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Background Taxane treatment may be a suitable therapeutic option for patients with castration‐resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR‐Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR‐V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored. Methods Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm3. Two cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole‐genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis. Results Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, both showed upregulation of the ATP‐binding cassette sub‐family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR‐antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1‐CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment. Conclusions Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR‐V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti‐androgens.

BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR va ...

Our results argue for a role for IDO mediated immune suppression in the early stages of prostate cancer progression. However, since the intra-tumor IDO expression in J(-/-) mice was indistinguishab ...

The epidermal growth factor receptor (EGFR) mediates regulatory signals in the normal prostate, but the functional importance of this is unclear.Adult male rats were castrated, or castrated + treated with gefitinib (Iressa, ZD1839), an EGFR tyrosine kinase inhibitor, for 3 days. Seven-day castrated rats were treated with testosterone, or testosterone + gefitinib, for 3 days.Both castration alone and testosterone treatment in castrated animals increased the mRNA and protein levels of EGFR and phospho-EGFR in the ventral prostate. Inhibition of EGFR during castration and during testosterone-stimulated prostate growth resulted in a decrease in total epithelial weight, epithelial cell proliferation, endothelial cell proliferation, and increased epithelial cell apoptosis.This study suggests that increased EGFR signaling during castration mediates stimulatory effects balancing castration-induced prostate regression, and that EGFR signaling is a necessary component in testosterone-stimulated prostate growth.

Castration-induced involution of the normal prostate is caused by primary effects in the prostate stroma and vasculature, but if this is the case also in tumors is unknown.Androgen-independent AT-1 prostate tumor cells were therefore injected into the ventral prostate (VP) in Copenhagen rats. Seven days later when the growing tumor was surrounded by normal VP tissue the rats were castrated and the effect examined 3 and 7 days later.Castration reduced vascular density in the surrounding VP tissue and this was accompanied by tumor cell hypoxia, apoptosis, and temporarily retarded tumor growth. Castration-induced VP tissue regression occurred more rapidly in the contra-lateral than in the tumor-bearing lobe.Androgen-independent tumor cell respond to castration when growing in an androgen-dependent environment. The presence of a tumor influences the castration response in the surrounding normal tissue. The microenvironment determines how prostate epithelial cells respond to castration.

Castration rapidly reduces stroma insulin-like growth factor (IGF)-1 synthesis and action in mouse prostate epithelium. We explore if similar changes are of importance for castration-induced prostate regression in humans.Epithelial and surrounding stroma cells were micro-dissected from patient biopsies obtained before and shortly after castration. IGF-1 mRNA levels were quantified by RT-PCR and related to epithelial apoptosis and IGF-1, IGF-1 receptor, and androgen receptor (AR) immunoreactivity.IGF-1 mRNA was principally produced in the stroma and IGF-R1 in the epithelium. Stroma IGF-1 mRNA levels were significantly decreased after castration in non-malignant but not malignant tissue. Lack of stroma IGF-1 reduction after castration was associated with low stroma AR expression before therapy. Reduction of IGF-1 mRNA levels in the tumor stroma and/or epithelium was associated with epithelial apoptosis after therapy.Low AR expression and maintained stroma IGF-1 synthesis may result in limited tumor cell death after castration therapy.

Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer.

BACKGROUND: Androgen ablation is the standard treatment for advanced prostate cancer but the short-term cellular effects are largely unknown. METHODS: Sextant prostate biopsies were taken from 77 p ...

Characterization of the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) as a model to study effects of castration therapy.

BACKGROUND Endoglin, a receptor for some of the members of the transforming growth factor-β (TGF-β) family, is expressed on proliferating endothelial cells and has been suggested as a marker of ongoing angiogenesis. In this study, endoglin was evaluated as a prognostic factor for prostate cancer progression. METHODS Immunohistochemical staining of endoglin was examined in 72 cases of prostate cancer and compared with immunohistochemical staining of the pan-endothelial marker von Willebrand factor (vWf), clinicopathological factors, and cancer-specific survival. Micro-vessels were measured in the most vascularized fields. Double staining with antibodies against smooth muscle actin and endoglin or vWf, respectively, was performed in order to evaluate vessel maturation. RESULTS Endoglin-stained tumor vessels were generally small and only 19% also stained with actin. Endoglin was a better prognostic marker than vWf. The median survival times were shorter for patients with tumor vascular count (vc) above median than for patients with vc below median (4 vs. 12 years, P = 0.0007, and 5 vs. 10 years, P = 0.018, for endoglin and vWf, respectively). Endoglin vc was associated with Gleason score (P = 0.001), local tumor stage (P = 0.0006), metastasis (P = 0.01), tumor cell immunoreactivity for TGF-β1 (P = 0.0003), and tumor cell proliferation index (rs = 0.319, P = 0.02). Endoglin, in contrast to vWf, vc was prognostic for survival in the subgroup of patients with Gleason score 5, 6, and 7 tumors. CONCLUSIONS Endoglin marks principally small, probably newly formed tumor vessels in zthe prostate, and is a promising prognostic marker for prostate cancer patients. Prostate 51: 268–275, 2002. © 2002 Wiley-Liss, Inc.

BACKGROUND Inhibitory effects of gonadotropin-releasing hormone (GnRH) analogs on prostate cancer cell proliferation, both in vivo and in vitro, indicate the presence of specific binding sites for GnRH on prostate cancer cells. To investigate this issue further, we examined the expression of GnRH receptor (GnRH-R) mRNA and protein in human prostate biopsies as well as in other extrapituitary tissues. METHODS The relative quantity of GnRH-R mRNA was determined by reverse transcriptase–polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) in human prostate biopsies. Extrapituitary GnRH-R levels were determined by a semiquantitative PCR reaction. RESULTS Using PCR, a relatively high expression level of GnRH-R mRNA was found in prostate tumor tissue followed by normal prostate, thymus, and kidney expression levels. The levels showed by heart, brain, placenta, lung, liver, skeletal muscle, pancreas, colon, ovary, small intestine, spleen, and testis were low but detectable, whereas peripheral blood leukocyte showed no demonstrable product. GnRH-R immunoreactivity was localized in both luminal and basal epithelial cells in benign and malignant prostate tissue, and GnRH-R were also observed in intraprostatic lymphocytes. The relative GnRH-R mRNA levels in prostate biopsies from 16 patients showed a wide range of individual differences, but these differences were not related to histological grade. Castration therapy did not significantly influence GnRH-R mRNA expression in normal and malignant prostate tissue. CONCLUSIONS These results suggest that epithelial cells and infiltrating lymphocytes are targets for GnRH action in the human prostate. Comparative data show relatively high GnRH-R expression in human prostate tissue compared to other human tissues. Prostate 47:276–284, 2001. © 2001 Wiley-Liss, Inc.

TGF-beta1 is an important regulator of the normal and malignant prostate. In the non-malignant prostate, TGF-beta1 stimulates cell differentiation, inhibits epithelial cell proliferation, and induces epithelial cell death. TGF-beta1 is secreted into semen where it is an important immunosuppressive factor. Prostate cancer cells express high levels of TGF-beta1, which seems to enhance prostate cancer growth and metastasis by stimulating angiogenesis and by inhibiting immune responses directed against tumour cells. Prostate cancer cells frequently lose their TGF-beta receptors and acquire resistance to the anti-proliferative and pro-apoptotic effects of TGF-beta1. Accordingly, high expression of TGF-beta1 and loss of TGF-beta receptor expression have been associated with a particularly bad prognosis in human prostate cancer patients. TGF-beta1 also seems to be a mediator of castration-induced apoptosis in androgen dependent normal and malignant prostate epithelial cells. The ability of some prostate tumours to avoid castration-induced apoptosis may not, however, be simply due to loss of TGF-beta receptor type I or type II expression in the tumour cells. It may also be related to an inability of these cells to up-regulate TGF-beta receptor levels in response to castration or possibly due to defects downstream of the receptors. Short-term therapy-induced changes in the TGF-beta system in prostate tumours can probably be used to predict the long-term response to androgen ablation treatment. Further investigations into the TGF-beta system in the prostate are needed, however, to elucidate how alterations in this system affect the behaviour of prostate tumours, and whether this system can be manipulated for therapeutical purposes.

BACKGROUND Continuous administration of gonadotropin-releasing hormone (GnRH) agonists in prostate cancer patients results in involution of the tumors due to suppression of androgen production. In addition to the effect of GnRH at the hypothalamic-pituitary level, experiments in vitro on breast, ovary, and prostatic cells have shown an inhibition of cell proliferation, indicating the presence of local GnRH receptors (GnRH-R). The aim of the present study was to investigate the expression of GnRH-R mRNA in the normal rat ventral prostate (VP) and Dunning R3327 PAP adenocarcinoma and to evaluate the effects of castration on receptor mRNA expression. METHODS RNA was prepared from ovaries, pituitaries, VP, and Dunning tumors from both intact and castrated animals. GnRH-R mRNA levels were quantified by a competitive reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS GnRH-R mRNA was detected in normal VP and Dunning tumors. Normal VP showed lower amounts of GnRH-R mRNA compared to Dunning tumors. An elevation of mRNA expression was observed 7 days after castration in Dunning tumors. CONCLUSIONS GnRH-R mRNA was found in both VP and Dunning tumors, indicating the presence of a local GnRH system. Normal VP showed lower amounts of GnRH-R mRNA when compared to malignant tissues. GnRH-R mRNA levels were elevated in Dunning tumors following castration. Prostate 39:101–107, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND. The mechanism behind castration-induced apoptosis in prostate cells is unknown, but data from other species suggest that transforming growth factor β1 (TGF-β1) may be involved. METHODS. By using quantitative RT-PCR and immunohistochemistry, expression of TGF-β1 and its receptors type I and II (RI and RII) was studied in normal and tumor areas of core biopsies taken before and 2-11 days after castration therapy. The TGF-β responses were related to changes in apoptotic index and to changes in serum prostate-specific antigen (PSA). RESULTS. In normal prostate tissue, apoptosis was generally increased by castration, and apoptosis was accompanied by an increase in TGF-β1 and RII mRNA levels (P < 0.05). In tumors, apoptosis was seen only in 44% of the cases and in these, but not in the others, TGF-β1, RI, and RII mRNA levels were increased (P < 0.05). In the patients showing a prognostically favorable PSA response (nadir PSA

BACKGROUND Prostate tumors express high levels of transforming growth factor-β1 (TGF-β1) and seem to acquire resistance to its antiproliferative effects with tumor progression. Moreover, TGF-β1 could be involved in tumor-promoting processes such as angiogenesis, cell migration, and immunosuppression. METHODS Immunoreactivity for TGF-β1 and its receptors type I and type II (TGFβ-RI and TGFβ-RII), tumor vascular count, and cell proliferation were studied in 73 cases of prostate cancer, diagnosed between 1975–1983 and followed with surveillance. RESULTS Patients with tumor overproduction of TGF-β1 had shorter median cancer-specific survival than patients with normal TGF-β1 immunoreactivity (5.0 vs. 10 years, P = 0.006). Furthermore, increased TGF-β1 staining was associated with tumor grade, high vascular counts, and metastasis (P = 0.02, 0.02, and 0.01, respectively). Patients with loss of tumor TGFβ-RII expression in combination with TGF-β1 overproduction showed particularly short survival (2.6 vs. 10 years, P = 0.0000), when compared to patients with normal immunoreactivity. CONCLUSIONS Overproduction of TGF-β1 and loss of TGFβ-RII expression are associated with poor clinical outcome in prostate cancer, and TGF-β1 may promote tumor progression by stimulating angiogenesis and metastasis. Prostate 37:19–29, 1998. © 1998 Wiley-Liss, Inc.