Breast cancer: implications of tumor cell kinetics on clinical outcome

The relevance of tumor proliferative activity as an indicator of biologic aggressiveness was analyzed on a series of 506 patients with primary breast cancer. In 258 patients with operable tumors without nodal and distant metastases, none of whom was subjected to postoperative irradiation or systemic adjuvant therapy, proliferative activity was significantly correlated with prognosis; 6-year relapse-free survival (RFS) and overall survival (OS) were higher for patients with slowly proliferating tumors for patient with fast-proliferating tumors (RFS: 80.5% vs 59.6%, p = 0.00004; OS: 90.8% vs 74.4%, p = 0.002). On a series of 196 patients with node-positive operable tumors, subjected to 6 or 12 cycles of cyclophosphamide, methotrexate and 5-fluorouracil, a trend in favor of longer 6-year RFS was observed for patients with slowly proliferating tumors than for patients with fast-proliferating tumors (62.5% vs 48.3%, p = 0.08), whereas proliferative activity did not influence OS. In 52 patients with locally advanced disease treated with a multimodality approach, including chemotherapy (adriamycin and vincristine), surgery or radiotherapy, tumor proliferative activity was a strong indicator of biologic aggressivity, since women with slowly proliferating cancers had a higher 4-year probability of OS than women with fast-proliferating tumors (68.1% vs 36.7%, p = 0.02).     

Green tea polyphenols for prostate cancer chemoprevention: A translational perspective

Every year nearly 200,000 men in the United States are diagnosed with prostate cancer (PCa), and another 29,000 men succumb to the disease. Within certain regions of the world population based studies have identified a possible role for green tea in the prevention of certain cancers, especially PCa. One constituent in particular, epigallocatechin-3-gallate also known as EGCG has been shown in cell culture models to decrease cell viability and promote apoptosis in multiple cancer cell lines including PCa with no effect on non-cancerous cell lines. In addition, animal models have consistently shown that standardized green tea polyphenols when administered in drinking water delay the development and progression of PCa. Altogether, three clinical trials have been performed in PCa patients and suggest that green tea may have a distinct role as a chemopreventive agent. This review will present the available data for standardized green tea polyphenols in regard to PCa chemoprevention that will include epidemiological, mechanism based studies, safety, pharmacokinetics, and applicable clinical trials. The data that has been collected so far suggests that green tea may be a promising agent for PCa chemoprevention and further clinical trials of participants at risk of PCa or early stage PCa are warranted.     

Growth factors in human prostate cancer cells: implications for an improved treatment of prostate cancer

It has been previously shown that estrogens may exert their action on human breast cancer cells through coordinated control of secreted growth factors which act in an autocrine and paracrine fashion. Growth stimulation of the androgen receptor negative prostate carcinoma cell line DU-145 by dihydrotestosterone in the presence of the androgen-responsive human prostate carcinoma cell line LNCaP now indicates that androgens may regulate growth of prostate carcinoma cells through related mechanisms. A variety of androgen-regulated growth modulatory activities with autocrine and paracrine potential can be detected in conditioned media from LNCaP cells partially purified by ion exchange chromatography. Androgen-induced growth of LNCaP cells is partially inhibited by the polyanions suramin and dextran sulfates which antagonize growth factor action. These data suggest the existence of at least two different mechanisms of growth regulation by androgen which can be distinguished by their different sensitivity to growth factor inhibitory agents. We conclude that the combination of antipeptidergic substances and androgen withdrawal would represent a new and promising strategy for treatment of human prostate cancer.     

Towards discovery-driven translational research in breast cancer

Discovery-driven translational research in breast cancer is moving steadily from the study of cell lines to the analysis of clinically relevant samples that, together with the ever increasing number of novel and powerful technologies available within genomics, proteomics and functional genomics, promise to have a major impact on the way breast cancer will be diagnosed, treated and monitored in the future. Here we present a brief report on long-term ongoing strategies at the Danish Centre for Translational Breast Cancer Research to search for markers for early detection and targets for therapeutic intervention, to identify signalling pathways affected in individual tumours, as well as to integrate multiplatform 'omic' data sets collected from tissue samples obtained from individual patients. The ultimate goal of this initiative is to coalesce knowledge-based complementary procedures into a systems biology approach to fight breast cancer.     

Ambra1 in cancer: implications for clinical oncology

Apoptosis - Activating molecule in Beclin-1-regulated autophagy protein 1 (Ambra1) is well known to mediate the autophagy process and promote the formation of autophagosomes. In addition, Ambra1 is...     

Cardiomyocyte death: mechanisms and translational implications

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Although treatments have improved, development of novel therapies for patients with CVD remains a major research goal. Apoptosis, necrosis, and autophagy occur in cardiac myocytes, and both gradual and acute cell death are hallmarks of cardiac pathology, including heart failure, myocardial infarction, and ischemia/reperfusion. Pharmacological and genetic inhibition of autophagy, apoptosis, or necrosis diminishes infarct size and improves cardiac function in these disorders. Here, we review recent progress in the fields of autophagy, apoptosis, and necrosis. In addition, we highlight the involvement of these mechanisms in cardiac pathology and discuss potential translational implications.     

Deep and quantitative top-down proteomics in clinical and translational research

It has long been understood that it is proteins, expressed and post-translationally modified, that are the primary regulators of both the fate and the function of cells. The ability to measure differences in the expression of the constellation of unique protein forms (proteoforms) with complete molecular specificity has the potential to sharply improve the return on investment for mass spectrometry-based proteomics in translational research and clinical diagnostics.     

Proteomics in prostate cancer research

The incidence of early prostate cancer (PCa) among middle-aged men has increased rapidly. For many of these men, curatively intended treatment does more harm than good. Established prognostic factors are tumor stage and grade. As a result of earlier detection a majority of patients now have nonpalpable tumors (T1c) of intermediate grade (Gleason score 6). Prostate specific antigen in serum in such cases is generally at a low level and not a reliable predictor of prognosis. Altogether there is an urgent need for adjunctive prognostic indicators. In the search for relevant tumor markers for improved patient selection an exploration of the proteome (the human proteins) could be fruitful. This paper critically reviews the use of 2-dimensional gel electrophoresis (2-DE) for proteome research. Additional steps such as image analysis and mass spectrometry are described. Techniques based on non-2-DE platforms: surface-enhanced laser desorption/ionization (SELDI), isotope coded affinity tags (ICAT) and array-based technologies are also summarized. Although labor-intensive and time-consuming, 2-DE is presently the most powerful method for analysis of cellular protein phenotype and may potentially reveal gene regulations that cannot be detected on a genetic level.     

Ethical hurdles for translational research

The notion of translational research has gained considerable currency over the past few years. While such an approach promises great scientific and clinical advances, the penumbra of translational research tends to incorporate prioritizing scientific projects based upon their potential for translation; tight financial connections between sponsors, scientists and clinical investigators; and sometimes research involving biological approaches for which there is little experience determining safety. It is these aspects of translational research that raise some serious ethical challenges. In this report, we examine three specific areas that raise ethical questions: (1) the potential implications of prioritizing research objectives based on the potential for translation; (2) cautions related to moving from bench to bedside (and back again); and (3) unique questions for translational research initiatives in academic medical centers. Based on this examination, it is clear that the financial and ethical costs as well as benefits of taking a translational approach need to be considered. In the meantime, exquisite attention needs to be paid whenever translational research is likely to affect the traditional fiduciary responsibilities of scientists, clinicians and institutions to research subjects, patients and students. Successful mechanisms that might be developed to address any untoward effects should be shared and evaluated.     

The application of basic science to translational cancer research

A report on the inaugural symposium of the Hutchison/MRC Research Centre, Cambridge, UK, 24-25 October 2002.