activation of NF-kB pathway in cancer tissues and the serum metabolomics were further analyzed.

Results

Gemcitabine considerably decreases the proportion of Gram- positive Firmicutes (from about 39 to 17%) and the Gram- negative Bacteroidetes (from 38 to 17%) which are the two dominant phyla in the gut of tumor-bearing control mice. This downshift was replaced by an increase of Proteobacteria (Escherichia coli and Aeromonas hydrophila) from 15 up to 32% and Verrucomicrobia (Akkermansia muciniphila) from 5 to 33% in the gut of drug-receiving mice. An overall increase in inflammation-associated bacteria was observed upon gemcitabine. Consistently, activation of the NF-kB canonical pathway was found in cancer tissues from gemcitabine-treated mice. Serum metabolomics revealed a significant decrease of the purine compounds inosine and xanthine, and a decreasing trend for their metabolically-related molecule hypoxanthine.

Discussion

Understanding chemotherapy side effects may explain the lack of activity or the chemoresistant processes and it may help to set up strategies to improve the effectiveness of therapy.
Literature
1.
2.
Conroy T, Bachet JB, Ayav A, Huguet F, Lambert A, Caramella C, Marechal R, Van Laethem JL, Ducreux M (2016) Current standards and new innovative approaches for treatment of pancreatic cancer. Eur J Cancer 57:10–22CrossRefPubMed
3.
Siegel RL, Miller KD, Jemal A, Cancer statistics (2016) CA Cancer. J Clin 66(1):7–30
4.
Cheema AR, O’Reilly EM (2016) Management of Metastatic Pancreatic Adenocarcinoma. Surg Clin North Am 96(6):1391–1414CrossRefPubMed
5.
D’Aronzo M, Vinciguerra M, Mazza T, Panebianco C, Saracino C, Pereira SP, Graziano P, Pazienza V (2015) Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. Oncotarget 6(21):18545–18557PubMedPubMedCentral
6.
7.
8.
Stathis A, Moore MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7(3):163–172CrossRefPubMed
9.
Greer JB, Whitcomb DC (2009) Inflammation and pancreatic cancer: an evidence-based review. Curr Opin Pharmacol 9(4):411–418CrossRefPubMed
10.
Steele CW, Kaur Gill NA, Jamieson NB, Carter CR (2016) Targeting inflammation in pancreatic cancer: clinical translation. World J Gastrointest Oncol 8(4):380–388CrossRefPubMedPubMedCentral
11.
12.
Momi N, Kaur S, Krishn SR, Batra SK (2012) Discovering the route from inflammation to pancreatic cancer. Minerva Gastroenterol Dietol 58(4):283–297PubMedPubMedCentral
13.
Uomo I, Miraglia S, Pastorello M (2010) Inflammation and pancreatic ductal adenocarcinoma: a potential scenario for novel drug targets. JOP 11(3):199–202PubMed
14.
15.
16.
17.
Zitvogel L, Galluzzi L, Viaud S, Vetizou M, Daillere R, Merad M, Kroemer G (2015) Cancer and the gut microbiota: an unexpected link. Sci Transl Med 7(271):271ps271CrossRef
18.
Panebianco C, Adamberg K, Adamberg S, Saracino C, Jaagura M, Kolk K, Di Chio AG, Graziano P, Vilu R, Pazienza V (2017) Engineered resistant-starch (ERS) diet shapes colon microbiota profile in parallel with the retardation of tumor growth in in vitro and in vivo pancreatic cancer models. Nutrients 9(4). https://​doi.​org/​10.​3390/​nu9040331
19.
Farrell JJ, Zhang L, Zhou H, Chia D, Elashoff D, Akin D, Paster BJ, Joshipura K, Wong DT (2012) Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut 61(4):582–588CrossRefPubMed
20.
Michaud DS, Joshipura K, Giovannucci E, Fuchs CS (2007) A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst 99(2):171–175CrossRefPubMed
21.
Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, Bruley des Varannes S, Le Vacon F, de La Cochetiere MF (2014) Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications. Aliment Pharmacol Ther 40(5):409–421PubMed
22.
Paglia G, Williams JP, Menikarachchi L, Thompson JW, Tyldesley-Worster R, Halldorsson S, Rolfsson O, Moseley A, Grant D, Langridge J, Palsson BO, Astarita G (2014) Ion mobility derived collision cross sections to support metabolomics applications. Anal Chem 86(8):3985–3993CrossRefPubMedPubMedCentral
23.
Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308(5728):1635–1638CrossRefPubMedPubMedCentral
24.
Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 102(31):11070–11075CrossRefPubMedPubMedCentral
25.
Hausmann S, Kong B, Michalski C, Erkan M, Friess H (2014) The role of inflammation in pancreatic cancer. Adv Exp Med Biol 816:129–151CrossRefPubMed
26.
Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13(11):460–469CrossRefPubMed
27.
28.
29.
30.
Guinane CM, Cotter PD (2013) Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther Adv Gastroenterol 6(4):295–308CrossRef
31.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444(7122):1027–1031CrossRefPubMed
32.
Arthur JC, Perez-Chanona E, Muhlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB, Rhodes JM, Stintzi A, Simpson KW, Hansen JJ, Keku TO, Fodor AA et al (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338(6103):120–123CrossRefPubMedPubMedCentral
33.
Shin NR, Whon TW, Bae JW (2015) Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 33(9):496–503CrossRefPubMed
34.
Lavelle A, Lennon G, O’Sullivan O, Docherty N, Balfe A, Maguire A, Mulcahy HE, Doherty G, O’Donoghue D, Hyland J, Ross RP, Coffey JC, Sheahan K, Cotter PD, Shanahan F, Winter DC et al (2015) Spatial variation of the colonic microbiota in patients with ulcerative colitis and control volunteers. Gut 64(10):1553–1561CrossRefPubMedPubMedCentral
35.
Matsuoka K, Kanai T (2015) The gut microbiota and inflammatory bowel disease. Semin Immunopathol 37(1):47–55CrossRefPubMed
36.
Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, Reyes JA, Shah SA, LeLeiko N, Snapper SB, Bousvaros A, Korzenik J, Sands BE, Xavier RJ, Huttenhower C (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13(9):R79CrossRefPubMedPubMedCentral
37.
Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA 104(34):13780–13785CrossRefPubMedPubMedCentral
38.
Ganesh BP, Klopfleisch R, Loh G, Blaut M (2013) Commensal Akkermansia muciniphila exacerbates gut inflammation in Salmonella Typhimurium-infected gnotobiotic mice. PLoS One 8(9):e74963CrossRefPubMedPubMedCentral
39.
Berry D, Schwab C, Milinovich G, Reichert J, Ben Mahfoudh K, Decker T, Engel M, Hai B, Hainzl E, Heider S, Kenner L, Muller M, Rauch I, Strobl B, Wagner M, Schleper C et al (2012) Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis. ISME J 6(11):2091–2106CrossRefPubMedPubMedCentral
40.
41.
Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ (2008) Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27(2):104–119CrossRefPubMed
42.
Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A (2011) Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol 17(12):1519–1528CrossRefPubMedPubMedCentral
43.
Chopin V, Toillon RA, Jouy N, Le Bourhis X (2002) Sodium butyrate induces P53-independent, Fas-mediated apoptosis in MCF-7 human breast cancer cells. Br J Pharmacol 135(1):79–86CrossRefPubMedPubMedCentral
44.
Gaschott T, Maassen CU, Stein J (2001) Tributyrin, a butyrate precursor, impairs growth and induces apoptosis and differentiation in pancreatic cancer cells. Anticancer Res 21(4A):2815–2819PubMed
45.
Scheppach W, Weiler F (2004) The butyrate story: old wine in new bottles? Curr Opin Clin Nutr Metab Care 7(5):563–567CrossRefPubMed
46.
Natoni F, Diolordi L, Santoni C, Gilardini Montani MS (2005) Sodium butyrate sensitises human pancreatic cancer cells to both the intrinsic and the extrinsic apoptotic pathways. Biochim Biophys Acta 1745(3):318–329CrossRefPubMed
47.
Blank-Porat D, Gruss-Fischer T, Tarasenko N, Malik Z, Nudelman A, Rephaeli A (2007) The anticancer prodrugs of butyric acid AN-7 and AN-9, possess antiangiogenic properties. Cancer Lett 256(1):39–48CrossRefPubMed
48.
Ogawa H, Rafiee P, Fisher PJ, Johnson NA, Otterson MF, Binion DG (2003) Sodium butyrate inhibits angiogenesis of human intestinal microvascular endothelial cells through COX-2 inhibition. FEBS Lett 554(1–2):88–94CrossRefPubMed
49.
Zgouras D, Wachtershauser A, Frings D, Stein J (2003) Butyrate impairs intestinal tumor cell-induced angiogenesis by inhibiting HIF-1alpha nuclear translocation. Biochem Biophys Res Commun 300(4):832–838CrossRefPubMed
50.
Farrow B, Rychahou P, O’Connor KL, Evers BM (2003) Butyrate inhibits pancreatic cancer invasion. J Gastrointest Surg 7(7):864–870CrossRefPubMed
51.
van Vliet MJ, Harmsen HJ, de Bont ES, Tissing WJ (2010) The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog 6(5):e1000879CrossRefPubMedPubMedCentral
52.
Yutin N, Galperin MY (2013) A genomic update on clostridial phylogeny: Gram-negative spore formers and other misplaced clostridia. Environ Microbiol 15(10):2631–2641PubMedPubMedCentral
53.
Bien J, Palagani V, Bozko P (2013) The intestinal microbiota dysbiosis and Clostridium difficile infection: is there a relationship with inflammatory bowel disease? Therap Adv Gastroenterol 6(1):53–68CrossRefPubMedPubMedCentral
54.
Anand A, Glatt AE (1993) Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 17(1):109–113CrossRefPubMed
55.
Masciullo V, Mainenti S, Lorusso D, Margariti PA, Scambia G (2010) Lethal clostridium difficile colitis associated with paclitaxel and carboplatin chemotherapy in ovarian carcinoma: case report and review of the literature. Obstet Gynecol Int 2010:749789PubMedPubMedCentral
56.
Raza S, Baig MA, Russell H, Gourdet Y, Berger BJ (2010) Clostridium difficile infection following chemotherapy. Recent Pat Antiinfect Drug Discov 5(1):1–9CrossRefPubMed
57.
Lin XB, Dieleman LA, Ketabi A, Bibova I, Sawyer MB, Xue H, Field CJ, Baracos VE, Ganzle MG (2012) Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats. PLoS One 7(7):e39764CrossRefPubMedPubMedCentral
58.
Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh AS, Hamilton J, Keefe DM (2009) Gastrointestinal microflora and mucins may play a critical role in the development of 5-fluorouracil-induced gastrointestinal mucositis. Exp Biol Med (Maywood) 234(4):430–441CrossRef
59.
Montrose DC, Zhou XK, McNally EM, Sue E, Yantiss RK, Gross SS, Leve ND, Karoly ED, Suen CS, Ling L, Benezra R, Pamer EG, Dannenberg AJ (2016) Celecoxib alters the intestinal microbiota and metabolome in association with reducing polyp burden. Cancer Prev Res (Phila) 9(9):721–731CrossRef
60.
Forsgard RA, Marrachelli VG, Korpela K, Frias R, Collado MC, Korpela R, Monleon D, Spillmann T, Osterlund P (2017) Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague–Dawley rats. Cancer Chemother Pharmacol 80(2):317–332CrossRefPubMedPubMedCentral
61.
Daliri EB, Wei S, Oh DH, Lee BH (2017) The human microbiome and metabolomics: current concepts and applications. Crit Rev Food Sci Nutr 57(16):3565–3576CrossRefPubMed
62.
He B, Hoang TK, Wang T, Ferris M, Taylor CM, Tian X, Luo M, Tran DQ, Zhou J, Tatevian N, Luo F, Molina JG, Blackburn MR, Gomez TH, Roos S, Rhoads JM et al (2016) Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors. J Exp Med 214(1):107–123CrossRefPubMed
63.
da Rocha Lapa F, da Silva MD, de Almeida Cabrini D, Santos AR (2012) Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors. Purinergic Signal 8(4):693–704CrossRefPubMedPubMedCentral
64.
Hasko G, Kuhel DG, Nemeth ZH, Mabley JG, Stachlewitz RF, Virag L, Lohinai Z, Southan GJ, Salzman AL, Szabo C (2000) Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J Immunol 164(2):1013–1019CrossRefPubMed
65.
Gomez G, Sitkovsky MV (2003) Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo. Blood 102(13):4472–4478CrossRefPubMed
66.
Metadata
Title
Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice
Authors
Concetta Panebianco
Kaarel Adamberg
Madis Jaagura
Massimiliano Copetti
Andrea Fontana
Signe Adamberg
Kaia Kolk
Raivo Vilu
Angelo Andriulli
Valerio Pazienza
Publication date
01-04-2018
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3549-0

Other articles of this Issue 4/2018

Cancer Chemotherapy and Pharmacology 4/2018 Go to the issue

Original Article

Long non-coding RNA TUSC7 inhibits temozolomide resistance by targeting miR-10a in glioblastoma

Original Article

Combination of S-1 and gefitinib increases the sensitivity to radiotherapy in lung cancer cells

Original Article

Electrophilic derivatives of omega-3 fatty acids counteract lung cancer cell growth

Short Communication

A novel way to manage trastuzumab cardiotoxicity

Original Article

Randomized phase II study of anastrozole plus tegafur-uracil as neoadjuvant therapy for ER-positive breast cancer in postmenopausal Japanese women (Neo-ACET BC)

Original Article

Safety profile of nivolumab administered as 30-min infusion: analysis of data from CheckMate 153
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits