Mitochondrial Morphological Features Are Associated with Fission and Fusion Events

Mitochondria are dynamic organelles that undergo constant remodeling through the regulation of two opposing processes, mitochondrial fission and fusion. Although several key regulators and physiological stimuli have been identified to control mitochondrial fission and fusion, the role of mitochondrial morphology in the two processes remains to be determined. To address this knowledge gap, we investigated whether morphological features extracted from time-lapse live-cell images of mitochondria could be used to predict mitochondrial fate. That is, we asked if we could predict whether a mitochondrion is likely to participate in a fission or fusion event based on its current shape and local environment. Using live-cell microscopy, image analysis software, and supervised machine learning, we characterized mitochondrial dynamics with single-organelle resolution to identify features of mitochondria that are predictive of fission and fusion events. A random forest (RF) model was trained to correctly classify mitochondria poised for either fission or fusion based on a series of morphological and positional features for each organelle. Of the features we evaluated, mitochondrial perimeter positively correlated with mitochondria about to undergo a fission event. Similarly mitochondrial solidity (compact shape) positively correlated with mitochondria about to undergo a fusion event. Our results indicate that fission and fusion are positively correlated with mitochondrial morphological features; and therefore, mitochondrial fission and fusion may be influenced by the mechanical properties of mitochondrial membranes.     

Mitochondrial Haplogroups and Control Region Polymorphisms Are Not Associated with Prostate Cancer in Middle European Caucasians

Background

Besides being responsible for energy production in the cell, mitochondria are central players in apoptosis as well as the main source of harmful reactive oxygen species. Therefore, it can be hypothesised that sequence variation in the mitochondrial genome is a contributing factor to the etiology of diseases related to these different cellular events, including cancer. The aim of the present study was to assess the frequency of haplogroups and polymorphisms in the control region (CR) of mitochondrial DNA of peripheral blood mononuclear cells from patients with prostate carcinoma (n = 304) versus patients screened for prostate disease but found to be negative for cancer on biopsy (n = 278) in a Middle European population.

Methodology/Principal Findings

The nine major European haplogroups and the CR polymorphisms were identified by means of primer extension analysis and DNA sequencing, respectively. We found that mitochondrial haplogroup frequencies and CR polymorphisms do not differ significantly between patients with or without prostate cancer, implying no impact of inherited mitochondrial DNA variation on predisposition to prostate carcinoma in a Middle European population.

Conclusions/Significance

Our results contrast with a recent report claiming an association between mtDNA haplogroup U and prostate cancer in a North American population of caucasian descent.     

Upregulation of SATB1 Is Associated with Prostate Cancer Aggressiveness and Disease Progression

Disease aggressiveness remains a critical factor to the progression of prostate cancer. Transformation of epithelial cells to mesenchymal lineage, associated with the loss of E-cadherin, offers significant invasive potential and migration capability. Recently, Special AT-rich binding protein (SATB1) has been linked to tumor progression. SATB1 is a cell-type restricted nuclear protein, which functions as a tissue-specific organizer of DNA sequences during cellular differentiation. Our results demonstrate that SATB1 plays significant role in prostate tumor invasion and migration and its nuclear localization correlates with disease aggressiveness. Clinical specimen analysis showed that SATB1 was predominantly expressed in the nucleus of high-grade tumors compared to low-grade tumor and benign tissue. A progressive increase in the nuclear levels of SATB1 was observed in cancer tissues compared to benign specimens. Similarly, SATB1 protein levels were higher in a number of prostate cancer cells viz. HPV-CA-10, DU145, DUPro, PC-3, PC-3M, LNCaP and C4-2B, compared to non-tumorigenic PZ-HPV-7 cells. Nuclear expression of SATB1 was higher in biologically aggressive subclones of prostate cancer cells with their respective parental cell lines. Furthermore, ectopic SATB1 transfection conferred increased cell motility and invasiveness in immortalized human prostate epithelial PZ-HPV-7 cells which correlated with the loss of E-cadherin expression. Consequently, knockdown of SATB1 in highly aggressive human prostate cancer PC-3M cells inhibited invasiveness and tumor growth in vivo along with increase in E-cadherin protein expression. Our findings demonstrate that SATB1 has ability to promote prostate cancer aggressiveness through epithelial-mesenchymal transition.     

Peripheral Blood Mitochondrial DNA Copy Number Is Associated with Prostate Cancer Risk and Tumor Burden

Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes (PBLs) and the risk of prostate cancer (PCa) has not been investigated. In a case-control study of 196 PCa patients and 196 age-paired healthy controls in a Chinese Han population, the association between mtDNA copy number in PBLs and PCa risk was evaluated. The relative mtDNA copy number was measured using quantitative real-time PCR; samples from three cases and two controls could not be assayed, leaving 193 cases and 194 controls for analysis. PCa patients had significantly higher mtDNA copy numbers than controls (medians 0.91 and 0.82, respectively; P<0.001). Dichotomized at the median value of mtDNA copy number in the controls, high mtDNA copy number was significantly associated with an increased risk of PCa (adjusted odds ratio  = 1.85, 95% confidence interval: 1.21–2.83). A significant dose-response relationship was observed between mtDNA copy number and risk of PCa in quartile analysis (P_trend = 0.011). Clinicopathological analysis showed that high mtDNA copy numbers in PCa patients were significantly associated with high Gleason score and advanced tumor stage, but not serum prostate-specific antigen level (P = 0.002, 0.012 and 0.544, respectively). These findings of the present study indicate that increased mtDNA copy number in PBLs is significantly associated with an increased risk of PCa and may be a reflection of tumor burden.     

Symptomatic and Incidental Venous Thromboembolic Disease Are Both Associated with Mortality in Patients with Prostate Cancer

Introduction

The association between malignancy and venous thromboembolic disease (VTE) is well established. The independent impact of VTE, both symptomatic and incidental, on survival in patients with prostate cancer is not known. We conducted a retrospective cohort study to evaluate the effect of VTE of survival in prostate cancer.

Methods

Data regarding clinical characteristics, treatment and outcomes of 453 consecutive prostate cancer patients were collected. Fisher exact (categorical variables) and t-test (continuous variables) were utilized to test associations with VTE and mortality. Survival was estimated using the Kaplan Meier method. A Cox regression model was used to model the mortality hazard ratio (HR).

Results

At diagnosis, 358 (83%) patients had early stage disease, 43 (10%) had locally advanced disease and 32 (7%) had metastatic disease. During the follow up period, 122 (27%) patients died and 41 (9%) developed VTE (33 deep vein thrombosis, 5 pulmonary embolism, and 3 patients with both DVT and PE). Twenty-five VTE events were symptomatic and 16 were incidentally diagnosed on CT scans obtained for other reasons. VTE was associated with increased mortality [HR 6.89 (4.29–11.08), p<0.001] in a multivariable analysis adjusted for cancer stage, performance status, treatments and co-morbidities. There was no difference in survival between patients who had symptomatic and incidental VTE.

Conclusion

Venous thromboembolic disease, both symptomatic and incidental, is a predictor of poor survival in patients with prostate cancer, especially those with advanced disease. Further studies are needed to evaluate the benefit of prophylactic and therapeutic anticoagulation in this population.     

雄激素受体共调节因子及其在前列腺癌进展中的作用

雄激素受体（AR）信号通路在前列腺癌的发生、进展和转移中发挥着重要作用,但AR介导组织对雄激素的特异应答是通过与其相互作用的AR共调节因子共同完成的,许多AR共调节因子的功能已被广泛研究。简要综述了目前发现的部分AR共调节因子在调节AR转录活性及前列腺癌发生、进展中的生物学作用。     

TIMP-1 Promotes Accumulation of Cancer Associated Fibroblasts and Cancer Progression

Treatment options for late stage prostate and colon cancer are limited and there is an urgent need to develop more effective and targeted novel therapies, which starts with identification and validation of novel therapeutic targets. Recent clinical studies have demonstrated that tissue inhibitor matrix metalloproteinase-1 (TIMP-1) levels are elevated in cancer patient plasma and elevated TIMP-1 levels are associated with worse clinical outcomes. However, it is unknown whether TIMP-1 serves merely as a biomarker of cancer progression or has a functional role in promoting cancer progression and can serve as a cancer therapeutic target, which is the main objective of this study. Here, we show that stroma of human prostate and colon cancer express higher levels of TIMP-1 compared to their normal counterparts and increased expression of TIMP-1 promotes in vivo growth of both cancer types. We demonstrate for the first time that increased TIMP-1 expression stimulates accumulation of cancer associated fibroblasts (CAFs) within prostate and colon cancer tissues and that TIMP-1 enhances prostate CAF proliferation and migration in vitro and promotes ERK1/2 kinase activation in these CAF cells. Our results establish the novel promotive effects of TIMP-1 on cancer progression and on accumulation of CAFs that in turn provides a pro-tumor microenvironment. Together, these results establish the potential of TIMP-1 as a novel target for cancer therapy and the mechanism underlying the pro-tumor activity of TIMP-1.     

Emerging Therapeutic for the Treatment of Skeletal-related Events Associated With Metastatic Castrate-resistant Prostate Cancer

Prostate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who succumb to the disease will ultimately develop bone metastasis. Morbidity from bone metastasis-referred to as skeletal-related events, which include fractures, cord compression, radiation to bone, and surgery to bone—leads to significant costs and impaired quality of life. This article reviews three agents and the roles they play in the ever-changing armamentarium of treatments for metastatic castrate-resistant prostate cancer (mCRPC). The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis.Key words: Metastatic castrate-resistant prostate cancer, Skeletal-related events, Bone metastasis, Zoledronic acid, Denosumab, Radium Ra 223 dichlorideProstate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who have the disease will ultimately develop bone metastasis.¹ Morbidity from bone metastasis—referred to as skeletal—related events (SREs), which include fractures, cord compression, radiation to bone, and surgery to bone-leads to significant costs and impaired quality of life. An estimated 241,740 men are diagnosed with prostate cancer each year in the United States¹; between 9.5% and 17.8% of these patients have M0 + M1 castrate-resistant prostate cancer (CRPC).^2,3Skeletal tumor burden and fracture are both independent predictors of death in men with metastatic CRPC (mCRPC).^2,3 In addition, pain is an independent prognosticator for death⁴; thus, agents that reduce pain may improve quality as well as quantity of life. In the past decade, three new agents have been approved in the United States for the treatment and/or prevention of SREs in men with mCRPC. However, urologists continue to under-treat this condition.⁵ A recent clinical trial that screened a large population of men thought to have CRPC without metastasis found nearly one third of patients to have metastatic prostate cancer.⁶ And a recent large clinical trial in men with mCRPC, most of whom had bone metastases, showed fewer than 50% of patients were receiving a bisphosphonate.⁷This article reviews these three agents and the new roles they play in the ever-changing armamentarium of treatments for mCRPC. The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis.     

Increased Expression Levels of WAVE3 Are Associated with the Progression and Metastasis of Triple Negative Breast Cancer

Background

Breast Cancer (BC) is a heterogeneous disease comprised of at least five genetically distinct subtypes, which together form the second leading cause of cancer death in women in the United States. Within BC subtypes, those classified as Triple Negative BCs (TNBCs) exhibit dismal survival rates due to their propensity to develop distant metastases. We have identified the WAVE3 protein, which is a critical regulator of actin cytoskeleton dynamics that are required for the motility and invasion of cancer cells through its activation of the Arp2/3 complex, as a key regulator of the different steps of the invasion-metastasis cascade in BC, especially in the more aggressive TNBCs. Our published studies have also shown that elevated expression levels of WAVE3 in the TNBC cell lines directly contribute to their increased invasion and metastasis potentials both in vitro and in vivo in murine models of BC metastasis.

Methodology/Principal Findings

Herein, we utilized both immunohistochemistry (IHC) of primary human BC tumors as well as quantitative real-time RT-PCR of WAVE3 in the peripheral blood of BC patients to clearly establish that WAVE3 is a predictive marker of overall BC patients’ survival. High levels of WAVE3 were predictive for reduced distant recurrence-free survival as well as for decreased disease-specific mortality. Our analysis of WAVE3 expression levels in the peripheral blood of BC patients showed that WAVE3 is highly expressed in the blood of patients who developed metastatic breast cancer compared to those who did not. WAVE3 expression was also highly upregulated in the blood of BC patients with the more aggressive TNBC subtype.

Conclusions

Together, these findings establish WAVE3 as a novel marker for increased risk of breast-cancer-specific mortality and for the metastatic potential of the TNBCs, and also identify WAVE3 as an attractive therapeutic target for the treatment of metastatic BC.     

雄激素受体信号转导途径及其在前列腺癌发展中的作用

前列腺癌是西方男性发病率最高的癌症之一,在采用雄激素阻断疗法后,大部分患者的病情可得到控制,但经过一段时间又会转变为雄激素非依赖型前列腺癌。雄激素受体(AR)在前列腺细胞中扮演重要的角色,它可调节大量基因的表达。在前列腺癌由雄激素依赖型向雄激素非依赖型的转变过程中,AR及其信号途径通过多种方式发挥作用,AR基因的扩增、AR的突变,以及与共激活子之间作用的改变都可能使细胞获得雄激素非依赖型的生长能力。此外,AR还受到多肽生长因子和细胞因子等的调节,表现激素非依赖型的转录激活活性。AR在前列腺癌中作用的阐明对前列腺癌的诊断与治疗有着重大的意义。     

Overexpression of ERG and Wild-Type PTEN Are Associated with Favorable Clinical Prognosis and Low Biochemical Recurrence in Prostate Cancer

Objectives

The aim of this study was to investigate the expression of two commonly altered genes ERG and PTEN in prostate cancer (PC) and evaluate their prognostic significance. Despite conflicting published results, TMPRSS2-ERG gene fusion and PTEN loss are generally considered unfavorable markers for PC progression.

Materials and Methods

Of the 762 prostatic adenocarcinoma specimens obtained from radical prostatectomy, 613 without neoadjuvant hormone therapy were included in tissue microarrays for quantitatively assessment of ERG and PTEN expression via immunohistochemistry. Statistical analysis of the association between such expression and clinicopathological parameters, including clinical prognosis, was performed with a p-value of <0.05 considered significant.

Results

During a median follow-up period of 44.0 months, 132 (21.5%) patients developed biochemical recurrence (BCR). ERG overexpression and PTEN loss were observed in 145 (23.7%) and 253 (41.3%) cases, respectively. BCR-free survival was significantly better in patients with ERG overexpression (p=0.005), but unfavorable among those with PTEN loss (p=0.142). Sub-group analysis revealed that patients with PTEN loss and negative ERG expression had the worst BCR-free survival outcome (p=0.021). Furthermore, multivariate analysis identified prostate-specific antigen level (≥10 ng/mL), Gleason score (>6), pathologic T stage (≥T3), positive surgical margin, and extraprostatic capsule extension as significant risk factors for BCR (p<0.05).

Conclusions

Our results indicated that ERG overexpression was associated with favorable BCR-free survival after radical prostatectomy for PC, whereas PTEN loss was with unfavorable outcomes.     

Primary Cilia Are Lost in Preinvasive and Invasive Prostate Cancer

Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN), and invasive prostate cancer (including perineural invasion)) were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human prostate cancer, and increase Wnt signaling occurs in a subset of cancers.     

综述: 与神经退行性疾病相关的RNA结合蛋白在线粒体损伤中的作用

线粒体是细胞内制造能量的细胞器,它还负责各种细胞信号的整合,参与协调多种复杂的细胞功能.线粒体是动态变化的,连续不断地进行分裂与融合,这是其功能维持和增殖遗传的关键.在过去20年中,参与线粒体分裂与融合的核心因子陆续被发现,它们在进化上高度保守,但是在形成分裂与融合复合物中的详细分子机制还有待于深入研究.线粒体分裂与融合的动态变化,是线粒体质量控制的重要组成部分,其动态平衡在细胞发育和稳态维持中起重要作用.线粒体动态变化失衡和功能失调,则会导致多种神经退行性疾病的发生.这些研究的发现为探索线粒体生物学及与疾病的关系开拓了令人振奋的新方向.