title: PV1 down-regulation via shRNA inhibits the growth of pancreatic adenocarcinoma xenografts.
abstract: PV1 is an endothelial-specific protein with structural roles in the formation of diaphragms in endothelial cells of normal vessels. PV1 is also highly expressed on endothelial cells of many solid tumours. On the basis of in vitro data, PV1 is thought to actively participate in angiogenesis. To test whether or not PV1 has a function in tumour angiogenesis and in tumour growth in vivo, we have treated pancreatic tumour-bearing mice by single-dose intratumoural delivery of lentiviruses encoding for two different shRNAs targeting murine PV1. We find that PV1 down-regulation by shRNAs inhibits the growth of established tumours derived from two different human pancreatic adenocarcinoma cell lines (AsPC-1 and BxPC-3). The effect observed is because of down-regulation of PV1 in the tumour endothelial cells of host origin, PV1 being specifically expressed in tumour vascular endothelial cells and not in cancer or other stromal cells. There are no differences in vascular density of tumours treated or not with PV1 shRNA, and gain and loss of function of PV1 in endothelial cells does not modify either their proliferation or migration, suggesting that tumour angiogenesis is not impaired. Together, our data argue that down-regulation of PV1 in tumour endothelial cells results in the inhibition of tumour growth via a mechanism different from inhibiting angiogenesis.
authors.affiliation: Departments of Pathology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Deharvengt
authors.forename: Dan
authors.initials: D
authors.lastname: Tse
authors.forename: Olga
authors.initials: O
authors.lastname: Sideleva
authors.forename: Caitlin
authors.initials: C
authors.lastname: McGarry
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gunn
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Longnecker
authors.forename: Catherine
authors.initials: C
authors.lastname: Carriere
authors.forename: Radu V
authors.initials: RV
authors.lastname: Stan
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C486772:Plvap protein, mouse; D034741:RNA, Small Interfering