Modeling prostate cancer in mice: limitations and opportunities

The complex dynamics of the tumor microenvironment and prostate cancer heterogeneity have confounded efforts to establish suitable preclinical mouse models to represent human cancer progression from early proliferative phenotypes to aggressive, androgen-independent, and invasive metastatic tumors. Current models have been successful in capitulating individual characteristics of the aggressive tumors. However, none of these models comprehensively mimics human cancer progression, establishing the challenge in their exploitation to study human disease. The ability to tailor phenotypic outcomes in mice by compounding mutations to target specific molecular pathways provides a powerful tool toward disruption of signaling pathways contributing to the initiation and progression of castration-resistant prostate cancer. Each model is characterized by unique features contributing to the understanding of prostate tumorigenesis, as well as limitations challenging our knowledge of the mechanisms of cancer development and progression. Emerging strategies utilize genomic manipulation technology to circumvent these limitations toward the formulation of attractive, physiologically relevant models of prostate cancer progression to advanced disease. This review discusses the current value of the widely used and well-characterized mouse models of prostate cancer progression to metastasis, as well as the opportunities begging exploitation for the development of new models for testing the antitumor efficacy of therapeutic strategies and identifying new biomarkers of disease progression.     

Bone and prostate cancer cell interactions in metastatic prostate cancer

The interplay in prostate cancer bone metastases between the 'seed' (the prostate cancer cells) and the 'soil' (the bone microenvironment) has been increasingly recognized as integral to the remarkable tropism for bone shown by prostate cancer. Increasing research into this area is elucidating the mechanisms involved in this complex 'cross-talk'. Recent developments, including the use of bisphosphonates in metastatic disease, highlight the important role of bone cells in the development and progression of metastatic prostate cancer. We review the current reports emphasising these possible mechanisms and indicating possible factors for future treatment directions.     

Advanced prostate cancer

Both the definition and therapy of advanced prostate cancer is challenging. The advanced prostate cancer session at "The 8th International Prostate Cancer Update" had discussions which tried to answer the questions of management of these patients who either present with advanced disease or fail any form of therapy for clinically confined prostate cancer. This article provides an overview of therapeutic options: monotherapy and minimal androgen blockade options versus maximal androgen blockade, adjuvant therapy, intermittent therapy and timing of therapy as well as chemotherapy when all these measures fail. The impact of these therapies on progression as well as quality of life is reviewed.     

A preliminary analysis and model of prostate injection distributions

PURPOSE: Understanding the internal dynamics of prostate injections, particularly injection pattern distribution is a key step to developing new therapies for prostate disease that may be best served with a direct injection approach. Due to excellent properties involving liquid contrast agents, MRI can be used for targeting and monitoring of injections into organs and tissues. MATERIALS AND METHODS: Eleven intraprostatic injections were performed in vivo with canines using a custom transrectal guiding and imaging system for use in a standard 1.5 T MR scanner. In addition, 25 injections were performed on excised cadaveric human prostates, using a MedRad Spectris injector system. MRI was used to guide the injections and monitor intraparenchymal injection distribution. RESULTS: T1 and T2-weighted MR images were correlated with histology to produce three-dimensional data sets that can be used to analyze trends in injection patterns. This analysis was used to develop strategies for injection prediction such as gadolinium pre-injections and diffusion-weighted imaging guidance. In addition, a rough model of prostate injections is described, and a preliminary injection guide is developed that takes into account the individual clinician's goals for therapy. CONCLUSIONS: MR visualization of injected therapeutic agents allows for prediction and monitoring of drug distributions, possibly improving efficacy and reducing side effects. Injection analysis and modeling may be used to assist in optimizing clinical treatments that require or would benefit from focal parenchymal injections into the prostate.     

Local-regional prostate cancer

Historically, locally advanced prostate cancer was defined clinically with the digital rectal exam (DRE). With the introduction of screening prostate specific antigen (PSA), further pretreatment stratification of locally advanced prostate cancer was possible. Tables and nomograms have been developed to predict pathologic staging prior to therapy. By combining DRE, PSA, Gleason score, and clinical staging, a patient's probability of treatment failure is estimated, thereby stratifying the risk of locally advanced disease. Pretreatment PSA velocity (PSAV) and PSA doubling time (PSADT) will likely continue to play a role in defining locally advanced prostate cancer. Imaging studies, especially high-field strength pelvic MRI, may provide additional information regarding the presence of locally advanced prostate cancer. In the future, molecular or genetic testing may permit further stratification of patients with locally advanced disease, who are at variable risk for recurrence and death after treatment. Future trials will need to assess the utility of multimodality treatments for patients in the diverse classification of locally advanced prostate cancer.     

Metastatic prostate cancer

Summary For decades the palliation of prostate cancer has centered around hormonal manipulation using orchiectomy or estrogen administration. Newer modalities, such as LHRH agonists and nonsteroidal antiandrogens, are now available. Patients receiving combination therapy enjoy superior progression-free and median survival rates.     

Hormone-refractory prostate cancer

Hormone-refractory prostate cancer is an advanced stage of the metastatic disease; it has a poor prognosis and a short median survival, about 9 to 18 months. The current article is based on a literature review regarding the prognostic factors and medical treatments, with a focus on recent advances in chemotherapy. With the use of docetaxel that increases the median survival of this disease and improves the symptoms, new clinical protocols have been developed, with promising results; these protocols propose a combination with calcitriol or antiangiogenic agents. Supportive care is also an important part of the treatment due to the high level of bone involvement and its consequences. Such recent advances constitute a real progress in the management of prostate cancer, namely the pharmacological combinations with a promising efficacy and little toxicity.     

Defining prostate cancer risk before prostate biopsy

Prostate cancer is the most commonly diagnosed cancer in men. At present, patients are selected for prostate biopsy on the basis of age, serum prostate specific antigen (PSA), and prostatic digital rectal examination (DRE) findings. However, due to limitations in the use of PSA and DRE, many patients undergo unnecessary prostate biopsy. A further problem arises as many patients are diagnosed and treated for indolent disease. This review of the literature highlights the strengths and weaknesses of existing methods of prebiopsy risk stratification and evaluates promising serum, urine, and radiologic prostate cancer biomarkers, which may improve risk stratification for prostate biopsy in the future.     

miRNA在前列腺癌中的研究进展

前列腺癌(PCa)是男性泌尿系最常见的恶性肿瘤之一,微小RNA(miRNA)是一类内源性的非编码小RNA,研究发现miRNA与PCa的发生和发展密切相关,多种miRNA在PCa中表达异常。本文通过描述miRNA在PCa中表达差异及其与预后的相关性,进一步分析miRNA与放化疗、雄激素受体,以及PCa转移的相关性,来阐明miRNA在PCa发生发展中的的作用。     

自噬与前列腺癌

自噬作用被认为具有高度复杂性及环境依赖性,在有些肿瘤中表现为肿瘤抑制和促进相对立两方面影响,比如乳腺癌和前列腺癌。本文综述了自噬对前列腺癌的发生、发展及治疗的最新研究进展。重点突出自噬调节在雄激素剥夺期间的影响,讨论了雄激素对前列腺癌细胞自噬作用所产生的调节效应。通过对一些研究的报道结果进行评价、分析,我们认为:自噬抑制并结合抗雄激素治疗对于前列腺癌是非常有前景的新型治疗方法。     

PET and prostate cancer

The diagnosis of prostate cancer leaves some questions without answers. The different diagnostic techniques are limited in three situations: (1) staging of the tumour: identification of node involvement, (2) quantification of the tumour volume and its location inside the gland, (3) premature identification of relapse after radical treatment. These are the three problems that we need to consider in the diagnosis of prostate carcinoma. Imaging techniques can tell us the morphological alterations in the structures and organs. Positron emission tomography (PET) introduces a new way of identifying damage by counting metabolic activity. The tracers are substances that are marked with a radioactive molecule that is picked up more readily by the tumours. The presence of these substances in a set anatomic zone means higher consumption and therefore more metabolic activity. The radiotracer most frequently used in PET is glucose marked with fluoride 18. The first studies with marked glucose and prostate tumours started at the end of the 1990s. There are many contradictions in the results of these studies due to renal elimination, which produces an accumulation in the urinary tract and does not correctly show the prostate zone and iliobturator nodes area, and its capitation by zones with inflammatory process or prostatic hyperplasia. Choline is a substance that is present in cellular membranes. When it is marked with carbon 11, it changes to a new tracer. This radiotracer has affinity with prostate damage and allows the better differentiation of malignant from benign processes. It also has the advantage of the absence of renal elimination. Trials that used choline marked with carbon 11 (11C choline) are beginning to obtain very promising results. This union of a method that identifies metabolic activity with an imaging technique increases the sensitivity in the diagnostic test and can help find the exact location of the 11C choline deposits. The PET-CT combines the PET with computerised tomography. The 11C choline PET-CT is presented as a promising technique for answering the three problems mentioned above.     

Leptin and prostate cancer

BACKGROUND: Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition). METHODS: In a study identifying determinants of clinically relevant prostate cancer, we compared plasma concentrations of leptin, an adiposity-related hormone, in 48 men with tumors 0.5 cc in volume or with histologic evidence of extraprostatic extension but without metastases ("high-volume disease"), matched by age (+/- 5 years) and year at diagnosis (+/- 1 year). RESULTS: Men with high-volume disease exhibited higher leptin concentrations overall and after stratification by age, testosterone level, height, and body mass index (BMI). Analysis revealed that men with elevated leptin concentrations had an increased risk of diagnosis with high-volume disease (odds ratio (OR) = 2.35, 95% confidence interval (CI) = 1.01-5.44), as did men with high leptin and high testosterone (OR = 9.73, 95% CI = 2.05-46.24) and men >/=5'8" with high leptin (OR = 3.67, 95% CI = 1.40-9.63). CONCLUSIONS: Leptin may affect the risk of clinically relevant prostate cancer through testosterone and factors related to stature and obesity.