title: The proline TP53 variant stimulates likely lymphangiogenesis in an orthotopic mouse model of pancreatic cancer.
abstract: BACKGROUND
  Pancreatic cancer is a deadly disease characterised by high incidence of TP53 mutations. Restoration of TP53 function is perceived as a highly attractive therapeutic strategy, whose effects are not well characterised.
  
  
  METHODS
  The current work adapted an inducible strategy of stage-specific reexpression of wild-type (wt) TP53 in an in vivo orthotopic mouse model of pancreatic cancer.
  
  
  RESULTS
  The reconstitution of wt TP53 function in TP53-mutant DanG and MiaPaCa-2 cells caused G1 cell cycle arrest but no evidence of apoptosis induction. Consistent with subcutaneous xenograft models, we found that wt TP53 reduced primary tumour growth. Wt TP53 reexpression during early tumour growth led to significant increase in vascularisation. This correlated with an unexpectedly high rate of micro-metastases in lymph nodes of animals with wt TP53 induction, despite the 90% decrease in median primary tumour weight. Reexpression of wt TP53 later in tumour development did not significantly affect the number of CD31-reactive vessels, but increased lymphatic vessel density.
  
  
  CONCLUSIONS
  The increased number of lymphatic vessels and micro-metastases suggests that wt TP53 induction complexly affected the biology of different tumour constituents of pancreatic cancer. Our observation suggests that combination of the inducible system with an orthotopic model can yield important insights into in vivo pancreatic cancer biology.
authors.affiliation: 1] Department of Internal Medicine, Division of Hepatology and Gastroenterology, Charité Berlin, Campus Virchow Clinic, 13353 Berlin, Germany. otto.noreen@mh-hannover.de
authors.forename: N
authors.initials: N
authors.lastname: Otto
authors.forename: P
authors.initials: P
authors.lastname: Schulz
authors.forename: A
authors.initials: A
authors.lastname: Scholz
authors.forename: P
authors.initials: P
authors.lastname: Hauff
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: K M
authors.initials: KM
authors.lastname: Detjen
authors.forename: B
authors.initials: B
authors.lastname: Wiedenmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016158:Genes, p53; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011392:Proline / Q000235:genetics*
chemical_list: D017931:DNA Primers; D011392:Proline