title: Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-Induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16.
abstract: OBJECTIVE
  The KRAS gene is mutated in most pancreatic ductal adenocarcinomas (PDAC). Expression of this KRAS oncoprotein in mice is sufficient to initiate carcinogenesis but not progression to cancer. Activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is required for KRAS for induction and maintenance of PDAC in mice. The somatostatin receptor subtype 2 (sst2) inhibits PI3K, but sst2 expression is lost during the development of human PDAC. We investigated the effects of sst2 loss during KRAS-induced PDAC development in mice.
  
  
  METHODS
  We analyzed tumor growth in mice that expressed the oncogenic form of KRAS (KRAS(G12D)) in pancreatic precursor cells, as well as sst2+/- and sst2-/-, and in crossed KRAS(G12D);sst2+/- and KRAS(G12D);sst2-/- mice. Pancreatic tissues and acini were collected and assessed by histologic, immunoblot, immunohistochemical, and reverse-transcription polymerase chain reaction analyses. We also compared protein levels in paraffin-embedded PDAC samples from patients vs heathy pancreatic tissues from individuals without pancreatic cancer.
  
  
  RESULTS
  In sst2+/- mice, PI3K was activated and signaled via AKT (PKB; protein kinase B); when these mice were crossed with KRAS(G12D) mice, premalignant lesions, tumors, and lymph node metastases developed more rapidly than in KRAS(G12D) mice. In crossed KRAS(G12D);sst2+/- mice, activation of PI3K signaling via AKT resulted in activation of nuclear factor-κB (NF-κB), which increased KRAS activity and its downstream pathways, promoting initiation and progression of neoplastic lesions. We found this activation loop to be mediated by PI3K-induced production of the chemokine CXCL16. Administration of a CXCL16-neutralizing antibody to KRAS(G12D) mice reduced activation of PI3K signaling to AKT and NF-κB, blocking carcinogenesis. Levels of CXCL16 and its receptor CXCR6 were significantly higher in PDAC tissues and surrounding acini than in healthy pancreatic tissues from mice or human beings. In addition, expression of sst2 was progressively lost, involving increased PI3K activity, in mouse lesions that expressed KRAS(G12D) and progressed to PDAC.
  
  
  CONCLUSIONS
  Based on analyses of mice, loss of sst2 from pancreatic tissues activates PI3K signaling via AKT, leading to activation of NF-κB, amplification of oncogenic KRAS signaling, increased expression of CXCL16, and pancreatic tumor formation. CXCL16 might be a therapeutic target for PDAC.
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Mounira
authors: M
authors: Chalabi-Dchar
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Stéphanie
authors: S
authors: Cassant-Sourdy
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Camille
authors: C
authors: Duluc
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Marjorie
authors: M
authors: Fanjul
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Hubert
authors: H
authors: Lulka
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Rémi
authors: R
authors: Samain
authors: UMR7286 CNRS-Aix-Marseille University, Neurobiology and Neurophysiology Research Center of Marseille, and Laboratory of Molecular Biology, AP-HM Conception, Marseille, France.
authors: Catherine
authors: C
authors: Roche
authors: Pathology Department, Toulouse Hospitals, Toulouse, France.
authors: Florence
authors: F
authors: Breibach
authors: Pathology Department, Toulouse Hospitals, Toulouse, France.
authors: Marie-Bernadette
authors: MB
authors: Delisle
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Mary
authors: M
authors: Poupot
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Marlène
authors: M
authors: Dufresne
authors: Department of Molecular Preventive Medicine, Graduate School of Medicine, Tokyo University, Tokyo, Japan.
authors: Takeshi
authors: T
authors: Shimaoka
authors: Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors: Shin
authors: S
authors: Yonehara
authors: EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France.
authors: Muriel
authors: M
authors: Mathonnet
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
authors: Stéphane
authors: S
authors: Pyronnet
authors: INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France. Electronic address: corinne.bousquet@inserm.fr.
authors: Corinne
authors: C
authors: Bousquet
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000556:secondary; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008207:Lymphatic Metastasis; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051116:Receptors, Scavenger / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; D016328:NF-kappa B; D051116:Receptors, Scavenger; D017481:Receptors, Somatostatin; C574734:SSTR2 protein, human; C570769:somatostatin receptor 2, mouse; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Mouse Model; Oncogene; Signal Transduction; Tumor Suppressor