title: A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model.
abstract: BACKGROUND
  Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma.
  
  
  METHODS
  Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies.
  
  
  RESULTS
  In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone.
  
  
  CONCLUSIONS
  The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.
authors.affiliation: Department of Medical Bioscience, Pathology, Umeå University, Sweden. anna.johansson@medbio.umu.se
authors.forename: Anna
authors.initials: A
authors.lastname: Johansson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jones
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
authors.forename: Sigrid
authors.initials: S
authors.lastname: Kilter
authors.forename: Asa
authors.initials: A
authors.lastname: Skytt
authors.forename: Stina Häggström
authors.initials: SH
authors.lastname: Rudolfsson
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059002:Androgen Receptor Antagonists; D042682:Angiopoietins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D004195:Disease Models, Animal; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D000068877:Imatinib Mesylate; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D008297:Male; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D009919:Orchiectomy; D010879:Piperazines / Q000494:pharmacology*; D011467:Prostate / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D042682:Angiopoietins; D000970:Antineoplastic Agents; D001549:Benzamides; D007141:Immunoglobulin Fc Fragments; D010879:Piperazines; D011743:Pyrimidines; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D042787:Receptor, TIE-2