SPAG9 promotes prostate cancer growth and metastasis

Sperm-associated antigen 9 (SPAG9) expression is increased in prostate tissues of prostate cancerpatients. This experimental study aimed to investigate the role of SPAG9 in bone metastasis of prostate cancer.Immunohistochemical analysis showed that SPAG9 staining was positive in 81.67% of 240 cases of prostatic carcinomabut only in 6.67% of 120 cases of benign prostate hyperplasia. Strong PAG9 staining was positively correlated withGleason score and bone metastasis in 240 prostate cancer patients (p < 0.05), but not with the age or serum prostatespecific antigen level (p > 0.05). PC-3 cells were transfected with shRNA against SPAG9, and CCK-8 assay in triplicateshowed that PC-3 cell viability was inhibited by SPAG9 knockdown. In addition, transwell assay in triplicate showedthat PC-3 cell invasion was inhibited by SPAG9 knockdown. Furthermore, total 2 × 106 PC-3 cells were injectedsubcutaneously into the right flank of nude mice which were randomly divided into three groups (N = 8) and treatedby intratumoral injection of SPAG9 shRNA, control shRNA or PBS, respectively. SPAG9 shRNA inhibited thegrowth, invasion and angiogenesis while promoted apoptosis of xenografted PC-3 cells. SPAG9 knockdown led to theupregulation of E-cadherin and the downregulation of MMP2 and vimentin in xenografted tumors. In conclusion,this is the first study to provide evidence that SPAG9 promotes bone metastasis of prostate cancer, and SPAG9 is apromising target to prevent or treat bone metastasis of prostate cancer.     

Role of insulin-like growth factor binding protein-3 in breast cancer cell growth

The mitogenic effects of insulin-like growth factors (IGFs) are regulated by a family of insulin-like growth factor binding proteins (IGFBPs). One member of this family, IGFBP-3, mediates the growth-inhibitory and apoptosis-inducing effects of a number of growth factors and hormones such as transforming growth factor-beta, retinoic acid, and 1,25-dihydroxyvitamin D3. IGFBP-3 may act in an IGF-dependent manner by attenuating the interaction of pericellular IGFs with the type-I IGF receptor. It may also act in an IGF-independent manner by initiating intracellular signaling from a cell surface receptor, or by direct nuclear action, or both. The possibility of a membrane-bound receptor is strengthened by recent studies which have identified members of the transforming growth factor-beta receptor family as having a role, either directly or indirectly, in signaling from the cell surface by IGFBP-3. A number of growth factors and hormones stimulate the expression and secretion of cellular IGFBP-3, which then signals from the cell surface to bring about some of the effects attributed to the primary agents. Within the cell, the apoptosis-inducing tumor suppressor, p53, can also induce IGFBP-3 expression and secretion. Since IGFBP-3 upregulates the cell cycle inhibitor, p21(Waf1), and increases the ratio of proapoptotic to antiapoptotic members of the Bcl family, it appears to exert the same effects on major downstream targets of cell signaling as p53 does. The nuclear localization of IGFBP-3 has been described in a number of cell types. IGFBP-3 may act to import IGFs or other nuclear localization signal-deficient signaling molecules into the nucleus. It may also act directly in the nucleus by enhancing the activity of retinoid X receptor-alpha and thereby promote apoptosis. All of the above phenomena will be discussed with particular emphasis on the growth of breast cancer cells.     

Angiogenesis in breast cancer: the role of transforming growth factor beta and CD105

The progression of breast cancer depends on the establishment of a neovasculature, by a process called angiogenesis. Angiogenesis is an invasive cellular event that requires the co-ordination of numerous molecules including growth factors and their receptors, extracellular proteins, adhesion molecules, and proteolytic enzymes. TGFbeta has emerged to be a major modulator of angiogenesis by regulating endothelial cell proliferation, migration, extracellular matrix (ECM) metabolism, and the expression of adhesion molecules. It is a potent growth inhibitor of normal mammary epithelial cells and a number of breast cancer cell lines. It seems that TGFbeta exerts pleiotropic effects in the oncogenesis of breast cancers in a contextual manner, i.e., it suppresses tumourigenesis at an early stage by direct inhibition of angiogenesis and tumour cell growth. However, over-production of TGFbeta by an advanced tumour may accelerate disease progression through indirect stimulation of angiogenesis and immune suppression. The cell membrane antigen CD105 (endoglin) binds TGFbeta1 and TGFbeta3 and is preferentially expressed in angiogenic vascular endothelial cells. The reduction of CD105 levels in HUVEC leads to in vitro angiogenesis inhibition and massive cell mortality in the presence of TGFbeta1. CD105 null mice die in utero with impaired vasculature, indicating the pivotal role of CD105 in vascular development. The administration of an immunotoxin-conjugate, mab to CD105, induces long-term and complete regression of breast cancer growth in SCID mice. Therefore, CD105 is a promising vascular target for antiangiogenic therapy.     

Biology of transforming growth factor beta in hepatocarcinogenesis

TGF-beta is an important factor in the regulation of liver growth. It is an inhibitor of hepatocyte DNA synthesis and may induce active cell death, e.g., to remove excessive tissue mass. Studies using transgenic mice suggest that expression in the resting liver has to be well balanced; either under- or overexpression appear to cause an increased turnover of hepatocytes and to predispose to hepatocarcinogenesis. TGF-beta overexpression is frequently observed in human hepatocellular carcinomas, probably as a late event in tumor development. In men and mice, TGF-beta overexpression appears to be associated with loss of TGF-beta responsiveness often by disruption of TGF-beta signaling. However, mechanisms as mutations in TGF-beta receptor II or Smad2 and 4 genes, frequently observed in other human cancers, have only rarely been observed in hepatocellular carcinomas. Further studies may clarify the mechanisms by which hepatocellular tumors escape TGF-beta growth control, as well as analyze possible roles of TGF-beta overexpression in immunosuppression and angiogenesis.     

Staging prostate cancer

Determining tumor stage provides a systematic way to describe the amount and the extent of a tumor at a certain point in time. In this short overview, the current version of the TNM system for prostate cancer is discussed. The TNM (tumor, lymph node, and metastasis) system is now used worldwide for determining tumor stage for prostate cancer. Tumor stage is essentially determined in two situations, at clinical evaluation of the patient (clinical stage) and after treatment by surgical removal of the prostate (pathological stage). In the ideal situation, clinical stage would be a reliable predictor of pathological stage, but in the current situation, tumors are clinically understaged in more than half of the cases. Additional clinical tools are needed to provide a firmer base on which the choice for patient treatment or management could be founded. Some of the criteria for the assessment of pathological stage are unclear. For instance, multifocal tumor, which occurs in more than half of the cases of prostate cancer, is not reckoned with in the current system, something that could hamper a correct and unambiguous assessment of pathological stage. In this report, we also discuss the criteria for extraprostatic extension, seminal vesicle invasion, and bladder neck invasion. Follow-up data obtained from a group of 123 patients that underwent radical prostatectomy at our hospital underline the importance of reporting the latter two.     

Molecular cytogenetics of prostate cancer

Prostate cancer is the most common malignancy among men in Western industrialized countries. The molecular pathogenesis of the disease is poorly known. Over the past 10 years, chromosomal aberrations in prostate cancer have been studied with several techniques, such as loss of heterozygosity (LOH), classical cytogenetics, and molecular cytogenetics, namely with fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). These analyses, especially those performed by CGH, have enabled the distinction of the predominant chromosomal regions of involvement in prostate cancer. Studies have shown that the most common chromosomal alterations in prostate cancer are losses at 1p, 6q, 8p, 10q, 13q, 16q, and 18q and gains at 1q, 2p, 7, 8q, 18q, and Xq. Fluorescence in situ hybridization (FISH) has been used to identify the target genes for some of these chromosomal alterations. For example, amplifications of AR (at Xq12), MYC (8q24), and EIF3S3 (8q23) have been found in a large fraction of hormone-refractory prostate cancer by FISH. However, many of the critical oncogenes and tumor suppressor genes located in the altered chromosomal regions have not yet been identified.     

Role of TGF-beta in immune-evasion of cancer

One of the major obstacles in tumor-immunology is the outgrowth of malignant tumors despite their immunogenicity and recognition by the immune-system. Multiple mechanisms for this phenomenon have been proposed. We review the possible involvement of transforming growth factor beta (TGF-beta) in this context. TGF-beta is a cytokine with pleiotropic functions, involved in multiple physiologic processes including immunoregulation. Immune elimination of most cancers ultimately depends on cytolytic T cells (CTL). We propose a mechanism of specific suppression of cytolytic T cell (CTL)-responses mediated through immunoglobulin-bound TGF-beta (IgG-TGF-beta), secreted by activated B cells, and a cell of myeloid origin. This mononuclear "Veto" cell presumably binds IgG-TGF-beta through Fc-receptors and activates latent TGF-beta. The suggestion that B cell responses can inhibit tumor rejection is supported by observations in B cell-deficient mice. Ways for enhancing effective cancer immunity by interfering with the network of interactions involving IgG-TGF-beta are discussed.     

Role of nerve growth factor in the olfactory system

Olfactory neurons are unique in the mammalian nervous system because of their capacity to regenerate in adult animals. It has been shown that olfactory receptor cells located in the olfactory epithelium are replaced on a continuous basis and in response to injury throughout the life span of most species. NGF, which is one of the neurotrophic factors, is present in many areas of the central and peripheral nervous system. It has been shown that NGF in the olfactory bulb plays a role in the survival of cholinergic neurons in the horizontal limb of the diagonal band (HDB). Recent studies of NGF in the olfactory bulb suggest that it is involved in the development, maintenance, and regeneration of olfactory receptor cells. In this study, we review reports examining the relationship between NGF in the olfactory bulb and neuronal regeneration and development in the mammalian olfactory systems. Low- and high-affinity NGF receptor immunoreactivity is markedly expressed during regeneration and at different stages of development in the mouse olfactory system. This level of immunoreactivity is no longer present after completion of regeneration and at maturation. Other findings indicate that NGF injected into the olfactory bulb is transported retrogradely to the olfactory epithelium. It has also been shown that continuous anti-NGF antibody injection into the olfactory bulb causes degeneration and olfactory dysfunction. Administration of NGF directory into nasal cavity results in an increase in the expression of olfactory marker protein within the olfactory epithelium in axotomized rats. These findings suggested that the presence of NGF in the olfactory bulb plays an essential role in regeneration, maintenance, and development in the olfactory system of mammals.     

Blood and serum substances for markers of prostate cancer

Serummarkers for prostate carcinoma are widely applied for the purpose of early detection of cancer and the differentiation between benign and malignant disease, for the pre-treatment staging of detected prostatic cancers, and for the monitoring of prostate cancer after curative or palliative therapies. This review illustrates the limitations of current markers for prostatic disease in blood en serum. It gives an overview of what is known about PSA and its isoforms, hK2, PSMA, and PSCA, and discusses, based on this information, in what direction current research is developing in order to improve these markers.     

经直肠实时组织超声弹性成像在前列腺癌筛查中的应用

目的探讨经直肠实时组织超声弹性成像（TRTE）在前列腺癌筛查中的应用价值。方法对2010年1月~2012年12月我院93例疑似前列腺癌拟行前列腺活检的患者,在穿刺活检前首先分别行TRTE和经直肠超声（TRUS）检查前列腺,再在其引导下穿刺活检,比较2种方法的前列腺癌检出率。结果 93例前列腺癌疑似患者病理检查结果显示：良性45例,恶性48例。TRTE诊断前列腺癌灵敏度93.8%（45/48）,特异度88.9%（40/45）,准确度91.4%（85/93）,阳性预测值90%（45/50）,阴性预测值93%（40/43）,明显优于TRUS检查（灵敏度77.1%,特异度37.8%,准确度58.1%,阳性预测值67.3%,阴性预测值44.7%,2种方法比较差异有统计学意义（P〈0.05）。结论 TRTE具有无创、经济、简单的优点,可提高前列腺癌的检出率,对于前列腺癌的早期筛查具有较高临床价值。     

Role of growth factors and their receptors in gastric ulcer healing

The repair of gastric ulcers requires the reconstitution of epithelial structures and the underlying connective tissue, including vessels and muscle layers. Several growth factors have been implicated in this process, since they are able to regulate important cell functions, such as cell proliferation, migration, differentiation, secretion, and degradation of extracellular matrix, all of which are essential during tissue healing. Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), hepatocyte growth factor (HGF), and trefoil factors (TFFs) are mainly involved in the reconstitution of the epithelial structures. Platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-beta) play a major role in the reconstitution of connective tissue, including vessels and smooth muscle cells, and provide the extracellular matrix substrate for cell migration and differentiation. The expression of these growth factors and their receptors is increased during ulcer healing and, in some cases, intracellular signaling related to receptor binding and transduction has been demonstrated. EGF, TGF-alpha and TFFs are normally present either in the gastric juice or in the mucosa, and may exert their effects immediately after damage, before newly synthesized EGF and TFFs are released from the ulcer margin. The inhibition of their effects by neutralizing antibodies may result in delayed ulcer healing, while the administration of recombinant or natural analogues may improve ulcer repair. In this review, we will summarize the basic molecular characteristics of some of these growth factors, and will discuss available evidence supporting their role in the ulcer repair process.     

Role of growth factors and their receptors in proliferation of microvascular endothelial cells

Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis. The biological significance of VEGF, EGF, and bFGF is mediated by their receptors, which belong to the family of tyrosine kinase receptors: Flt-1 (VEGFR-1), KDR (VEGFR-2), EGFR, FGFR-1, FGFR-2, FGFR-3, and FGFR-4. Deeper understanding of the mechanism of activation of these growth factor receptors has allowed the development of a new pharmacological strategy aimed at controlling cancer cell proliferation. The results of a large body of preclinical as well as early clinical studies conducted suggest that targeting the growth factor receptors could represent a significant contribution to cancer therapy.     

Instructive induction of prostate growth and differentiation by a defined urogenital sinus mesenchyme

Instructive influences of fetal mesenchyme were examined in heterotypic tissue recombinants consisting of urogenital sinus mesenchyme (UGM) from male and female rats and distal ductal tips from adult rat prostate. Tissues were grown under the renal capsule of male hosts for periods up to 28 days. Resultant growths exhibited typical prostate histology. Expression of lobe-specific proteins for the ventral (prostatic steroid binding protein [PSBP]) lateral (seminal vesicle secretion II [SVS II]), and dorsal prostate (secretory transglutaminase [TGase]) were examined by immunocytochemistry. Male or female UGM combined with terminal segments of the ventral or dorsal prostate and immunolabeled with antibodies to lobe-specific proteins demonstrated expression of all three secretory products. The pattern of staining was consistent with a compound inductive response from the UGM. Unique to this study was our ability to use a defined mesenchymal tissue (female ventral mesenchymal pad [VMP]). This tissue is specifically associated with ductal branching morphogenesis and cytodifferentiation of the ventral prostate. Distal ductal tips from the dorsal lobe of the adult male prostate when recombined with female VMP and grown in vivo exhibited transformation of secretory phenotype, and the epithelium expressed mRNAs for PSBP. Immunocytochemistry of serial sections did not demonstrate labeling for TGase in the new epithelial growth. Ultrastructural analysis of the heterotypic recombinants indicated that the epithelium had similar characteristics to those of normal ventral prostate. Early stages of the mesenchymal-epithelial interactions resulted in dedifferentiation of the adult epithelium to solid cords of stratified cells. These findings illustrate the potent instructive capacity of a defined fetal UGM to influence development and cytodifferentiation of adult prostate epithelium. © 1995 Wiley-Liss, Inc.     

Evaluation of a nonlinear Hertzian‐based model reveals prostate cancer cells respond differently to force than normal prostate cells

Understanding how the mechanical properties of cells alter with disease may help with the development of novel diagnostics and treatment regimes. The emergence of tools such as the atomic force microscope (AFM) has enabled us to physically measure the mechanical properties of cells. However, suitable models for the analysis of real experimental data are either absent, or fail to provide a simple analysis tool in which experimental data can be analyzed quickly and reliably. The Hertz model has been widely used to study AFM data on living cells, however it makes assumptions that are untrue for cells, namely that cells behave as linear elastic bodies. This article presents and evaluates an alternative nonlinear Hertz model, which allows the Young's modulus to vary according to a second order polynomial function of indentation depth. Evaluation of the model revealed that prostate cancer cells (PC3) responded more uniformly to force compared to the normal PNT2 cells. Also, more energy (J) was needed to deform the normal prostate cells compared to the prostate cancer cells. Finally, the model described here suggests that overall the normal prostate cells behave in a more linear fashion to applied force compared to the prostate cancer cells. Microsc. Res. Tech., 2013. © 2012 Wiley Periodicals, Inc.     

Association of hypoxia-inducible factor-1α (HIF1α) 1772C/T gene polymorphism with susceptibility to renal cell carcinoma/prostate cancer

In this study, we used a meta-analysis method to evaluate the relationship between hypoxia-inducible factor-1α (HIF1α) 1772C/T gene polymorphism (rs 11549465) and renal cell carcinoma (RCC)/prostate cancer risk. We searched for relevant studies (before March 1, 2019) on Cochrane Library, Embase, and PubMed. Studies meeting the inclusion criteria were recruited into this meta-analysis. The outcome of dichotomous data was showed in the way of odds ratios (OR), and 95% confidence intervals (CI) were also counted. In this investigation, there was no association between HIF1α 1772C/T gene polymorphism and susceptibility to RCC in Caucasians, Asians as well as overall populations. In addition, HIF1α 1772C/T gene polymorphism was not found to be relevant to the survival in RCC. Interestingly, the T allele was relevant to prostate cancer risk in all populations, but not in Caucasians and Asians. However, the TT genotype and the CC genotype were not related to prostate cancer susceptibility in Asian, Caucasian, and all populations. In conclusion, the T allele of the HIF1α 1772C/T gene polymorphism was related to prostate cancer risk in the overall populations.     

Role of monocyte chemoattractant protein-1 in Propionibacterium acnes-induced pulmonary granulomatosis

The inflammatory process in granulomatous disorders such as sarcoidosis is mainly the consequence of delayed hypersensitivity induced by causative antigens. Propionibacterial DNA was isolated recently by PCR from human sarcoidosis tissue. Hence, we developed a model using sensitized rabbits for T cell-mediated pulmonary granulomatosis induced by Propionibacterium acnes (P. acnes) and investigated the role of monocyte chemoattractant protein-1 (MCP-1) in the pathogenesis of the granuloma formation in vivo. Intravenous injection of P. acnes into sensitized rabbits induced massive pulmonary granulomas on day 3. Maximum levels of MCP-1 in sera and bronchoalveolar lavage fluid (BALF) were detected on day 1 and preceded recruitment of monocyte/macrophages and T cells. In BALF, monocyte chemotaxis peaked 1 day after P. acnes challenge, and T cell chemotaxis peaked 3 days after P. acnes challenge. Anti-MCP-1 IgG inhibited monocyte chemotaxis by 80.2% and T cell chemotaxis by 35.7%. Phenotypic analysis of migrating T cells revealed that activated and memory T cells (CD26(+)/CD45RO(+)) but not naive cells were preferentially attracted to BALF. Administration of MCP-1 antiserum in vivo inhibited the development of granulomas in both size 59.9% reduction and number 28.6% reduction, the number of infiltrating leukocytes in BALF, and the expression of adhesion molecules on leukocytes in peripheral blood and BALF. Our data indicate that MCP-1 plays important roles in granuloma formation by attracting and activating specific types of cells in this model. Furthermore, results suggest that the rabbit model resembles human angiocentric granulomatosis and would be useful for investigating the immunopathogenesis of human pulmonary granulomatosis.