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A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model
Author(s) -
Johansson Anna,
Jones Jonathan,
Pietras Kristian,
Kilter Sigrid,
Skytt Åsa,
Rudolfsson Stina Häggström,
Bergh Anders
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20657
Subject(s) - stroma , prostate cancer , stromal cell , castration , androgen receptor , prostate , involution (esoterism) , androgen , medicine , androgen deprivation therapy , immunohistochemistry , endocrinology , cancer research , biology , pathology , cancer , hormone , consciousness , neuroscience
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‐Rβ 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‐Rβ 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. Prostate 67: 1664–1676, 2007. © 2007 Wiley‐Liss, Inc.