The epigenome of colorectal cancer

Epigenetic alterations (eg, DNA methylation) play important roles in silencing cancer-related genes in colorectal cancers (CRCs). DNA methylation occurs in genes involved in cell cycle checkpoints, apoptosis, signal transduction, DNA repair, and maintenance of the genome’s integrity. Recent developments of new methods for detecting DNA methylation have enabled us to create epigenetic profiles of CRC and to classify them into three distinct subgroups based on genetic and epigenetic alterations. DNA methylation also leads to silencing of some microRNAs, which in turn leads to dysregulation of oncogenic proteins, which are their targets. Moreover, for diagnosis, epigenetic information may be used to detect cancer cells in serum and stool. Obtaining a fuller understanding of the epigenome will be an important step toward understanding the molecular mechanisms underlying CRC and may provide the basis for the development of novel diagnostic tools and approaches to therapy.     

Targeting the epigenome for treatment of cancer

Cancer genome analyses have revealed that the enzymes involved in epigenetic gene regulation are frequently deregulated in cancer. Here we describe the enzymes that control the epigenetic state of the cell, how they are affected in cancer and how this knowledge can be exploited to treat cancer with a new arsenal of selective therapies.     

S-phase fraction and breast cancer - a decade of experience

During the past decade, more than 300 articles, abstracts, and book chapters have been published about S-phase fraction (SPF) determined by DNA flow cytometry and its clinical utility for patients with breast cancer. However, the use of SPF for making treatment decisions for breast cancer patients remains controversial.After reviewing 273 published articles, we conclude: 1) Despite different techniques and cutpoints, correlations between SPF and other prognostic markers are relatively consistent across studies; higher SPF is generally associated with worse tumor grade, absence of steroid receptors, larger tumors, and positive axillary lymph nodes. 2) Higher SPF is generally associated with worse disease-free and overall survival in both univariate and multivariate analyses; SPF values from laboratories that have conducted validation studies can be used, in combination with other factors, to estimate the prognosis of patients with primary breast cancer. 3) There is considerable variability among laboratories regarding assay methodology, cell- cycle analysis techniques, and cutpoints for classifying and interpreting SPF; use of SPF values from different laboratories is problematic, and there remains a need for standardization of these processes and well-designed confirmation studies.We conclude that measurement of SPF does have clinical utility for patients with breast cancer, but standardization and quality control must be improved before it can be routinely used in community settings.     

甲状腺癌过去与未来十年

甲状腺癌近年来发病率激增,已成为最常见恶性肿瘤之一。国内外甲状腺癌整体学术水平也在近十年得到飞速发展,我国甲状腺癌整体规范化诊治水平及科研能力明显提升。本文对甲状腺癌临床诊治及基础科研等方面的十年进展及未来展望进行评述,以期提高专业工作者对甲状腺癌精准诊疗的全面认识,促进甲状腺癌研究与诊疗的进展。      

Interleukin-6 and its receptor in cancer: implications for translational therapeutics

Interleukin-6 (IL-6) plays a major role in the response to injury or infection and is involved in the immune response, inflammation, and hematopoiesis. Its deregulation impacts numerous disease states, including many types of cancer. Consequently, modulating IL-6 may be an innovative therapeutic strategy in several diseases. A review of relevant published literature regarding IL-6 and its receptor was performed. In addition, a review of the relevance of this cytokine system to human illness, particularly in cancer, was undertaken. IL-6 is a pleiotropic cytokine that is involved in the physiology of virtually every organ system. Aberrant expression of this cytokine has been implicated in diverse human illnesses, most notably inflammatory and autoimmune disorders, coronary artery and neurologic disease, gestational problems, and neoplasms. In cancer, high levels of circulating IL-6 are observed in almost every type of tumor studied and predict a poor outcome. Furthermore, elevated IL-6 levels are associated strongly with several of the striking phenotypic features of cancer. Several molecules have been developed recently that target the biologic function of IL-6. Early results in the clinic suggest that this strategy may have a significant salutary impact on diverse tumors. The field of cytokine research has yielded a deep understanding of the fundamental role of IL-6 and its receptor in health and disease. Therapeutic targeting of IL-6 and its receptor in cancer has strong biologic rationale, and there is preliminary evidence suggesting that targeting of the IL-6 system may be beneficial in the treatment of cancer.     

The epigenome and cancer prevention: A complex story of dietary supplementation

Epigenetic changes have been implicated in virtually all types of human malignancies. In contrast to genetic changes, epigenetic changes occur in a gradual manner during the tumorigenic process and they are potentially reversible. Because epigenetic changes have frequently been detected in high-risk populations, they are attractive targets to prevent the initiation of premalignant lesions or their advance to a malignant stage. A wide range of chemical entities has been found capable of altering the epigenome in animal models and humans. Epidemiological and laboratory-based studies suggested that these agents may have an anti-neoplastic effect against different cancer types. Several of these agents have been tested as dietary supplements, often with conflicting results. In this review, we discuss recent developments in our understanding of agents capable of modulating the epigenome and their potential to prevent human cancer when administered as dietary supplements.     

Targeting the epigenome for the treatment and prevention of lung cancer

Alterations in chromatin structure resulting from aberrant DNA methylation and perturbations of the histone code profoundly influence gene expression during pulmonary carcinogenesis. Recent studies indicate that DNA demethylating agents and histone deacetylase (HDAC) inhibitors synergistically induce gene expression and apoptosis in cultured lung cancer cells, and prevent lung cancer development in animals following exposure to tobacco carcinogens. Preliminary clinical trials have established proof of principle regarding the use of DNA demethylating agents and HDAC inhibitors for enhancing immunogenicity and apoptosis of lung cancer cells, and have revealed the complexities concerning the mechanisms by which chromatin remodeling agents mediate antitumor effects in vivo. These data support additional investigations pertaining to the epigenetics of lung cancer, and the evaluation of chromatin remodeling agents for the treatment and prevention of this disease.     

Rewiring the solid tumor epigenome for cancer therapy

Introduction: Whereas tumorigenic processes have traditionally been attributed to gene amplification, deletion, or mutation, it is now clear that epigenetic changes represent an additional hallmark of cancer. This review explains the basic principles of epigenetic regulation and therapy, provides an overview of clinically approved drugs, introduces novel targets and compounds, and discusses the potential reasons behind treatment success and failure.

Areas covered: We provide a brief introduction to the concept of epigenetic regulation in general and explain how epigenetic pathways are altered in cancer. Based on this, we go on to explore the rational behind epigenetic cancer therapy, provide an overview of clinical success and failure of specific drugs, describe novel pharmaceutical targets, review epigenetic combination treatment, and finally discuss biological concepts influencing treatment success.

Expert commentary: Even though many early epigenetic therapy trials had disappointing results, lessons learned from these studies have heavily influenced the design of modern trials leading to improved therapeutic outcomes. Better preclinical model systems may help to reduce the risk of clinical failure and to identify high-confidence targets for clinical follow-up.     

Inflammatory breast cancer: A decade of experience

Inflammatory breast cancer (IBC) is an aggressive and rare form of breast cancer. At present, there are no established diagnostic, radiological, pathological or molecular diagnostic criteria for this entity. The aim of this study was to examine the patterns of presentation, treatment and outcomes of IBC in this institution over the course of a decade. This is a retrospective observational study using data from the Royal Perth Hospital from January 2001 to December 2010. Our results identified 57 women with IBC, representing 1.9% of all new breast cancer presentations. Human Epidermal Growth Factor Receptor 2 (HER2)‐positive and triple negative tumors were overrepresented (41% and 18%, respectively). Forty‐four (77%) patients had early disease at diagnosis, of whom 35 underwent surgery and 16 are relapse‐free. All six patients achieving complete pathological response were relapse‐free in contrast to 11 (38%) with lesser responses at a median follow‐up of 59 months. Median survival in 13 patients with metastatic disease at diagnosis was 21.7 months, with two patients still in remission. Clearly, this small but important group continues to offer management challenges and warrants ongoing study, including better molecular and pathological profiling of tumors to allow improved diagnostic clarity and more effective targeted therapy.     

Roadmap for investigating epigenome deregulation and environmental origins of cancer

The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene–environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor‐specific (“fingerprints”) that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed and advances in epigenomics that may help in understanding the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed and how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment.     

Induced pluripotent stem cell technology for dissecting the cancer epigenome

Cancer arises through the accumulation of both genetic and epigenetic alterations. Although the causal role of genetic mutations on cancer development has been established in vivo, similar evidence for epigenetic alterations is limited. Moreover, mutual interactions between genetic mutations and epigenetic alterations remain unclear. Cellular reprogramming technology can be used to actively modify the epigenome without affecting the underlying genomic sequences. Here we introduce recent studies that have utilized this property for cancer research. We propose that just as it has potential for regenerative medicine and disease modeling, cell reprogramming could also be a powerful tool for dissecting the role of the cancer epigenome in the development and maintenance of cancer cells.     

Aberrant DNA methylation in lung cancer: biological and clinical implications

Genetic abnormalities of proto-oncogenes and tumor suppressor genes are well-known changes that are frequently involved in lung cancer pathogenesis. However, another mechanism for inactivation of tumor suppressor genes is coming more and more into focus. Epigenetic inactivation of certain tumor suppressor genes by aberrant promoter methylation is frequently observed in lung carcinomas and seems to play an important role in the pathogenesis of this tumor type. While genetic abnormalities are associated with changes in DNA sequence, epigenetic events may lead to changes in gene expression that occur without changes in DNA sequence. Recent findings demonstrate that aberrant methylation can also be detected in the smoking-damaged bronchial epithelium from cancer-free heavy smokers, suggesting that aberrant methylation might be an ideal candidate biomarker for lung cancer risk assessment and monitoring of chemoprevention trials. Moreover, in vitro studies demonstrate that methylation can be reversed by demethylating agents resulting in gene re-expression. This concept is currently under investigation in clinical trials. In summary, recent studies demonstrate that aberrant methylation may be the most common mechanism of inactivating cancer-related genes in lung cancer, occurs already in smoking-damaged bronchial epithelium from cancer-free individuals, can be reversed in vitro by demethylating agents, and may be a useful biomarker for lung cancer risk assessment.     

Mapping the emergence and development of translational cancer research

Cancer research is one of the principal targets of translational research, yet the nature of the relationships between different forms of cancer research remains controversial. The paper examines publications in the cancer field during the 1980–2000 period. A network analysis software program was used to map evolving patterns of inter-citations between cancer publications, their different research levels and the transformation of their relational content. Both inter-citation and content maps provide striking evidence of the consolidation in the 1990s of a translational interface that was practically non existent a few decades before. In 1980, research was polarized according to the allegiance to either a clinical or a laboratory style. This same duality obtains in the year 2000, albeit with the additional presence of a third, biomedical player whose activities are similarly structured by a common orientation, rather than by an exclusive commitment to a specific sub-domain.     

肿瘤治疗的几种新模式

未来10年肿瘤的治疗模式将发生变化,光遗传学治疗、时间治疗、机械治疗、神经治疗、微生物治疗、微型机器人治疗、适应性治疗和数字治疗等新的治疗模式将进入临床,它们可能成为最终战胜肿瘤的“特洛伊木马”,肿瘤治疗将更加个体、更加精准与更加智慧。