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.

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.

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.

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.