Abstract
Characterization of the mechanism(s) of androgen-driven human angiogenesis could have significant implications for modeling new forms of anti-angiogenic therapies for CaP and for developing targeted adjuvant therapies to improve efficacy of androgen-deprivation therapy. However, models of angiogenesis by human endothelial cells localized within an intact human prostate tissue architecture are until now extremely limited. This report characterizes the burst of angiogenesis by endogenous human blood vessels in primary xenografts of fresh surgical specimens of benign prostate or prostate cancer (CaP) tissue that occurs between Days 6–14 after transplantation into SCID mice pre-implanted with testosterone pellets. The wave of human angiogenesis was preceded by androgen-mediated up-regulation of VEGF-A expression in the stromal compartment. The neo-vessel network anastomosed to the host mouse vascular system between Days 6–10 post-transplantation, the angiogenic response ceased by Day 15, and by Day 30 the vasculature had matured and stabilized, as indicated by a lack of leakage of serum components into the interstitial tissue space and by association of nascent endothelial cells with mural cells/pericytes. The angiogenic wave was concurrent with the appearance of a reactive stroma phenotype, as determined by staining for α-SMA, Vimentin, Tenascin, Calponin, Desmin and Masson's trichrome, but the reactive stroma phenotype appeared to be largely independent of androgen availability. Transplantation-induced angiogenesis by endogenous human endothelial cells present in primary xenografts of benign and malignant human prostate tissue was preceded by induction of androgen-driven expression of VEGF by the prostate stroma, and was concurrent with and the appearance of a reactive stroma phenotype. Androgen-modulated expression of VEGF-A appeared to be a causal regulator of angiogenesis, and possibly of stromal activation, in human prostate xenografts.
Highlights
Angiogenesis, the formation of new capillaries from pre-existing blood vessels, provides oxygen and nutrients for organogenesis during fetal development and homeostasis of adult tissue, as well as for survival and proliferation of cancer cells, functions crucial for organism and tumor growth [1,2]
This study describes the dynamics of human angiogenesis that occurs in primary xenografts of human prostate tissue, either benign or prostate cancer tissue, transplanted to immuno-compromised (SCID) mice pre-implanted with a source of systemic androgen to maintain human serum levels of testosterone
The smallto-medium caliber neo-vessels were dispersed throughout the xenografts, in contrast to vasculature in the initial tissue (IT) specimen that predominantly was localized adjacent to glandular structures
Summary
Angiogenesis, the formation of new capillaries from pre-existing blood vessels, provides oxygen and nutrients for organogenesis during fetal development and homeostasis of adult tissue, as well as for survival and proliferation of cancer cells, functions crucial for organism and tumor growth [1,2]. Conspicuous limitations of xenograft models based on implantation of permanent cultures of human tumor cells into immune-compromised mouse hosts include that the neo-vasculature of the xenografts is of mouse host origin, and that the neo-vessels develop and mature in response to a hybrid signaling milieu that emanates from both the host stromal microenvironment and the human tumor cells These compromises are exacerbated in cell-line based prostate cancer xenografts by their inability to model the unique biological characteristics of human prostate vasculature, that human prostate endothelial cells demonstrate the highest proliferative index, and possibly the highest level of constitutive remodeling, of any vascular bed in the human body [8], and that the prostate endothelial cells express AR [15]. The human prostate primary xenograft model provides a unique tool for evaluation of the individual contributions of the endothelial compartment, the epithelial/ cancer epithelial compartment, and the stromal compartment, to androgen-mediated homeostasis, or angiogenesis, of human prostate microvascular endothelial cells
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