Epithelial-mesenchymal transition transcription factors and mi RNAs: “Plastic surgeons” of breast cancer

Growing evidence suggests that breast cancer cell plasticity arises due to a partial reactivation of epithelialmesenchymal transition(EMT) programs in order to give cells pluripotency, leading to a stemness-like phenotype. A complete EMT would be a dead end program that would render cells unable to fully metastasize to distant organs. Evoking the EMT-mesenchymal-toepithelial transition(MET) cascade promotes successful colonization of distal target tissues. It is unlikely that direct reprogramming or trans-differentiation without passing through a pluripotent stage would be thepreferred mechanism during tumor progression. This review focuses on key EMT transcriptional regulators, EMT-transcription factors involved in EMT(TFs) and the mi RNA pathway, which are deregulated in breast cancer, and discusses their implications in cancer cell plasticity. Cross-regulation between EMT-TFs and mi RNAs, where mi RNAs act as co-repressors or co-activators, appears to be a pivotal mechanism for breast cancer cells to acquire a stem cell-like state, which is implicated both in breast metastases and tumor recurrence. As a master regulator of mi RNA biogenesis, the ribonuclease type Ⅲ endonuclease Dicer plays a central role in EMTTFs/mi RNAs regulating networks. All these EMT-MET key regulators represent valuable new prognostic and predictive markers for breast cancer as well as promising new targets for drug-resistant breast cancers.

Decrease in liver cancer incidence rates in Bamako,Mali over 28 years of population-based cancer registration(1987-2015)

BACKGROUND Primary liver cancer is common in West Africa due to endemic risk factors.However,epidemiological studies of the global burden and trends of liver cancer are limited.We report changes in trends of the incidence of liver cancer over a period of 28 years using the population-based cancer registry of Bamako,Mali.To assess the trends and patterns of liver cancer by gender and age groups by analyzing the cancer registration data accumulated over 28 years(1987-2015)of activity of the population-based registry of the Bamako district.METHODS Data obtained since the inception of the registry in 1987 through 2015 were stratified into three periods(1987-1996,1997-2006,and 2007-2015).Age-standardized rates were estimated by direct standardization using the world population.Incidence rate ratios and the corresponding 95%confidence intervals(CI)were estimated using the early period as the reference(1987-1996).Joinpoint regression models were used to assess the annual percentage change and highlight trends over the entire period(from 1987 to 2015).RESULTS Among males,the age-standardized incidence rates significantly decreased from 19.41(1987-1996)to 13.12(1997-2006)to 8.15(2007-2015)per 105 person-years.The incidence rate ratio over 28 years was 0.42(95%CI:0.34-0.50),and the annual percentage change was-4.59[95%CI:(-6.4)-(-2.7)].Among females,rates dropped continuously from 7.02(1987-1996)to 2.57(2007-2015)per 105 person-years,with an incidence rate ratio of 0.37(95%CI:0.28-0.45)and an annual percentage change of-5.63[95%CI:(-8.9)-(-2.3)].CONCLUSION The population-based registration showed that the incidence of primary liver cancer has steadily decreased in the Bamako district over 28 years.This trend does not appear to result from biases or changes in registration practices.This is the first report of such a decrease in an area of high incidence of liver cancer in Africa.This decrease may be explained by the changes and diversity of diet that could reduce exposure to aflatoxins through dietary contamination in this population.

Design and Production of a Patient Guide to Support Return to Work after Breast Cancer:An Application of Intervention Mapping

Aims.Return to work(RTW)after breast cancer is a complex process that questions the individual trajectories of patients and stakeholders.Program planning in this context requires relying on appropriate methods like Intervention Mapping(IM)which encompasses such complexity.The aim of the methodological study is to describe an application of IM for both the design and production of a patient guide supporting RTW after breast cancer.Procedure.According to IM,the guide was co-constructed with a Community Advisory Board(CAB)of stakeholders(patients/associations,health professionals,companies,institutions)after considering other options(interactive website,mobile application).The design was done with empirical and theoretical anchoring,guided here by an Ecosystem Process of Change model.A communication agency was chosen to produce the document.Pre-tests were conducted with a representative panel of the target audience to assess the different prototypes elaborated,using questionnaires and a focus group.Results.The final structure of the guide is presented with comments in order to concretely illustrate the management of IM steps 3 and 4.The final structure of the guide is presented,along with a description of its components that target women(according to Prochaska et Di Clemente’s stages of change)and their environment(by use of levers they may activate).The results of the pre-test led to the simplification of the guide and its structure.Conclusion.IM allows a rich integration of experiential knowledge in the planning of complex health and public health programs.The development of the guide has attempted to integrate its aspects,in particular to promote both its implementation and its effects.Reflections are brought about the realistic evaluation of such complex interventions.

LKB1, A New Biomarker in Breast Cancer

Breast cancer is the most common cancer in women worldwide. Estrogen signaling pathways have been identified as efficient targets of breast cancer therapy, given their key role in promoting breast tumor growth. Agents blocking estrogen-mediated pathways are routinely used in clinical applications in patients displaying estrogen-sensitive breast cancer subtypes;however intrinsic or acquired resistance to treatment often occurs or develops, thus limiting their efficacy. This limitation has highlighted an imperative need to identify new predictive biomarkers. Recent findings have highlighted a role for the Liver Kinase B1 (LKB1) in breast cancer tumorigenesis. LKB1 is a serine/threonine kinase mutated in Peutz-Jeghers syndrome (PJS), implicated in many cellular processes including energy metabolism, cell polarization and cell cycle arrest and has also been shown to play an essential role as a tumor suppressor gene by negatively regulating the mTOR pathway. This review provides an overview of previous findings and ongoing research on LKB1, and substantiates the use of this kinase as a potential prognostic and predictive biomarker of breast cancer.

Peer-Support in Oncology: A Qualitative Study of Caregivers Perception in a Cancer Center

This study aimed to gather healthcare professionals’expectations and reluctance toward peer support in a cancer center.Semistructured interviews were conducted among 12 professionals,recruited in different professions.The interviews were fully transcribed,and a thematic analysis was then conducted.Of the data analysis,three main themes about professionals’expectations emerged:the need for the strongest support of the patients,to break the isolation in the sickness,and to enhance the care system.Three main themes also emerged from the data analysis about professionals’reluctances:the limitations related to the intervention of the peer-workers,the psychological issues of the relationship,and institutional barriers to the implementation of peer-support interventions.Our study shows that peer support could be a response to the expectations of healthcare professionals’,but its implementation should consider their reluctance.

Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

Lorentz force electrical impedance tomography using pulse compression technique

Lorentz force electrical impedance tomography （LFEIT） combines ultrasound stimulation and electromagnetic field detection with the goal of creating a high contrast and high resolution hybrid imaging modality. In this study, pulse compression working together with a linearly frequency modulated ultrasound pulse was investigated in LFEIT. Experiments were done on agar phantoms having the same level of electrical conductivity as soft biological tissues. The results showed that：（i） LFEIT using pulse compression could detect the location of the electrical conductivity variations precisely; （ii） LFEIT using pulse compression could get the same performance of detecting electrical conductivity variations as the traditional LFEIT using high voltage narrow pulse but reduce the peak stimulating power to the transducer by 25.5 dB; （iii） axial resolution of 1 mm could be obtained using modulation frequency bandwidth 2 MHz.

Involvement of CRF2 signaling in enterocyte differentiation

To determine the role of corticotropin releasing factor receptor (CRF2) in epithelial permeability and enterocyte cell differentiation.METHODSFor this purpose, we used rat Sprague Dawley and various colon carcinoma cell lines (SW620, HCT8R, HT-29 and Caco-2 cell lines). Expression of CRF2 protein was analyzed by fluorescent immunolabeling in normal rat colon and then by western blot in dissociated colonic epithelial cells and in the lysates of colon carcinoma cell lines or during the early differentiation of HT-29 cells (ten first days). To assess the impact of CRF2 signaling on colonic cell differentiation, HT-29 and Caco-2 cells were exposed to Urocortin 3 recombinant proteins (Ucn3, 100 nmol/L). In some experiments, cells were pre-exposed to the astressin 2b (A2b) a CRF2 antagonist in order to inhibit the action of Ucn3. Intestinal cell differentiation was first analyzed by functional assays: the trans-cellular permeability and the para-cellular permeability were determined by Dextran-FITC intake and measure of the transepithelial electrical resistance respectively. Morphological modifications associated to epithelial dysfunction were analyzed by confocal microscopy after fluorescent labeling of actin (phaloidin-TRITC) and intercellular adhesion proteins such as E-cadherin, p120ctn, occludin and ZO-1. The establishment of mature adherens junctions (AJ) was monitored by following the distribution of AJ proteins in lipid raft fractions, after separation of cell lysates on sucrose gradients. Finally, the mRNA and the protein expression levels of characteristic markers of intestinal epithelial cell (IEC) differentiation such as the transcriptional factor krüppel-like factor 4 (KLF4) or the dipeptidyl peptidase IV (DPPIV) were performed by RT-PCR and western blot respectively. The specific activities of DPPIV and alkaline phosphatase (AP) enzymes were determined by a colorimetric method.RESULTSCRF2 protein is preferentially expressed in undifferentiated epithelial cells from the crypts of colon and in human colon carcinoma cell lines. Furthermore, CRF2 expression is down regulated according to the kinetic of HT-29 cell differentiation. By performing functional assays, we found that Ucn3-induced CRF2 signaling alters both para- and trans-cellular permeability of differentiated HT-29 and Caco-2 cells. These effects are partly mediated by Ucn3-induced morphological changes associated with the disruption of mature AJ in HT-29 cells and tight junctions (TJ) in Caco-2 cells. Ucn3-mediated activation of CRF2 decreases mRNA and protein expression levels of KLF4 a transcription factor involved in IEC differentiation. This signaling is correlated to a down-regulation of key IEC markers such as DPPIV and AP, at both transcriptional and post-transcriptional levels.CONCLUSIONOur findings suggest that CRF2 signaling could modulate IEC differentiation. These mechanisms could be relevant to the stress induced epithelial alterations found in inflammatory bowel diseases.

Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment(TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients’ quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy-most commonly using a local high single dose-are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.

Development of NK cell-based cancer immunotherapies through receptor engineering

Natural killer(NK)cell-based immunotherapies are attracting increasing interest in the field of cancer treatment.Early clinical trials have shown promising outcomes,alongside satisfactory product efficacy and safety.Recent developments have greatly increased the therapeutic potential of NK cells by endowing them with enhanced recognition and cytotoxic capacities.This review focuses on surface receptor engineering in NK cell therapy and discusses its impact,challenges,and future directions.Most approaches are based on engineering with chimeric antigen receptors to allow NK cells to target specific tumor antigens independent of human leukocyte antigen restriction.This approach has increased the precision and potency of NK-mediated recognition and elimination of cancer cells.In addition,engineering NK cells with T-cell receptors also mediates the recognition of intracellular epitopes,which broadens the range of target peptides.Indirect tumor peptide recognition by NK cells has also been improved by optimizing immunoglobulin constant fragment receptor expression and signaling.Indeed,engineered NK cells have an improved ability to recognize and destroy target cells coated with specific antibodies,thereby increasing their antibodydependent cellular cytotoxicity.The ability of NK cell receptor engineering to promote the expansion,persistence,and infiltration of transferred cells in the tumor microenvironment has also been explored.Receptor-based strategies for sustained NK cell functionality within the tumor environment have also been discussed,and these strategies providing perspectives to counteract tumor-induced immunosuppression.Overall,receptor engineering has led to significant advances in NK cell-based cancer immunotherapies.As technical challenges are addressed,these innovative treatments will likely reshape cancer immunotherapy.

The scaffold protein menin is essential for activating the MYC locus and MYC-mediated androgen receptor transcription in androgen receptor-dependent prostate cancer cells

Dear Editor,The proto-oncogene MYC has a well-documented role in driving androgen receptor(AR)oncogenic functions in prostate cancer(PCa cells)[1]and was recently reported as a key activator in the regulation of AR transcription[2].Dissecting the mechanisms underlying MYC-mediated AR regulation may be crucial for better understanding PCa development and improving its management.We recently demonstrated that menin,encoded by the MEN1 gene,plays an oncosuppressive role in the generation of ARlow/CD44+microinvasive prostate adenocarcinoma in mice but exerts oncogenic effects specifically in ARdependent human PCa cells,both likely by modulating AR transcription and AR targets[3].We herein wondered whether this oncogenic function of menin would occur through its interaction with other factors known to play a crucial role forAR transcription in PCa,in particular,MYC.

p53 functional loss,stemness and hepatocellular carcinoma

The tumor suppressor p53 is a key player in the control of genomic integrity and homeostasis in connection with p63 and p73,the two other members of the p53 family.Loss of functional p53 leads to the proliferation and survival of mature cells and progenitor or stem cells that accumulate genetic alterations,thus favoring tumorigenesis.p53 loss of function,observed in a wide variety of human tumor types,is frequently caused by missense mutations more frequently found in the DNA binding domain,but can also be due to the expression of a plethora of viral and cellular negative regulators.Human hepatocellular carcinoma(HCC)represents a specific situation,first because the TP53 gene mutations pattern exhibits a“hot spot”rarely found in other tumor types that is linked to Aflatoxin B1 exposure and,second,because many HCCs do not exhibit any TP53 mutation.Here,we provide an overview of the current knowledge about the inhibition of p53 functions by the N-terminal(ΔN)truncated forms of the family,and their role in the emergence and maintenance of pre-malignant cells with stem cell characteristics and in HCC development.We focus in particular on the Nanog-IGF1R-ΔNp73 axis that is associated with stem-like features in HCC cells and that may provide an attractive new therapeutic target and help to develop new biomarkers for HCC risk stratification,as well as preventive strategies.

Generation and characterization of Men1 mutant mouse models for studying MEN1 disease

Patients with multiple endocrine neoplasia type 1(MEN1)mutations are predisposed to MEN1 syndrome affecting various endocrine cell lineages.Following its identification in the late 1990s,laboratories around the world,including our own,used gene-targeting approaches in murine models to study the MEN1 gene and its related diseases.Subsequently,this field of research witnessed an upsurge in the use of Men1 mutant mouse models to dissect MEN1 functions.These studies led to unraveling the natural history of MEN disease,and highlighted cellular and molecular mechanisms underlying the development of the disease.In this review,we present the currently available data concerning the generation and characterization of Men1 mutant mouse models in connection with MEN1 syndrome.