Epithelial-mesenchymal transition as a therapeutic target for overcoming chemoresistance in pancreatic cancer

Pancreatic cancer has one of the worst prognoses among all cancers due to the late manifestation of identifiable symptoms and high resistance to chemo- and radiation therapies. In recent years, a cancer development phase termed epithelial-mesenchymal transition(EMT) has gained increasing research focus. The process is implicated in tumour metastasis, and emerging evidence suggests EMT also contributes or induces chemoresistance in several cancers. Nevertheless, the applicability of therapeutic targeting of EMT faces many challenges. In this mini-review, we summarise the evidence supporting the role of EMT in pancreatic cancer progression, focusing particularly on its association with chemoresistance.

Role of epithelial-mesenchymal transition in chemoresistance in pancreatic ductal adenocarcinoma

Pancreatic cancer(PC)is the seventh leading cause of cancer death worldwide.The vast majority of patients who have PC develop metastases,resulting in poor treatment effects.Although great progress in therapeutic approaches has been achieved in recent decades,extensive drug resistance still persists,representing a major hurdle to effective anticancer therapy for pancreatic ductal adenocarcinoma(PDAC).Therefore,there is an urgent need to better understand the drug resistance mechanisms and develop novel treatment strategies to improve patient outcomes.Numerous studies suggest that chemoresistance is closely related to epithelial-mesenchymal transition(EMT)of PDAC cells.Thus,this article summarizes the impact of EMT on PDAC from the perspective of chemotherapy resistance and discusses the possible novel applications of EMT inhibition to develop more effective drugs against PDAC.

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Epithelial-mesenchymal transition(EMT)and autophagy are both known to play important roles in the development of cancer.Subsequently,these processes are now being utilised as targets for therapy.Cancer is globally one of the leading causes of death,and,despite many advances in treatment options,patients still face many challenges.Drug resistance in cancer-therapy is a large problem,and both EMT and autophagy have been shown to contribute.However,given the context-dependent role of these processes and the complexity of the interactions between them,elucidating how they both act alone and interact is important.In this review,we provide insight into the current landscape of the interactions of autophagy and EMT in the context of malignancy,and how this ultimately may affect drug resistance in cancer therapy.

Epithelial-mesenchymal transition:a hallmark in pancreatic cancer stem cell migration,metastasis formation,and drug resistance

Metastasis,tumor progression,and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma(PDAC).Tumor dissemination is associated with the activation of an epithelial-tomesenchymal transition(EMT)process,a program by which epithelial cells lose their cell polarity and cell-tocell adhesion,and acquire migratory and invasive abilities to become mesenchymal stem cells(MSC).These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal state.Therefore,EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of cells.Furthermore,a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells(PCSCs)or cancer-initiating cells in pancreatic tumors.PCSCs may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth.These cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into mice.Therefore,the presence of PCSCs has prognostic relevance and influences the therapeutic response of tumors.PCSCs express markers of cancer stem cells(CSCs)including CD24,CD133,CD44,and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium.A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells metastasize.Evidence highlights a linkage between CSC and EMT.In this review,The current understanding of the PCSCs,signaling pathways regulating these cells,PDAC heterogeneity,EMT mechanism,and links between EMT and metastasis in PCSCs are summarised.This information may provide potential therapeutic strategies to prevent EMT and trigger CSC growth inhibition and cell death.

FBW7 increases chemosensitivity in hepatocellular carcinoma cells through suppression of epithelial-mesenchymal transition

BACKGROUND: FBW7 is a tumor suppressor which regulates a network of proteins with central roles in cell division, cell growth and differentiation. This study aimed to evaluate the role of FBW7in chemosensitivity and epithelial-mesenchymal transition (EMT) in different hepatocellular carcinoma (HCC) cell lines and to investigate the relevant underlying mechanisms.METHODS: Different human HCC cell lines (Hep3B, Huh-7,and SNU-449) were cultured. The cell viability was evaluated by cell counting kit-8, and FBW7 mRNA transcription and protein expression were quantitated by real-time PCR and Western blotting. Expressions of vimentin (mesenchymal biomarker)and E-cadherin (epithelial biomarker) were evaluated by Western blotting and immunocytochemistry. Cell invasion was assayed by Transwell migration, and FBW7 plasmid or siRNA was used to evaluate the effect of FBW7 overexpression or silencing on cell chemosensitivity.RESULTS: FBW7 expression affected tumor cell chemosensitivity to doxorubicin and tumor cell invasive capacity in different HCC cell lines. FBW7hi (high FBW7 expression) Hep3B and FBW7mi (median FBW7 expression) Huh-7 cells were more sensitive to doxorubicin and lower in invasive capacity than FBW7lo (low FBW7 expression) SNU-449 cells. Silencing of FBW7in Huh-7 and Hep3B cells induced the resistance to doxorubicin and enhanced cell invasion, whereas overexpression of FBW7in SNU-449 cells restored the sensitivity to doxorubicin andsignificantly reduced invasive capacity. Furthermore, doxorubicin induced EMT toward mesenchyme in HCC cells. Downregulation of FBW7 in Huh-7 and Hep3B cells or upregulation of FBW7 in SNU-449 cells altered the direction of EMT.CONCLUSIONS: The level of FBW7 expression impacted the tumor resistance to doxorubicin and the invasion capability of HCC cells. FBW7 therefore may be a potential target for the chemotherapy of HCC through the regulation of EMT.

Regulatory role of the transforming growth factor-β signaling pathway in the drug resistance of gastrointestinal cancers

Gastrointestinal(GI)cancer,including esophageal,gastric,and colorectal cancer,is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths.Despite significant advances in therapeutic strategies for GI cancers in recent decades,drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers.Accumulating evidence has demonstrated that the transforming growth factor(TGF)-βsignaling pathway has crucial,complex roles in many cellular functions related to drug resistance.This review summarizes current knowledge regarding the role of the TGF-βsignaling pathway in the resistance of GI cancers to conventional chemotherapy,targeted therapy,immunotherapy,and traditional medicine.Various processes,including epithelial-mesenchymal transition,cancer stem cell development,tumor microenvironment alteration,and microRNA biogenesis,are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers.Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-βsignaling pathway,but this approach needs to be verified in additional clinical studies.Moreover,the identification of potential biological markers that can be used to predict the response to TGF-βsignaling pathway inhibitors during anticancer treatments will have important clinical implications in the future.

Targeting epithelial-mesenchymal transition-an ongoing wild goose chase

Epithelial-mesenchymal transition(EMT)is a natural phenomenon thatoccurs during embryodevelopment.It is a phenomenon involving the transition of adherence-dependent stationary epithelial cells to adherence-independent migratory mesenchymal cells.Tumours reactivate this machinery and evade anti-tumour immunity and inhibition by cancer-specific drugs.EMT harnesses complex crosstalk among cancer cell signalling pathways that make it difficult to tackle therapeutically,and it plays a pivotal role in cancer metastasis.Most screening platforms and approved drugs are limited by their applicability to epithelial cancers.There is a significant need for developing new strategies targeting metastatic cancers.Here,we review the challenges with the current methods of screening and available drugs for EMT and shed some light on the key essentials needed for next-generation drug discovery attempts.

Cancer stem cells,plasticity,and drug resistance

Melanoma is a highly aggressive tumor and almost always fatal when metastatic.Herein,we discuss recent findings on the mechanisms of resistance of human cutaneous melanoma.To achieve a precision medicine approach,the heterogeneity and plasticity of tumor cells are two crucial aspects to be investigated in depth.In fact,to understand the mechanisms that cells use to acquire a resistant phenotype after chemotherapy or how resistant cells inside the tumor are selected,it is the most important issue for a successful therapy.Since new therapeutic strategies are trying to go in this direction,we discuss here the state of the art of the research and the clinical impact of these strategies.We also discuss and suggest future research directions to develop approaches able to define the best concentration and time of exposure of the drug or the cocktails of drugs for each specific patient based on his/her biological features.

Notch signaling in female cancers: a multifaceted node to overcome drug resistance

Drug resistance is one of the main challenges in cancer therapy,including in the treatment of female-specific malignancies,which account for more than 60%of cancer cases among women.Therefore,elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches.Notably,Notch signaling,including either receptors or ligands,has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer.Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts,several studies focused on the Notch-dependent regulation of the cancer stem cell(CSC)subpopulation or the induction of the epithelial-to-mesenchymal transition(EMT),both features implicated in either intrinsic or acquired resistance.Indeed,the present review provides an up-to-date overview of the published results on Notch signaling and EMT-or CSC-driven drug resistance.Moreover,other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment.Collectively,there is a long way to go before every facet will be fully understood;nevertheless,some small pieces are falling neatly into place.Overall,the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.

Insights into mechanisms of tumor dissemination from circulating tumor cell lines of small cell lung cancer

Despite the fact that the majority of cancer patients succumb to metastatic disease,most aspects of tumor metastasis are not understood in detail at present.Cell biologic steps of dissemination are difficult to characterize in human tumors and research is in large part confined to cell line and experimental animal studies.Epithelial-mesenchymal transition(EMT),intravasation of malignant cells,dissemination as circulating tumor cells(CTCs)and eventually mesenchymal-epithelial transition(MET)at distal sites are steps believed to be involved in metastasis.Small cell lung cancer(SCLC)is distinguished by early dissemination and excessive numbers of CTCs,which allowed for the ex vivo expansion of six permanent CTC lines taken from relapsed patients.Cells exhibit an epithelial phenotype with partial EMT traits and are chemoresistant due to formation of large tumorospheres.Since cells may have invaded without undergoing EMT,the role of MET is uncertain.These SCLC CTC cell lines seem to represent the metastasis-inducing cancer cells;these are the minute subpopulation of CTCs capable of surviving in the circulation and transitioning to metastases,leading in turn to resistance and failure of therapy.Full characterization of these lines is expected to provide the markers to find the relevant CTCs among the highly heterogeneous population observable in the context of tumor recurrence.

Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy

Colorectal cancer(CRC)is a predominant life-threatening cancer,with liver and peritoneal metastases as the primary causes of death.Intestinal inflammation,a known CRC risk factor,nurtures a local inflammatory environment enriched with tumor cells,endothelial cells,immune cells,cancer-associated fibroblasts,immunosuppressive cells,and secretory growth factors.The complex interactions of aberrantly expressed cytokines,chemokines,growth factors,and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes.Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment,which is partly achieved by the recruitment of immunosuppressive cells.These cells impart features such as cancer stem cell-like properties,drug resistance,invasion,and formation of the premetastatic niche in distant organs,promoting metastasis and aggressive CRC growth.A deeper understanding of the cytokineand chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC.Here,we summarized the current knowledge of cytokine-and chemokine-mediated crosstalk in the inflammatory tumor microenvironment,which drives immunosuppression,resistance to therapeutics,and metastasis during CRC progression.We also outlined the potential of this crosstalk as a novel therapeutic target for CRC.The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.

Cyclooxygenase-2 promotes ovarian cancer cell migration and cisplatin resistance via regulating epithelial mesenchymal transition

Objective: Drug-resistance and metastasis are major reasons for the high mortality of ovarian cancer(OC) patients. Cyclooxygenase-2(COX-2) plays a critical role in OC development. This study was designed to evaluate the effects of COX-2 on migration and cisplatin(cis-dichloro diammine platinum, CDDP) resistance of OC cells and explore its related mechanisms. Methods: Cell counting kit-8(CCK-8) assay was used to detect the cytotoxicity effects of celecoxib(CXB) and CDDP on SKOV3 and ES2 cells. The effect of COX-2 on migration was evaluated via the healing test. Western blot and real-time quantitative polymerase chain reaction(q PCR) were used to analyze E-cadherin, vimentin, Snail, and Slug levels. Results: COX-2 promoted drug-resistance and cell migration. CXB inhibited these effects. The combination of CDDP and CXB increased tumor cell sensitivity, reduced the amount of CDDP required, and shortened treatment administration time. COX-2 upregulation increased the expression of Snail and Slug, resulting in E-cadherin expression downregulation and vimentin upregulation. Conclusions: COX-2 promotes cancer cell migration and CDDP resistance and may serve as a potential target for curing OC.

Decoding cancer's camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy,chemotherapy,and targeted therapies.Here,we aimed to explore how EMP contributes to cancer cell camouflage,allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies.The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment.The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated,particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis.High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions.This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells.Therapeutic strategies currently in clinical development will be discussed.

蛋白质翻译重编程在肿瘤中的研究进展

蛋白质翻译重编程是细胞在应对各种刺激时做出的重要代偿性改变,使细胞蛋白质组发生快速、特异性的变化。肿瘤细胞通过内部核糖体进入位点(IRES)、非帽依赖性翻译增强子(CITE)及N6-甲基腺苷(m^(6)A)修饰等机制调控蛋白质翻译重编程,这在肿瘤的发生、进展与治疗抵抗过程中发挥重要作用。深入研究蛋白质翻译重编程在肿瘤中的作用,有望发掘新的药物靶点,为肿瘤治疗提供新的方向。

microRNAs, an active and versatile group in cancers

microRNAs （miRNAs） are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein-coding genes are regulated by miRNAs, indicating that miRNAs are master regulators of many important biological processes, such as cancer development, miRNAs frequently have deregulated expression in many types of human cancers, and play critical roles in tumorigenesis, which functions either as tumor suppressors or as oncogenes. Recent studies have shown that miRNAs are highly related with cancer progression, including initiating, growth, apoptosis, invasion, and metastasis. Furthermore, miRNAs are shown to be responsible for the cancer-related inflam- mation, anti-cancer drug resistance, and regulation of cancer stem ceils. Therefore, miRNAs have generated great interest as a novel strategy in cancer diagnosis and therapy. Here we review the versatile roles of miRNAs in cancers and their potential applications for diagnosis, prognosis, and treatment as biomarkers.

miR-30 c-5p在肿瘤中表达和功能的研究进展

miR-30 c-5p是miR-30家族的重要成员,研究表明其在肺癌、乳腺癌、前列腺癌、子宫内膜癌等多种肿瘤组织以及患者血浆、血清中表达异常,并且其作用于肿瘤的增殖、侵袭和迁移以及多种肿瘤相关基因和通路等,暗示其在肿瘤诊断、治疗、监测和预后预测等方面有一定的应用价值。本文就miR-30 c-5p在肿瘤中表达和功能的研究进展进行简要综述。

基质力学对肿瘤发生发展及肿瘤细胞生物学行为影响的研究进展

实体瘤的发生发展常伴随着细胞外基质的异常沉积、交联和基质刚度增加.基质刚度增加和肿瘤细胞软化引起肿瘤微环境的力学异质性.基质力学通过影响肿瘤细胞的增殖、迁移、转移、上皮间质转换、肿瘤干细胞特性和耐药性等调控肿瘤的发生、恶性转变和转移.研究基质力学对肿瘤发生发展的影响不仅可深化对肿瘤发展的认识,也可为研究新的诊治方法提供理论基础.本文论述了细胞外基质力学特性对肿瘤发生发展及肿瘤细胞生物学行为影响的研究进展,并展望了其发展前景.

转移性乳腺癌循环肿瘤细胞的上皮间质转化水平对化疗疗效的预测意义

目的检测转移性乳腺癌患者外周血循环肿瘤细胞(CTCs)不同亚型相关基因的表达,探讨其对化疗疗效的预测意义。方法应用免疫磁性分选(MACS)技术联合逆转录-聚合酶链反应(RT-PCR)法检测58例转移性乳腺癌患者和10例健康人外周血中CTCs上皮型标志物上皮角蛋白(CK18、CK19)和间质型标志物(波形蛋白、纤连蛋白)mRNA的表达。分析上皮型标志物及间质型标志物表达与不同亚型乳腺癌之间的关系,并分别评估具有不同表型CTCs患者之间疗效的差异。结果在10例健康志愿者的血液样本中,未检测出CK18、CK19、波形蛋白和纤连蛋白mRNA的表达。在58例转移性乳腺癌患者的血液样本中,检测出36例(62.1%)上皮角蛋白表达,19例(32.8%)间质型标志物表达。Luminal A组和HER-2阳性组的上皮型标志物阳性表达率高于三阴性乳腺癌组(P=0.008),而间质型标志物阳性表达率则低于三阴性乳腺癌组(P<0.001)。根据不同标志物的表达情况,将患者分为CKs+/EMT-组、CKs-/EMT-组、CKs+/EMT+组和CKs-/EMT+组,4组有效率依次为76.7%、55.6%、33.3%和15.4%,差异有统计学意义(P=0.002)。间质型标志物阴性者的化疗有效率高于间质型标志物阳性者(71.8%vs.15.8%,P=0.000)。结论转移性乳腺癌患者中部分CTCs将发生上皮间质转化而丢失上皮型细胞的表型,获得间质型细胞表型。间质型CTCs因具有更强的抵抗化疗药物的能力而存活,这可能是三阴性乳腺癌疗效不佳的原因之一。

上皮间质转化与肿瘤耐药

肿瘤药物治疗过程中常常要面临肿瘤细胞耐药的问题。上皮间质转化(epithelial-mesenchymaltransition,EMT)在肿瘤耐药方面的作用为解决该问题提供了可能。该文围绕EMT基本特征、EMT与肿瘤耐药的关系、EMT在肿瘤耐药过程中机制的研究进展进行详细综述。

原发性肝细胞癌对索拉非尼耐药机制的研究进展

索拉非尼是目前公认的治疗晚期原发性肝细胞癌的分子靶向药物,但原发性肝细胞癌对其耐药性的出现,影响了药物对肝癌的疗效。原发性肝细胞癌对索拉非尼耐药存在多种机制。肝癌细胞本身表皮生长因子受体的表达上调及其下游信号通路的异常改变,沉默信息调节因子1的过表达,肝癌细胞的自噬能力增强及间充质转变均可能导致其对索拉非尼耐药。肝癌血管内皮细胞出现耐药,肿瘤微环境中缺氧诱导因子-1α、趋化因子及其受体上调等也可能影响肿瘤对索拉非尼的敏感性。该文就原发性肝细胞癌对索拉非尼耐药机制的研究进展进行综述。