A multilevel pan-cancer map links gene mutations to cancer hallmarks

Background:A central challenge in cancer research is to create models that bridge the gap between the molecular level on which interventions can be designed and the cellular and tissue levels on which the disease phenotypes are manifested.This study was undertaken to construct such a model from functional annotations and explore its use when integrated with large-scale cancer genomics data.Methods:We created a map that connects genes to cancer hallmarks via signaling pathways.We projected gene mutation and focal copy number data from various cancer types onto this map.We performed statistical analyses to uncover mutually exclusive and co-occurring oncogenic aberrations within this topology.Results:Our analysis showed that although the genetic fingerprint of tumor types could be very different,there were less variations at the level of hallmarks,consistent with the idea that different genetic alterations have similar functional outcomes.Additionally,we showed how the multilevel map could help to clarify the role of infrequently mutated genes,and we demonstrated that mutually exclusive gene mutations were more prevalent in pathways,whereas many co-occurring gene mutations were associated with hallmark characteristics.Conclusions:Overlaying this map with gene mutation and focal copy number data from various cancer types makes it possible to investigate the similarities and differences between tumor samples systematically at the levels of not only genes but also pathways and hallmarks.

Effect of oridonin-mediated hallmark changes on inflammatory pathways in human pancreatic cancer(BxPC-3) cells

AIM: To investigate the effect of oridonin on nuclear transcription factors and to study the relationship between biological behavior and inflammatory factors in human pancreatic cancer (BxPC-3) cells.

Resistance to apoptosis should not be taken as a hallmark of cancer

In the research community, resistance to apoptosis is often considered a hallmark of cancer. However, pathologists who diagnose cancer via microscope often see the opposite. Indeed, increased apoptosis and mitosis are usually observed simultaneously in cancerous lesions. Studies have shown that increased apoptosis is associated with cancer aggressiveness and poor clinical outcome. Furthermore, overexpression of Bcl-2, an antiapoptotic protein, is linked with better survival of cancer patients. Conversely, Bax, CD95, Caspase-3, and other apoptosis-inducing proteins have been found to promote carcinogenesis. This notion of the role of apoptosis in cancer is not new; cancer cells were found to be short-lived 88 years ago. Given these observations, resistance to apoptosis should not be considered a hallmark of cancer.

ABC transporters and the hallmarks of cancer:roles in cancer aggressiveness beyond multidrug resistance

The ATP-binding cassette transporters(ABC transporters)have been intensely studied over the past 50 years for their involvement in the multidrug resistance(MDR)phenotype,especially in cancer.They are frequently overexpressed in both naive and post-treatment tumors,and hinder effective chemotherapy by reducing drug accumulation in cancer cells.In the last decade however,several studies have established that ABC transporters have additional,fundamental roles in tumor biology;there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness,progression,and patient prognosis.This review highlights these studies in relation to some well-described cancer hallmarks,in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tum or development.Unraveling these new roles offers an opportunity to define new strategies and targets for therapy,which would include endogenous substrates or signaling pathways that regulate these proteins.

基质硬度在肿瘤特征中的生物学意义

肿瘤是全球第二大死亡因素,也是人类关注度最高的疾病之一。在恶性肿瘤的发生、发展过程中,肿瘤细胞通过获得遗传和表观遗传的变异进化出一系列特征,使它们能够生存并适应肿瘤微环境(TME)的应激相关条件。这些特征被认为是“肿瘤的标志”,包括持续的增殖信号、肿瘤转移、血管生成、代谢重编程、抵抗细胞死亡、促肿瘤炎症等。近年来,TME中的力学因素如基质硬度、流体剪切力、门静脉压力等的变化在肿瘤发生发展中的生物学作用越来越受到关注。其中,基质硬度也被称为细胞外基质(ECM)应力,是TME的一个关键物理因素。实体肿瘤中的基质硬度由于胶原蛋白的过度产生、病理性胶原交联和纤维排列而显著增加,而肿瘤细胞能够感知这种异常的ECM应力并通过其力学感受器将力学信号转化为生化信号,加剧疾病症状。然而,基质硬度与肿瘤发生及恶性转化的确切机制尚不完全明确。本文综述了ECM力学信号在调控肿瘤特征方面的研究进展,并讨论了靶向ECM硬度作为治疗肿瘤策略的可能性,为开发基于基质力学的临床肿瘤治疗提供新思路。

癌症标志本体构建与应用

目的构建一种可溯源的癌症标志知识本体,支持基因突变、癌症标志和细胞系等相关数据整合、标准化和关联,并基于该本体实现新知识发现。方法基于“七步法”和现阶段本体的构建方法,明确癌症标志本体覆盖范围、框架结构、可复用的术语和新增术语;以结直肠癌为例,利用文本挖掘和文本分类技术对PubMed文献中结直肠癌标志相关知识进行提取,利用癌症标志本体对提取的知识进行规范化表达。结合癌症体细胞突变目录中已有的癌症标志证据和进一步语义检索,实现新知识的发现。结果最终构建癌症标志本体包含类9910个,实例6138个,实现2310篇涉及结直肠癌标志文献摘要和26个结直肠癌标志相关证据的语义表示。与癌症体细胞突变目录数据集相比,本研究发现与结直肠癌相关的多个基因的癌症标志的新证据。结论本研究有助于整合癌症分子层面的致病机制,了解基因突变在癌症发生过程中的具体作用,实现癌症标志知识的快速发现。

Oncogenic MORC2 in cancer development and beyond

Microrchidia CW-type zinc finger 2(MORC2)is a member of the MORC superfamily of nuclear proteins.Growing evidence has shown that MORC2 not only participates in gene transcription and chromatin remodeling but also plays a key in human disease and tumor development by regulating the expression of downstream oncogenes or tumor suppressors.The present review provides an updated overview of MORC2 in the aspect of cancer hallmark and therapeutic resistance and summarizes its upstream regulators and downstream target genes.This systematic review may provide a favorable theoretical basis for emerging players of MORC2 in tumor development and new insight into the potential clinical application of basic science discoveries in the future.

The systemic hallmarks of cancer

Cancer is not just a lump of cells that divide,invade,and spread randomly,but rather a multi-layered precisely tuned process that requires the participation of the whole organism.There is an urgent need to zoom-out from the cellular and the local stromal view and broaden our perspective by including the whole organism level.Geographically separated cancer tissues communicate between themselves,forming a system that interacts with the rest of the organism through cancer induced systemic pathogenic networks.In the present paper,I introduce six systemic hallmarks of cancer that emerge as a result of these interactions.I also describe several potential therapeutic approaches that can be developed using the cancer system concept.Overall,I argue that the tumoricentric paradigm should be replaced with a broader approach that brings into focus the“cancerized”organism.

基于肿瘤特征的抗肿瘤中药药理学机制探析

目的:基于肿瘤特征的抗肿瘤中药药理机制研究进展和有关研究标准化的问题。方法:检索PubMed,CNKI,重庆维普,百链云图书馆、读秀学术搜索网上数据库,针对肿瘤特征,将抗肿瘤中药药理学机制研究进行归纳总结。结果:基于肿瘤特征的抗肿瘤中药药理学机制研究可分为11大类:抗增殖信号维持、抗生长抑制逃避、增强免疫、抗无限复制、抗癌性促炎反应、抗侵袭转移、抗血管生成、抗基因组不稳定与突变、抗细胞死亡抵抗、抗细胞能量代谢失衡、抗肿瘤干细胞。结论与展望:基于肿瘤特征的抗肿瘤中药药理学机制分类方法有利于中药抗肿瘤的标准化研究,值得推广。并随着对肿瘤特征研究的深入,中药针对这些特征的研究必将随之发展。

解读癌症研究的里程碑:Hallmarks of Cancer

征服癌症是人类永恒的话题。20世纪后半叶,肿瘤研究开始进入分子时代,癌症复杂多样的表型、机制及治疗反应逐渐被认识。2000年,一篇开创性综述“Hallmarks of Cancer”问世,更新至今,已总结出了癌症的14个特征,将肿瘤研究中日益繁杂的概念提炼成一门逻辑科学,有助于更全面地理解癌症发生、发展机制并将这些知识应用于肿瘤的诊断和治疗中,掌握、应用以及继续探索癌症的特征必将有助于在未来更加自信地面对肿瘤疾病带来的挑战。

肿瘤新特征研究进展

2011年HANAHAN和WEINBERG提出肿瘤具有十大标志性特征,过去10年我们对肿瘤的特征又有了新认识,这些新的肿瘤特征包括表观遗传可塑、细胞自食、克隆进化、肿瘤内异质性、共生微生物群失调和生物钟紊乱。靶向肿瘤新特征产生了肿瘤表观遗传治疗、进化治疗、精准治疗、微生物治疗和时间治疗等新治疗模式。联合治疗和精准治疗将是未来肿瘤治疗的方向。

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis,cancer,and liver failure.Liver cancer is the third leading cause of cancer-associated mortality,of which hepatocellular carcinoma(HCC)represents 90%of all primary liver cancers.Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management.Chronic infection with hepatitis B virus(HBV),hepatitis delta virus(HDV),and hepatitis C virus(HCV)are the greatest etiological risk factors for HCC.Due to the significant role of chronic viral infection in HCC development,it is important to investigate direct(viral associated)and indirect(immune-associated)mechanisms involved in the pathogenesis of HCC.Common mechanisms used by HBV,HCV,and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response,immune and viral protein-mediated oxidative stress,and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection,and metabolic reprogramming leading to steatosis is driven by HCV infection.The current review aims to provide a brief overview of HBV,HCV and HDV molecular biology,and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC,and current as well as emerging treatments for HCC.

Microbiome and colorectal carcinogenesis:Linked mechanisms and racial differences

Various studies have shown the interplay between the intestinal microbiome,environmental factors,and genetic changes in colorectal cancer(CRC)development.In this review,we highlight the various gut and oral microbiota associated with CRC and colorectal adenomas,and their proposed molecular mechanisms in relation to the processes of“the hallmarks of cancer”,and differences in microbial diversity and abundance between race/ethnicity.Patients with CRC showed increased levels of Bacteroides,Prevotella,Escherichia coli,enterotoxigenic Bacteroides fragilis,Streptococcus gallolyticus,Enterococcus faecalis,Fusobacterium nucleatum(F.nucleatum)and Clostridium difficile.Higher levels of Bacteroides have been found in African American(AA)compared to Caucasian American(CA)patients.Pro-inflammatory bacteria such as F.nucleatum and Enterobacter species were significantly higher in AAs.Also,AA patients have been shown to have decreased microbial diversity compared to CA patients.Some studies have shown that using microbiome profiles in conjunction with certain risk factors such as age,race and body mass index may help predict healthy colon vs one with adenomas or carcinomas.Periodontitis is one of the most common bacterial infections in humans and is more prevalent in Non-Hispanic-Blacks as compared to Non-Hispanic Whites.This condition causes increased systemic inflammation,immune dysregulation,gut microbiota dysbiosis and thereby possibly influencing colorectal carcinogenesis.Periodontal-associated bacteria such as Fusobacterium,Prevotella,Bacteroides and Porphyromonas have been found in CRC tissues and in feces of CRC patients.Therefore,a deeper understanding of the association between oral and gastrointestinal bacterial profile,in addition to identifying prevalent bacteria in patients with CRC and the differences observed in ethnicity/race,may play a pivotal role in predicting incidence,prognosis,and lead to the development of new treatments.

Tumor diagnosis using carbon-based quantum dots:Detection based on the hallmarks of cancer

Carbon-based quantum dots(CQDs)have been shown to have promising application value in tumor diagnosis.Their use,however,is severely hindered by the complicated nature of the nanostructures in the CQDs.Furthermore,it seems impossible to formulate the mechanisms involved using the inadequate theoretical frameworks that are currently available for CQDs.In this review,we re-consider the structure-property relationships of CQDs and summarize the current state of development of CQDs-based tumor diagnosis based on biological theories that are fully developed.The advantages and deficiencies of recent research on CQDs-based tumor diagnosis are thus explained in terms of the manifestation of nine essential changes in cell physiology.This review makes significant progress in addressing related problems encountered with other nanomaterials.

An Integrative Meta-analysis of MicroRNAs in Hepatocellular Carcinoma

We aimed to shed new light on the roles of microRNAs （miRNAs） in liver cancer using an integrative in silico bioinformatics analysis. A new protocol for target prediction and functional analysis is presented and applied to the 26 highly differentially deregulated miRNAs in hepatocellular carcinoma. This framework comprises： （1） the overlap of prediction results by four out of five target prediction tools, including TargetScan, PicTar, miRanda, DIANA-microT and miRDB （combining machine-learning, alignment, interaction energy and statistical tests in order to minimize false positives）, （2） evidence from previous microarray analysis on the expression of these targets, （3） gene ontology （GO） and pathway enrichment analysis of the miRNA targets and their pathways and （4） linking these results to oncogenesis and cancer hallmarks. This yielded new insights into the roles of miRNAs in cancer hallmarks. Here we presented several key targets and hundreds of new targets that are significantly enriched in many new cancer-related hallmarks. In addition, we also revealed some known and new oncogenic pathways for liver cancer. These included the famous MAPK, TGFβ and cell cycle pathways. New insights were also provided into Wnt signaling, prostate cancer, axon guidance and oocyte meiosis pathways. These signaling and developmental pathways crosstalk to regulate stem cell transformation and implicate a role of miRNAs in hepatic stem cell deregulation and cancer development. By analyzing their complete interactome, we proposed new categorization for some of these miRNAs as either tumor-suppressors or oncomiRs with dual roles. Therefore some of these miRNAs may be addressed as therapeutic targets or used as therapeutic agents. Such dual roles thus expand the view of miRNAs as active maintainers of cellular homeostasis.

DNA瞬态损伤的快速修复阻断癌变最早事件的发展

DNA瞬态损伤(DNA自由基)引起DNA碱基对断裂和双螺旋结构下沉,导致基因失稳,可能是构成癌变的最早事件。基因失稳是癌的共同特征标志之一,而DNA修复可通过维持基因完整性来降低癌的发生。修复DNA的能力低下也是癌的共同特征标志之一。近年新发现了一种独特的修复机制,称为快速修复,专一地修复DNA瞬态损伤,只需几个微秒就能完成,比已知的酶性修复快十亿倍,修复速率常数达到109L.mol-1.s-1。还发现凡是具有快速修复能力的植物多酚类几乎都能不同程度地削弱癌的特征标志,包括使癌细胞形态正常化、抑制癌细胞增殖、促进癌细胞分化或凋亡、降低端粒酶活性、减少植瘤率、阻止细胞迁移和扩散、抑制血管生成、延长存活时间、降低患癌风险等。

Overview of genetic signaling pathway interactions within cutaneous malignancies

Melanoma and non-melanoma cutaneous malignancies are some of the leading causes of cancer-related death in the United States.Though melanoma is more known to have a high mortality rate,the total mortality per year is nearly equal for between melanoma and non-melanoma skin cancer.Moreover,the non-melanoma types of cutaneous malignancies have potential to become locally invasive and even metastasize with very little to no treatment options when advanced.The development of these malignancies involves various genetic pathways through the four hallmarks of cancer development:malignant cell growth,apoptosis evasion,the use of supporting stroma and vascularization,and modulating and promoting an inadequate immune response.The genetic signaling pathways of basal cell carcinoma,squamous cell carcinoma,verrucous carcinoma,basosquamous cell carcinoma,melanoma,and cutaneous T-cell lymphoma interact with each other through genetic predisposition as well as with environmental exposures.Furthermore,solar ultraviolet radiation and chronic inflammatory states are found to initiate the progression of many of these cutaneous malignancies.This paper includes validated models of genetic pathways,emerging pathways,and crosstalk between genetic pathways through the four hallmarks of cancer development.Moreover,unlike most reviews addressing oncogenetics of the well-recognized,as well as newly discovered,genetic pathway mutations,this review stresses that these pathways are not fixed but rather exist in dynamic,interrelated,interactive,complex,and adaptive flux states.