Implications of pleiotrophin in human PC3 prostate cancer cell growth in vivo

Pleiotrophin (PTN) is a heparin‐binding growth factor with diverse functions related to tumor growth, angiogenesis, and metastasis. Pleiotrophin seems to have a significant role in prostate cancer cell growth and to mediate the stimulatory actions of other factors that affect prostate cancer cell functions. However, all studies carried out up to date are in vitro, using different types of human prostate cancer cell lines. The aim of the present work was to study the role of endogenous PTN in human prostate cancer growth in vivo. For this purpose, human prostate cancer PC3 cells were stably transfected with a plasmid vector, bearing the antisense PTN sequence, in order to inhibit PTN expression (AS‐PC3). Migration, apoptosis, and adhesion on osteoblastic cells were measured in vitro. In vivo, PC3 cells were s.c. injected into male NOD/SCID mice, and tumor growth, survival rates, angiogenesis, apoptosis, and the number of metastasis were estimated. Pleiotrophin depletion resulted in a decreased migration capability of AS‐PC3 cells compared with the corresponding mock‐transfected or the non‐transfected PC3 cells, as well as increased apoptosis and decreased adhesiveness to osteoblastic cells in vitro. In prostate cancer NOD/SCID mouse xenografts, PTN depletion significantly suppressed tumor growth and angiogenesis and induced apoptosis of cancer cells. In addition, PTN depletion decreased the number of metastases, providing a survival benefit for the animals bearing AS‐PC3 xenografts. Our data suggest that PTN is implicated in human prostate cancer growth in vivo and could be considered a potential target for the development of new therapeutic approaches for prostate cancer.     

Vascular endothelial growth factor and insulin-like-growth factors in prostate cancer.

To study the levels of vascular endothelium growth factor (VEGF), insulin-like growth factor of type I and II (IGF-I and IGF-II), prostate-specific antigen (PSA) and their correlations in prostatic cancer (PC) and benign prostatic hyperplasia (BPH), we examined 38 PC patients (mean age 66.6 +/- 5.5 years) and 80 BPH patients (mean age 60.3 +/- 2.5 years). Serum concentrations of VEGF, IGF-I and IGF-II were measured using kits made by R&D (USA), PSA by Boehringer Mannheim (Germany). Sensitivity and specificity of the tests were analysed by plotting the curves. The serum VEGF concentration in PC patients was 518.9 +/- 60.7 pkg/ml, in BPH patients--267.9 +/- 99.9 pkg/ml (p < 0.001). The IGF-I and IGF-II it was 178 +/- 19 and 136 +/- 9 ng/ml (p < 0.05), 400 +/- 31 and 351 +/- 23 ng/ml (p < 0.05), respectively. The ratio of growth factor concentration to PSA concentration in the blood serum in BPH patients was higher than in PC patients (p < 0.01). Sensitivity and specificity of PSA (4 ng/ml) made up 85.7 and 57%, VEGF (151.5 pg/ml)--76.2 and 57.6%, IGF-I (157 ng/ml)--57.6 and 50%; IGF-II (392 ng/ml)--57.5 and 50%, respectively. Sensitivity and specificity VEGF/PSA was 85.7 and 70%; IGF-I/PSA--84.2 and 75%; IGF-II/PSA--84.2 and 79.6%, respectively. Thus, the ratio of concentrations of IGF-I, IGF-II and VEGF to PSA level in blood serum has high sensitivity and specificity for PC detection. Clinical implications of serum levels of VEGF, IGF-I and IGF-II for prediction of PC course and detection is to be elicited.     

Inhibition of metastasis of circulating human prostate cancer cells in the chick embryo by an extracellular matrix produced by foreskin fibroblasts in culture

We have previously demonstrated the increased metastatic potential of human prostate cancer circulating tumor cells (CTC), compared to their parental cells, in both orthotopic mouse models and the chick embryo model. In the current study, we asked whether an extracellular matrix (ECM), produced by human foreskin fibroblasts in culture, could inhibit PC-3 human prostate cancer CTC metastasis in the chick embryo model. The chorioallantoic membranes (CAM) of 18 chicken embryos were inoculated with either PC-3 human prostate cancer cells or PC-3 CTCs, both stably expressing green fluorescent protein (GFP). Embryos were divided into six groups: PC-3 parental-cell control; PC-3 plus soluble ECM; PC-3 parental cells plus semi-solid ECM; PC-3 CTC control; PC-3 CTC plus soluble ECM, and PC-3 CTC plus semi-solid ECM. Twelve hours following inoculation of the cells, a single dose of 100 μl of either soluble or semi-solid ECM was added to the appropriate group. Embryo brains were removed on day 8 post-inoculation, and were processed for cryosectioning. Imaging was performed on the cryosections using a scanning laser microscope in order to count metastatic foci. PC-3 controls had an average of 11.1 metastatic foci compared to 2.55 in the PC-3 plus soluble ECM group and 2.76 (p<0.0001) in the PC-3 plus semi-solid ECM group (p<0.0001). ECM treatment had even greater efficacy on the CTC cells, with an average of 30.9 metastatic foci in the CTC controls compared to 4.38 in the CTC plus soluble ECM group (p<0.0001) and 4.18 in the CTC plus semi-solid ECM group (p<0.0001). The results demonstrate that reduction of CTC metastatic potential is possible, in this case with an ECM produced by human foreskin fibroblasts in culture.     

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

Histone deacetylase inhibitors (HDACs) are known to exhibit antiproliferative effects on various carcinoma cells. In this study, the in vivo efficiency of two HDACs, sodium butyrate and tributyrin, on prostate cancer growth inhibition were investigated. To gain an insight into the possible underlying pathways, cell culture experiments were performed focusing on the expression of p21, Rb and c-myc. For in vivo testing, prostate cancer cell lines (PC3 and TSU-Pr1) were seeded on the chorioallantois membrane (CAM) and implanted in a xenograft model using nude mice. Standard Western blot analysis was performed for protein expression of p21, Rb and c-myc in HDAC-treated vs untreated prostate cancer cells. Both sodium butyrate and tributyrin had a considerable treatment effect on microtumours on the chicken egg at already very low concentrations of 0.1 mM. Tributyrin-treated tumours showed the strongest effect with 38% apoptotic nuclei in the prostate cancer cell line PC3. In the mouse model, there was almost no difference between sodium butyrate and tributyrin. In untreated animals the tumours were almost double the size 4 weeks after implantation. Tumours of the treatment groups had a significantly lower percentage of Ki-67-positive-stained nuclei. As demonstrated by Western blot analysis, these effects seem to be independent of p53 status and a pathway via p21-Rb-c-myc is possibly involved. In this study we have demonstrated a substantial in vivo treatment effect, which can be induced by the application of sodium butyrate or the orally applicable tributyrin in human prostate cancer. The given results may provide the rationale to apply these drugs in well-controlled clinical trials in patients being at high risk of recurrence after specific therapy or in patients with locally or distant advanced prostate cancer.     

Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells.

PURPOSE: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). EXPERIMENTAL DESIGN: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume. RESULTS: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P < 0.001) and 89% (P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P < 0.001) and 74% (P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and down-regulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells. CONCLUSION: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo.     

Fibroblast growth factor 5 proto-oncogene is expressed in normal human fibroblasts and induced by serum growth factors.

Fibroblast growth factor 5 (FGF-5) is a member of the fibroblast growth factor family with transforming potential. It has been found to be expressed in several human tumor cell lines, but nothing is known about expression of this growth factor in normal cells and its biological functions. Here we show that the FGF-5 gene is expressed in exponentially growing normal human fibroblasts. In quiescent fibroblasts, expression of FGF-5 is strongly induced by serum and several growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). This induction can be mediated by at least two different pathways involving protein kinase C or cAMP-dependent kinases. Since the effect is independent of de novo protein synthesis, FGF-5 represents the product of a primary response gene. In addition our data suggest that FGF-5 is mitogenic for human fibroblasts, indicating the existence of an FGF-5-mediated positive feedback in these cells which could amplify and prolong the cellular response to the initial stimulus.     

Basic fibroblast growth factor in human prostate cancer cells.

To increase our understanding of the potential role of basic fibroblast growth factor (bFGF) in malignant progression of prostate cancer, we determined the production of bFGF, the expression of FGF receptor (flg), and the response to exogenous bFGF in LNCaP, DU 145, and PC 3 cells. We observed that these three prostate cancer cell lines, which differed in their dependence on androgens for growth in vitro and in their in vivo behavior in nude mice, could be distinguished as follows: (a) androgen-sensitive LNCaP cells, which do not metastasize in nude mice, did not produce measurable amounts of bFGF, expressed small but measurable amounts of FGF receptor mRNA, and did respond to exogeneous bFGF; (b) androgen-insensitive, moderately metastatic DU 145 cells did produce measurable amounts of biologically active bFGF, expressed large amounts of FGF receptor mRNA, and responded to exogeneous bFGF and the heparin-binding fractions from DU 145 cell extracts; (c) androgen-insensitive and highly metastatic PC3 cells also produced measurable amounts of bFGF but did not demonstrate a growth response to either the heparin-binding fractions from PC3 cell extracts or exogenous bFGF, even though large amounts of FGF receptor mRNA were expressed in PC 3 cells. These results suggest the possibility that differences in production of, and response to, bFGF may be associated with different biological behavior.     

Bone marrow macrophages support prostate cancer growth in bone

Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone.     

A human monocyte growth factor produced by lung cancer cells

Human lung cancer cell line, T3M-30, has been shown to produce a growth factor that stimulates proliferation of peripheral blood monocytes. In the presence of this factor, human circulating monocytes were able to proliferate in vitro. Gel exclusion chromatography of the conditioned medium revealed a single peak of monocyte growth-promoting activity at an apparent molecular weight of 16,000. The growth-promoting activity was adsorbed to an anion-exchange column, Mono Q, and eluted with a salt gradient as a single peak of bioactivity at 300 mM NaCl. When the sample was applied to a Vydac C4 column, a reverse-phase high-performance liquid chromatography column, a single peak of activity was observed at a concentration of 76% acetonitrile in 0.1% trifluoroacetic acid. The monocyte growth-promoting activity was heat stable at 56 degrees C. It was partially destroyed by trypsin. The activity was lost after treatment with 2-mercaptoethanol.     

Leukemia derived growth factors produced by human malignant T-lymphoid cell lines

An autocrine (noninterleukin 2) growth factor, which we term leukemia derived growth factor (LDGF), has previously been found in the culture supernatant of the human malignant T-lymphoid cell line MOLT-4f. We now show that two other human malignant T-lymphoid cell lines, CCRF-CEM and CCRF-HSB-2 also produce such a factor. All three factors, i.e., the LDGF from MOLT-4f, CCRF-CEM, and CCRF-HSB-2 are similar to each other both in biological activity and in physicochemical characteristics. In addition to their autocrine activity, these LDGFs stimulate the growth of other malignant T-lymphoid cell lines, but they do not stimulate B-lymphoblastoid or myeloid cell lines. The results therefore suggest that these LDGFs are T-cell specific.     

Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors

Advanced prostate cancer frequently involves the bone that has the largest content of insulin-like growth factors (IGFs). However, the role of bone-derived IGFs in bone metastasis of prostate cancer has not been studied extensively because of the lack of a reliable animal model. Therefore, we investigated whether a novel antibody directed against human IGF-I and IGF-II (KM1468) could inhibit the development of new bone tumors and the progression of established bone tumors in nonobese diabetic/severe combined immunodeficient mice implanted with human adult bone. We first confirmed that KM1468 bound specifically to human IGF-I, human IGF-II, and mouse IGF-II but not to insulin. It also blocked autophosphorylation of the type I IGF receptor induced by the binding of IGFs in human-type I IGF receptor-overexpressing BALB/c 3T3 cells, and it inhibited the IGF-stimulated growth of MDA PCa 2b cells in vitro. Then mice were injected intraperitoneally with KM1468 once weekly for 4 weeks either immediately or 4 weeks after inoculation of MDA PCa 2b cells. KM1468 markedly and dose-dependently suppressed the development of new bone tumors and the progression of established tumor foci, as determined by histomorphometry, and it also decreased serum prostate-specific antigen levels, compared with the control. This is the first report of an IGF ligand-specific inhibitory antibody that suppresses the growth of human prostate cancer cells in human adult bone. These results indicate that the IGF signaling axis is a potential target for prevention and treatment of bone metastases arising from prostate cancer.     

大黄素通过抑制雄激素受体表达抑制前列腺癌细胞生长的体内实验研究

目的进一步证实大黄素在体内对前列腺癌的作用和作用机制.方法选用PC3-AR荷瘤裸鼠和C3(1)/SV40转基因小鼠作为动物模型,分别设对照组和治疗组,对照组腹腔注射DMSO,治疗组腹腔注射大黄素40mg/(kg·d).每周测动物体重及肿瘤大小.结果在PC3-AR荷瘤裸鼠中,治疗组小鼠肿瘤体积明显小于对照组(P＜0.001).在C3(1)/SV40转基因小鼠中,治疗组小鼠的生存时间明显长于对照组(P＜0.001).与治疗组相比,对照组小鼠的体重明显降低,皮毛光滑度差,活动能力差.对C3(1)/SV40转基因小鼠肿瘤进行组织化学染色和Western bloting分析表明:治疗组小鼠肿瘤表达雄激素受体阳性细胞明显减少(P＜O.05);雄激素受体的表达与对照组相比也有明显的降低.此外,对照组小组(1/7)与治疗组(7/7)相比更具有向周围组织转移和浸润的倾向.以上结果证明了大黄素在体内对前列腺癌的作用机制与体外相同.结论大黄素不但对前列腺癌的生长有明显的抑制作用,还可抑制前列腺癌的发生.提示大黄素不仅可用于前列腺癌的临床治疗,也可用于前列腺癌的预防.     

Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors

The metabolism of arachidonic acid by either the cyclooxygenase (COX) or lipoxygenase (LOX) pathway generates eicosanoids, which have been implicated in the pathogenesis of a variety of human diseases, including cancer. They are believed to play important roles in tumor promotion, progression, and metastasis. Involvement of LOXs expression and function in tumor growth and metastasis has been reported in human tumor cell lines. Expressions of 5- and 12-LOX in prostate cancer (PC) patients, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues were examined, as well as effects of their inhibitors on cell proliferation in 2 PC cell lines (PC3, DU-145). Expression of 5- and 12-LOX protein was detected by immunohistochemistry. Effects of LOX inhibitors on prostate cancer cell growth were examined by MTT assay, and Hoechst staining was used to determine whether or not the LOX inhibitors induce apoptosis. While 5- and 12-LOX expressions were slightly detected in BPH and NP tissues, marked expressions of 5- and 12-lipoxygenase were detected in PIN and PC tissues. The LOX inhibitors caused marked reduction of prostate cancer cells in a concentration- and time-dependent manner. The LOX inhibitors caused marked inhibition of PC cells through apoptosis. LOX is induced in prostate cancer, and our results suggest that LOX inhibitors may mediate potent antiproliferative effects against prostate cancer cells. Thus, LOX may become a new target in treatment of prostate cancer.     

Diallyl trisulfide suppresses growth of PC-3 human prostate cancer xenograft in vivo in association with Bax and Bak induction.

PURPOSE: The present study was undertaken to determine the effect of garlic constituent diallyl trisulfide (DATS) on growth of PC-3 human prostate cancer xenograft in vivo. EXPERIMENTAL DESIGN: DATS was given orally (6 micromoL, thrice weekly) to male athymic mice s.c. implanted with PC-3 cells. Tumor sections from control and DATS-treated mice were examined for apoptotic bodies by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Protein levels of apoptosis and cell cycle regulating proteins in tumor tissues of control and DATS-treated mice were determined by immunoblotting. The effect of DATS treatment on in vivo angiogenesis was determined by immunohistochemical analysis of CD31 in tumors. RESULTS: Oral gavage of DATS significantly retarded growth of PC-3 xenografts in athymic mice without causing weight loss. For instance, 20 days after starting therapy, the average tumor volume in control mice was approximately 3-fold higher compared with DATS-treated mice. Tumors from DATS-treated mice exhibited a markedly higher count of apoptotic bodies compared with control tumors. Consistent with the results in cultured PC-3 cells, the DATS-mediated suppression of PC-3 xenograft growth correlated with induction of proapoptotic proteins Bax and Bak. Although DATS treatment inhibited migration of cultured PC-3 cells in association with down-regulation of vascular endothelial growth factor receptor-2 protein, formation of new blood vessels was comparable in tumors of control and DATS-treated mice as judged by CD31 immunostaining. CONCLUSIONS: The present study indicates that DATS administration inhibits growth of PC-3 xenografts in vivo in association with induction of Bax and Bak.     

Short-term human prostate primary xenografts: an in vivo model of human prostate cancer vasculature and angiogenesis

Transgenic spontaneously occurring and transplantable xenograft models of adenocarcinoma of the prostate (CaP) are established tools for the study of CaP progression and metastasis. However, no animal model of CaP has been characterized that recapitulates the response of the human prostate vascular compartment to the evolving tumor microenvironment during CaP progression. We report that primary xenografts of human CaP and of noninvolved areas of the human prostate peripheral zone transplanted to athymic nude mice provide a unique model of human angiogenesis occurring in an intact human prostate tissue microenvironment. Angiogenesis in human kidney primary xenografts established from human renal cell carcinoma and noninvolved kidney tissue, a highly vascular organ and cancer, was compared with angiogenesis in xenografts from the relatively less vascularized prostate. Immunohistochemical identification of the human versus mouse host origin of the endothelial cells and of human endothelial cell proliferation in the human prostate and human kidney xenografts demonstrated that: (a) the majority of the vessels in primary xenografts of benign and malignant tissue of both organs were lined with human endothelial cells through the 30-day study period; (b) the mean vessel density was increased in both the CaP and benign prostate xenografts relative to the initial tissue, whereas there was no significant difference in mean vessel density in the renal cell carcinoma and benign kidney xenografts compared with the initial tissue; and (c) the number of vessels with proliferating endothelial cells in primary xenografts of CaP and benign prostate increased compared with their respective initial tissue specimens, whereas the number of vessels with proliferating endothelial cells decreased in the benign kidney xenografts. Short-term primary human prostate xenografts, therefore, represent a valuable in vivo model for the study of human angiogenesis within a human tissue microenvironment and for comparison of angiogenesis in CaP versus benign prostate.     

Expression of transforming growth factor-beta 1 and growth in soft agar differentiate prostate carcinoma-associated fibroblasts from normal prostate fibroblasts

Carcinoma-associated fibroblasts (CAF) promote tumor progression of pre-neoplastic epithelial cells. To investigate the basis of this phenomenon, we compared the properties of fibroblasts cultured from normal human prostate (NHPF) to prostate CAF. NHPF and CAF were assayed for growth potential, cell death and proliferative capacity by measuring population doubling time, cell cycle distribution and capability to form colonies in soft agar. Resistance to genotoxic (UV radiation: 0-50 J/cm2) and chemotoxic (0-200 nM Taxol) agents were compared between CAF and NHPF by measuring cell viability and cell cycle analysis. Transforming growth factor beta1 (TGF-beta1) immunoreactivity was assessed in non-malignant and malignant prostatic tissue. No detectable differences were found when comparing CAF and NHPF with respect to population doubling time, cell cycle distribution and response to genotoxic and chemotoxic agents. The mean number of colonies in soft agar was 120.5 for CAF vs. 18.2 for NHPF (p < 0.05). Because TGF-beta1 and matrix metalloproteinase (MMP)-9 have been associated with growth of fibroblasts in soft agar and tumor promotion, we measured the expression of these factors in NHPF and CAF by ELISA. There was no difference in expression of MMP-9; however, TGF-beta1 was expressed in higher concentrations in CAF than in NHPF (p < 0.0014). Furthermore, TGF-beta1 expression was higher in the carcinoma-associated stroma of prostate cancer tissue than stroma of non-malignant prostatic tissue. Increased capability of CAF as compared to NHPF to form colonies in soft agar may be due to a higher expression of TGF-beta1 and correlates with the ability of CAF to promote malignant progression of prostate epithelial cells.     

Insulin-like growth factors and prostate cancer: a population-based case-control study in China.

Insulin-like growth factors (IGFs) have potent mitogenic and antiapoptotic effects on prostate epithelial cells. Through modulation of IGF bioactivity and other mechanisms, IGF-binding proteins (IGFBPs) also have growth-regulatory effects on prostate cells. Recently, IGF-I and IGFBP-3 have been implicated in prostate cancer risk among Western populations. To assess whether IGF-I, IGF-II, IGFBP-1, or IGFBP-3 are also associated with prostate cancer in a low-risk population, we measured plasma levels of these factors among 128 newly diagnosed prostate cancer cases and 306 randomly selected population controls in Shanghai, China. Relative to the lowest quartile of IGF-I levels, men in the highest quartile had a 2.6-fold higher prostate cancer risk, with a significant trend [odds ratio (OR) = 2.63; 95% confidence interval (95% CI) = 1.19-5.79; P(trend) = 0.01]. In contrast, men in the highest quartile of IGFBP-3 levels had a 46% decreased risk relative to the lowest quartile (OR = 0.54; 95% CI = 0.26-1.15; P(trend) = 0.08). A similar but less distinct result was observed for IGFBP-1 (OR = 0.60; 95% CI = 0.31-1.17; P(trend) = 0.25). Men in the highest quartile for the IGF-I:IGFBP-3 molar ratio (an indirect measure of free IGF-I) had a 2.5-fold higher risk compared with the lowest quartile (OR = 2.51; 95% CI = 1.32-4.75, P(trend) < 0.001). These associations were more pronounced after adjustment for serum 5alpha-androstane-3alpha,17beta-diol glucuronide and sex hormone-binding globulin levels. There was no significant association with IGF-II levels. Our findings in a low-risk population provide evidence that IGF-I, IGFBP-3, and IGFBP-1 are determinants of prostate cancer and indicate that additional studies are needed to evaluate their effects on ethnic and geographic incidence differentials and to elucidate carcinogenic mechanisms.     

Markers of bone turnover in prostate cancer.

Prostate cancer is the most common malignancy in elderly men and is often associated with bone metastases. Although bone metastases are osteosclerotic, histological and biochemical studies clearly indicate an increase of both bone formation and bone resorption, providing the rational for using bisphosphonate as a palliative treatment in these patients. The recent development of specific and sensitive biochemical markers, reflecting the overall rate of bone formation and bone resorption, has improved the non-invasive assessment of bone turnover abnormalities in patients with prostate cancer. The immunoassays for bone-specific alkaline phosphatase and type I collagen propeptides are currently the most sensitive markers to assess bone, formation. The best indices of bone resorption are the immunoassay for the pyridinoline cross-links and the related peptides that can be measured in urine and more recently in serum. A better knowledge of the biochemistry, especially of the age-related post-translational modifications of type I collagen in the abnormal bone matrix, associated with bone metastases from prostate cancer may lead to markers of increased sensitivity. A recent example is the demonstration that the isomerization and racemization of the aspartic acid residue in C-telopeptides of type I collagen is impaired in patients with prostate cancer and bone metastases, a pattern than can be detected with specific conformational antibodies.The most sensitive markers of bone formation and bone resorption are markedly increased in patients with bone metastases compared with patients with cancer but without metastases, the levels correlating with the extent of the bone involvement. However, their sensitivity remains limited, suggesting that the currently available biochemical markers cannot be used as a surrogate for bone scintigraphy in the diagnosis of bone involvement. A few studies have suggested that the measurement of bone markers may be useful in the assessment of response to anti-endocrine therapy, although available data indicate a lower sensitivity than with prostates specific antigen. Additional longitudinal studies are required to assess the potential use of bone markers, especially to identify patients who relapse during the course of the treatment and, more specifically 3 those that result from the progression in bone metastases.Clearly, the established use of bone markers is for monitoring effects of bisphosphonate treatment. Several studies have shown a rapid decrease of bone resorption markers in patients with prostate cancer and bone metastases, the magnitude of the decrease correlating with the efficacy of the treatment in reducing bone pain. Thus, bone markers are likely to become a useful and objective tool to monitor bisphosphonate treatment and individual the therapy scheme.