title: Differentiation therapy: targeting human renal cancer stem cells with interleukin 15.
abstract: BACKGROUND
  Many renal cancer patients experience disease recurrence after immunotherapy or combined treatments due to persistence of cancer stem cells (CSCs). The identification of reliable inducers of CSC differentiation may facilitate the development of efficient strategies for eliminating CSCs. We investigated whether interleukin 15 (IL-15), a regulator of kidney homeostasis, induces the differentiation of CD105-positive (CD105(+)) CSCs from human renal cancers.
  
  
  METHODS
  CD105(+) CSCs were cultured to preserve their stem cell properties and treated with recombinant human IL-15 (rhIL-15) to evaluate their ability to differentiate, to acquire sensitivity to chemotherapeutic drugs, and to form spheroids in vitro and tumors in vivo. Expression of stem cell and epithelial markers were studied by flow cytometry, immunocytochemistry, and immunoblotting. Identification of a CSC side population fraction and its sensitivity to chemotherapy drugs and expression of ATP-binding cassette (ABC) transporters and aldehyde dehydrogenase (ALDH) activities were determined by flow cytometry. Spheroid formation was determined in limiting dilution assay. Xenograft tumors were generated in severe combined immunodeficient mice (n = 12-18 mice per group). All statistical tests were two-sided.
  
  
  RESULTS
  CD105(+) CSCs treated with rhIL-15 at 10 pg/mL differentiated into cells expressing epithelial markers. rhIL-15 induced epithelial differentiation of all CD105(+) CSCs subsets and blocked CSC self-renewal (sphere-forming ability) and their tumorigenic properties in severe combined immunodeficient mice. Vinblastine and paclitaxel induced statistically significant higher levels of apoptosis in rhIL-15-differentiated epithelial cells compared with CD105(+) CSCs (mean percentage of apoptotic cells, vinblastine: 33% vs 16.5%, difference = 16.5%, 95% confidence interval = 12.25% to 20.74%, P = .0025; paclitaxel: 35% vs 11.6%, difference = 23.4%, 95% confidence interval = 22.5% to 24.24%, P = .0015). The higher sensitivity of rhIL-15-differentiated epithelial cells to chemotherapeutic drugs was associated with loss of detoxifying mechanisms such as ALDH and ABC transporter activities.
  
  
  CONCLUSIONS
  IL-15 directs the epithelial differentiation of renal CSCs and meets the criteria for a treatment strategy: CSC pool depletion and generation of differentiated nontumorigenic cells that are sensitive to chemotherapeutic agents.
authors: INSERM UMR, Paul Brousse Hospital, Villejuif, France.
authors: Sandy
authors: S
authors: Azzi
authors: Stefania
authors: S
authors: Bruno
authors: Julien
authors: J
authors: Giron-Michel
authors: Denis
authors: D
authors: Clay
authors: Aurore
authors: A
authors: Devocelle
authors: Michela
authors: M
authors: Croce
authors: Silvano
authors: S
authors: Ferrini
authors: Salem
authors: S
authors: Chouaib
authors: Aimé
authors: A
authors: Vazquez
authors: Bernard
authors: B
authors: Charpentier
authors: Giovanni
authors: G
authors: Camussi
authors: Bruno
authors: B
authors: Azzarone
authors: Pierre
authors: P
authors: Eid
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000071063:Endoglin; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D055502:Secondary Prevention; D014183:Transplantation, Heterologous
chemical_list: D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D000970:Antineoplastic Agents; C064206:ENG protein, human; D000071063:Endoglin; D019409:Interleukin-15; D011956:Receptors, Cell Surface; D050799:STAT5 Transcription Factor; D000444:Aldehyde Dehydrogenase