title: Metabolomics and transcriptomics demonstrate severe oxidative stress in both localized chemotherapy-treated and bystander tumors.
abstract: BACKGROUND
  Localized radiotherapy is long known to cause damages to not only targeted but also non-targeted cells, the so-called bystander (BS) effect. Recently, BS effect was demonstrated in response to chemotherapy. To get further insight into the mechanism of chemotherapy-induced BS effect in vivo, we investigated the response of normal tissues and untreated BS melanomas, at distance from localized chemotherapy-treated melanomas.
  
  
  METHODS
  B16 melanoma cells were inoculated sc in one flank, in mice. Chemotherapy was administered intratumorally. After 3 weeks, untreated melanomas were implanted into the other flank. Tumors were analyzed morphologically, and using metabolomics and transcriptomics.
  
  
  RESULTS
  Locally-treated melanomas showed growth inhibition and pleiotropic metabolic and transcriptional alterations. Tumors recovered slow proliferation while exhibiting prominent oxidative stress response (decreased glutathione level, and increased expression of genes including Mt1, Gpx3, Sod3, and Hmox1). Plasma contained increased levels of oxidative stress products. However, liver and soleus muscle displayed unaltered morphological characteristics. In contrast, untreated BS melanomas induced from naive B16 cells showed reduced growth, marked oxidative stress response (decreased glutathione level, and increased expression of genes including Sod2, Gpx1 and Gsr), and ras oncogene expression alterations. Furthermore, metabolomics and transcriptomics enabled to estimate the proportion of cells undergoing the BS effect within treated tumors.
  
  
  CONCLUSIONS
  Treatment of tumors with chemotherapy induces BS effects, underpinned by oxidative stress, in abnormal proliferating tissues in vivo, not in normal tissue, that significantly contribute to overall tumor response. General significance BS effect significantly contributes to response to chemotherapy, and may be exploited to improve overall response to cancer treatment.
authors.affiliation: UDA University, 49 Boulevard François Mitterrand, CS 60032, 63001 Clermont Ferrand Cedex 1, France; Centre Jean Perrin, 58 Rue Montalembert, F-63011 Clermont Ferrand, France. Electronic address: ademidem@clermont.inra.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morvan
authors.affiliation: UMR 1019 INRA/UDA University, ECREIN, Laboratoire de Biochimie Biologie Moléculaire, Faculté de Pharmacie, 28 Place Henri Dunant, F-63001 Clermont Ferrand, France. Electronic address: Daniel.Morvan@udamail.fr.
authors.forename: Aicha
authors.initials: A
authors.lastname: Demidem
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D024201:Bystander Effect; D049109:Cell Proliferation / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate
keywords: BS; Bystander tumor; CTL; Chemotherapy; INH; Metabolomics; Oxidative stress; REC; Transcriptomics; bystander; control; i.p.; i.t.; inhibition phase; intraperitoneal; intratumor; recovery phase