Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.
Lindsay G Carter, John A D'Orazio and Kevin J Pearson
W Solarek, A M Czarnecka, B Escudier, Z F Bielecka, F Lian and C Szczylik
Insulin and IGFs play a significant role in cancer development and progression, including renal cell carcinoma (RCC). RCC is the most frequent type of kidney cancer in adults and the tenth most common malignancy worldwide. Insulin is normally associated with metabolism control, whereas IGFs are defined as proliferation regulators. Today, there is convincing evidence of an association between obesity and the risk of RCC. Indicated risk factors together with type 2 diabetes are irreversibly connected with circulating insulin and IGF levels. The interplay between these molecules, their receptors, and IGF-binding proteins might be crucial for RCC cell biology and RCC progression. Given the potent activity IGF/IGF receptor 1 (IGF1R) inhibitors demonstrate against RCC in basic research, some type of combination therapy may prove to be beneficial clinically in the management of RCC. This review addresses not only molecular but also clinical associations between insulin and IGF1 signaling pathways and both RCC biology and clinical course. Revealing these interactions may improve our understanding of basic molecular oncology processes in RCC and improve treatment strategies.
José O Alemán, Azeez Farooki and Monica Girotra
Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.
Frederieke M Brouwers, Sven Gläsker, Amanda F Nave, Alexander O Vortmeyer, Irina Lubensky, Steven Huang, Mones S Abu-Asab, Graeme Eisenhofer, Robert J Weil, Deric M Park, W Marston Linehan, Karel Pacak and Zhengping Zhuang
Pheochromocytomas are catecholamine-producing tumors that can occur in the context of von Hippel–Lindau syndrome (VHL) and multiple endocrine neoplasia type 2 (MEN2). Pheochromocytomas in these two syndromes differ in histopathological features, catecholamine metabolism, and clinical phenotype. To further investigate the nature of these differences, we compared the global protein expressions of 8 MEN2A-associated pheochromocytomas with 11 VHL-associated pheochromocytomas by two-dimensional gel electrophoresis proteomic profiling followed by sequencing and identification of differentially expressed proteins. Although both types of pheochromocytoma shared similarities in their protein expression patterns, the expression of several proteins was distinctly different between VHL- and MEN2A-associated pheochromocytomas. We identified several of these differentially expressed proteins. One of the proteins with higher expression in MEN2-associated tumors was chromogranin B, of which the differential expression was confirmed by western blot analysis. Our results expand the evidence for proteomic differences between these two tumor entities, and suggest that VHL-associated pheochromocytomas may be deficient in fundamental machinery for catecholamine storage. In light of these new findings, as well as existing evidence for differences between both types of pheochromocytomas, we propose that these tumors may have different developmental origins.
Shalini Patiar and Adrian L Harris
Hypoxia occurs in solid tumours due to a mismatch between tumour growth and angiogenesis. Hypoxia in solid tumours is associated with an aggressive phenotype and resistance to radiation therapy and chemotherapy leading to poor patient prognosis. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor, which is activated in response to intratumoural hypoxia and as a result of genetic alterations that activate oncogenes and inactivate tumour suppressor genes. It plays a key role in the adaptation of tumour cells to hypoxia by activating the transcription of genes, which regulate several biological processes including angiogenesis, cell proliferation and survival, glucose metabolism, pH regulation and migration. This makes HIF-1 an attractive target for the development of anticancer agents. The success of these agents depends on reliable methods to identify those patients most likely to benefit from HIF-1-targeted therapy. Several novel small molecule inhibitors of HIF-1 have been identified and are moving towards clinical trials, but none of these are specific for HIF-1. Further work is ongoing to identify more selective HIF-1 inhibitors.
Ju-Yeon Moon, Man Ho Choi and Jayoung Kim
Cholesterol and sex steroid hormones including androgens and estrogens play a critical role in the development and progression of urological diseases such as prostate cancer. This disease remains the most commonly diagnosed malignant tumor in men and is the leading cause of death from different cancers. Attempts to understand the role of cholesterol and steroid metabolism in urological diseases have been ongoing for many years, but despite this, our mechanistic and translational understanding remains elusive. In order to further evaluate the problem, we have taken an interest in metabolomics; a discipline dedicated to the systematic study of biologically active metabolites in cells, tissues, hair and biofluids. Recently, we provided evidence that a quantitative measurement of cholesterol and sex steroid metabolites can be successfully achieved using hair of human and mouse models. The overall goal of this short review article is to introduce current metabolomic technologies for the quantitative biomarker assay development and also to provide new insight into understanding the underlying mechanisms that trigger the pathological condition. Furthermore, this review will place a particular emphasis on how to prepare biospecimens (e.g., hair fiber), quantify molecular profiles and assess their clinical significance in various urological diseases.
Mathis Grossmann and Gary Wittert
Metabolic disorders such as diabetes, obesity and the metabolic syndrome have been shown to modulate prostate cancer (PCa) risk and aggressiveness in population-based and experimental studies. While associations between these conditions are modest and complex, two consistent findings have emerged. First, there is observational evidence that obesity and associated insulin excess are linked to increased PCa aggressiveness and worse outcomes. Secondly and somewhat paradoxically, long-standing diabetes may be protective against PCa development. This apparent paradox may be due to the fact that long-standing diabetes is associated with insulin depletion and decreased IGF1 signalling. Men with obesity or diabetes have moderate reductions in their androgen levels. The interconnectedness of metabolic and androgen status complicates the dissection of the individual roles of these factors in PCa development and progression. Metabolic factors and androgens may promote prostate carcinogenesis via multiple mechanisms including inflammation, adipokine action, fatty acid metabolism and IGF signalling. Moreover, androgen deprivation, given to men with PCa, has adverse metabolic consequences that need to be taken into account when estimating the risk benefit ratio of this therapy. In this review, we will discuss the current epidemiological and mechanistic evidence regarding the interactions between metabolic conditions, sex steroids and PCa risk and management.
Changes in glycan composition are common in cancer and can play important roles in all of the recognised hallmarks of cancer. We recently identified glycosylation as a global target for androgen control in prostate cancer cells and further defined a set of 8 glycosylation enzymes (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3), which are also significantly upregulated in prostate cancer tissue. These 8 enzymes are under direct control of the androgen receptor (AR) and are linked to the synthesis of important cancer-associated glycans such as sialyl-Tn (sTn), sialyl LewisX (SLeX), O-GlcNAc and chondroitin sulfate. Glycosylation has a key role in many important biological processes in cancer including cell adhesion, migration, interactions with the cell matrix, immune surveillance, cell signalling and cellular metabolism. Our results suggest that alterations in patterns of glycosylation via androgen control might modify some or all of these processes in prostate cancer. The prostate is an abundant secretor of glycoproteins of all types, and alterations in glycans are, therefore, attractive as potential biomarkers and therapeutic targets. Emerging data on these often overlooked glycan modifications have the potential to improve risk stratification and therapeutic strategies in patients with prostate cancer.
Denise K Reaves, Erika Ginsburg, John J Bang and Jodie M Fleming
Dietary ingestion of persistent organic pollutants (POPs) is correlated with the development of obesity. Obesity alters metabolism, induces an inflammatory tissue microenvironment, and is also linked to diabetes and breast cancer risk/promotion of the disease. However, no direct evidence exists with regard to the correlation among all three of these factors (POPs, obesity, and breast cancer). Herein, we present results from current correlative studies indicating a causal link between POP exposure through diet and their bioaccumulation in adipose tissue that promotes the development of obesity and ultimately influences breast cancer development and/or progression. Furthermore, as endocrine disruptors, POPs could interfere with hormonally responsive tissue functions causing dysregulation of hormone signaling and cell function. This review highlights the critical need for advanced in vitro and in vivo model systems to elucidate the complex relationship among obesity, POPs, and breast cancer, and, more importantly, to delineate their multifaceted molecular, cellular, and biochemical mechanisms. Comprehensive in vitro and in vivo studies directly testing the observed correlations as well as detailing their molecular mechanisms are vital to cancer research and, ultimately, public health.
Atsushi Mizokami, Eitetsu Koh, Kouji Izumi, Kazutaka Narimoto, Masashi Takeda, Seijiro Honma, Jinlu Dai, Evan T Keller and Mikio Namiki
One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5α-reductase inhibitor dutasteride appears to function not only as a 5α-reductase inhibitor but also as a 3β-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis.