title: Stem cells increase in numbers in perinecrotic areas in human renal cancer.
abstract: OBJECTIVE
  Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis-associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC.
  
  
  METHODS
  We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4-coexpressing cells derived from the two responder xenograft models were used for in vitro studies.
  
  
  RESULTS
  In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4-coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4-coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased.
  
  
  CONCLUSIONS
  In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France.
authors.forename: Mariana
authors.initials: M
authors.lastname: Varna
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gapihan
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Feugeas
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ratajczak
authors.affiliation: INSERM, U1165-Paris, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tan
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France.
authors.forename: Irmine
authors.initials: I
authors.lastname: Ferreira
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Leboeuf
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France.
authors.forename: Niclas
authors.initials: N
authors.lastname: Setterblad
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Duval
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France. AP-HP-Hôpital Saint-Louis, Service de Pathologie-Paris, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Verine
authors.affiliation: AP-HP-Hôpital Saint-Louis, Service de Pathologie-Paris, Paris, France. Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France. CNRS UMR 7241, Paris, France. INSERM U 1050, Paris, France. MEMOLIFE Laboratory of excellence and Paris Science Lettre, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France. AP-HP-Hôpital Saint-Louis, Service d'Urologie-Paris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mongiat-Artus
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France. AP-HP-Hôpital Saint-Louis, Service de Pathologie-Paris, Paris, France. guilhem.bousquet@sls.aphp.fr anne.janin728@gmail.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France. guilhem.bousquet@sls.aphp.fr anne.janin728@gmail.com.
authors.forename: Guilhem
authors.initials: G
authors.lastname: Bousquet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D011758:Pyrroles / Q000627:therapeutic use; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib