Two-Stage Segmentation of Lung Cancer Metastasis Lesions by Fusion of Multi-Resolution Features

The deep learning method automatically extracts advanced features from a large amount of data, avoiding cumbersome manual feature screening, and using digital pathology and artificial intelligence technology to build a computer-aided diagnosis system to help pathologists quickly make objective and reliable diagnoses and improve work efficiency. Because pathological images are limited by factors such as sample size, manual labeling expertise, and complexity, artificial intelligence algorithms have not been extensively and in-depth researched on pathological images of lung cancer metastasis. Therefore, this paper proposes a lung cancer metastasis segmentation method based on pathological images, to further improve the computer-aided diagnosis method of lung cancer.

Advances in understanding the molecular mechanism of pancreatic cancer metastasis

BACKGROUND： Pancreatic cancer（PC） is usually diagnosed at the late-stage and therefore, has widespread metastasis and a very high mortality rate. The mechanisms underlying PC metastasis are not well understood. Recent advances in genomic sequencing have identified groups of gene mutations that affect PC metastasis, but studies elucidating their roles are lacking. The present review was to investigate the molecular mechanisms of PC metastasis.DATA SOURCES： Relevant articles on PC metastasis were searched in MEDLINE via Pub Med prior to April 2015. The search was limited in English publications.RESULTS： PC metastatic cascades are multi-factorial events including both intrinsic and extrinsic elements. This review highlights the most important genetic alterations and other mechanisms that account for PC invasion and metastasis, with particular regard to epithelial-mesenchymal transition, inflammation, stress response, and circulating tumor cells.CONCLUSIONS： Analyses of relevant gene functions and signaling pathways are needed to establish the gene regulatory network and to define the pivotal modulators. Another promising area of study is the genotyping and phenotyping of circulating tumor cells, which could lead to a new era of personalized therapy by identifying specific markers and targets.

In vitro three-dimensional cancer metastasis modeling:Past,present,and future

Metastasis is the leading cause of most cancer deaths, as opposed to dysregulated cell growth of the primary tumor. Molecular mechanisms of metastasis have been studied for decades and the findings have evolved our understanding of the progression of malignancy. However, most of the molecular mechanisms fail to address the causes of cancer and its evolutionary origin, demonstrating an inability to find a solution for complete cure of cancer. After being a neglected area of tumor biology for quite some time, recently several studies have focused on the impact of the tumor microenvironment on cancer growth. The importance of the tumor microenvironment is gradually gaining attention, particularly from the per- spective of biophysics. In vitro three-dimensional （3-D） metastatic models are an indispensable platform for investigating the tumor microenvironment, as they mimic the in vivo tumor tissue. In 3-D metastatic in vitro models, static factors such as the mechanical properties, biochemical factors, as well as dynamic factors such as cell-cell, cell-ECM interactions, and fluid shear stress can be studied quantitatively. With increasing focus on basic cancer research and drug development, the in vitro 3-D models offer unique advantages in fundamental and clinical biomedical studies.

Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

Current landscape of preoperative neoadjuvant therapies for initial resectable colorectal cancer liver metastasis

Colorectal cancer liver metastasis(CRLM)presents a clinical challenge,and optimizing treatment strategies is crucial for improving patient outcomes.Surgical resection,a key element in achieving prolonged survival,is often linked to a heightened risk of recurrence.Acknowledging the potential benefits of preoperative neoadjuvant chemotherapy in managing resectable liver metastases,this approach has gained attention for its role in tumor downsizing,assessing biological behavior,and reducing the risk of postoperative recurrence.However,the use of neoadjuvant chemotherapy in initially resectable CRLM sparks ongoing debates.The balance between tumor reduction and the risk of hepatic injury,coupled with concerns about delaying surgery,necessitates a nuanced approach.This article explores recent research insights and draws upon the practical experiences at our center to address critical issues regarding considerations for initially resectable cases.Examining the criteria for patient selection and the judicious choice of neoadjuvant regimens are pivotal areas of discussion.Striking the right balance between maximizing treatment efficacy and minimizing adverse effects is imperative.The dynamic landscape of precision medicine is also reflected in the evolving role of gene testing,such as RAS/BRAF and PIK3CA,in tailoring neoadjuvant regimens.Furthermore,the review emphasizes the need for a multidisciplinary approach to navigate the comp-lexities of CRLM.Integrating technical expertise and biological insights is crucial in refining neoadjuvant strategies.The management of progression following neoadjuvant chemotherapy requires a tailored approach,acknowledging the diverse biological behaviors that may emerge.In conclusion,this review aims to provide a comprehensive perspective on the considerations,challenges,and advancements in the use of neoadjuvant chemotherapy for initially resectable CRLM.By combining evidencebased insights with practical experiences,we aspire to contribute to the ongoing discourse on refining treatment paradigms for improved outcomes in patients with CRLM.

Inetetamab combined with pyrotinib and chemotherapy in the treatment of breast cancer brain metastasis: A case report

BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.

HBXIP blocks myosin-ⅡA assembly by phosphorylating and interacting with NMHC-ⅡA in breast cancer metastasis

Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.

Immune cell membrane-based biomimetic nanomedicine for treating cancer metastasis

Metastasis is the leading cause of cancer-related death.Despite extensive treatment,the prognosis for patients with metastatic cancer remains poor.In addition to conventional surgical resection,radiotherapy,immunotherapy,chemotherapy,and targeted therapy,various nanobiomaterials have attracted attention for their enhanced antitumor performance and low off-target effects.However,nanomedicines exhibit certain limitations in clinical applications,such as rapid clearance from the body,low biological stability,and poor targeting ability.Biomimetic methods utilize the natural biomembrane to mimic or hybridize nanoparticles and circumvent some of these limitations.Considering the involvement of immune cells in the tumor microenvironment of the metastatic cascade,biomimetic methods using immune cell membranes have been proposed with unique tumor-homing ability and high biocompatibility.In this review,we explore the impact of immune cells on various processes of tumor metastasis.Furthermore,we summarize the synthesis and applications of immune cell membrane-based nanocarriers increasing therapeutic efficacy against cancer metastases via immune evasion,prolonged circulation,enhanced tumor accumulation,and immunosuppression of the tumor microenvironment.Moreover,we describe the prospects and existing challenges in clinical translation.

A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression

Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies.Heat shock protein 90(Hsp90)as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance.Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance.In this study,a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX,and a COAmodified 4-arm PEG polymer(4PSC)was synthesized.COA,an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression,was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity.Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity.By blocking the Hsp90 signaling pathway,4PSC significantly enhanced the antitumor effect of PTX,inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro.Remarkable results were further confirmed in vivo with two preclinical tumor models.These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.

Emerging Regulatory Mechanisms of N6-Methyladenosine Modification in Cancer Metastasis

Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes.A metastatic cas-cade is a series of complicated biological processes.N6-methyladenosine(m^(6)A)is the most abundant and conserved epi-transcriptomic modification in eukaryotic cells,which has great impacts on RNA production and metabolism,including RNA splicing,processing,degradation and translation.Accumulating evidence demonstrates that m^(6)A plays a critical role in regulating cancer metastasis.However,there is a lack of studies that review the recent advances of m^(6)A in cancer metastasis.Here,we systematically retrieved the functions and mechanisms of how the m^(6)A axis regulates metastasis,and especially summarized the organ-specific liver,lung and brain metastasis mediated by m^(6)A in various cancers.Moreover,we discussed the potential application of m^(6)A modification in cancer diagnosis and therapy,as well as the present limitations and future perspectives of m^(6)A in cancer metastasis.This review provides a comprehensive knowledge on the m^(6)A-mediated regulation of gene expression,which is helpful to extensively understand the complexity of cancer metastasis from a new epitranscriptomic point of view and shed light on the developing novel strategies to anti-metastasis based on m^(6)A alteration.

Apigenin is an anoikis sensitizer with strong anti-metastatic properties in experimental breast cancer

Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods.Among 19 tested dietary phytochemicals,the best results were obtained with apigenin,a natural component of celery.Phenotypically,apigenin sensitized breast cancer cells to anoikis,lowered the number of circulating tumor cells,and protected against breast cancer metastasis to lung in mice.Mechanistically,we demonstrated that the thromboxane A_(2)(TXA_(2))-TXA_(2)receptor(TP)axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway.Blockage of TXA_(2)signaling up-regulated p53 as well as its target gene p21,caused a G1 phase arrest,and finally led to apoptosis in breast cancer cells.TXA_(2)level was positively correlated with breast cancer cell anoikis rate,and apigenin significantly inhibited TXA_(2)biosynthesis in vitro and in vivo.Collectively,we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer,and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.

Waist subcutaneous soft tissue metastasis of rectal mucinous adenocarcinoma: A case report

BACKGROUND Rectal mucinous adenocarcinoma(MAC)is a rare pathological type of rectal can-cer with unique pathological features and a poor prognosis.It is difficult to diag-nose and treat early because of the lack of specific manifestations in some aspects of the disease.The common metastatic organs of rectal cancer are the liver and lung;however,rectal carcinoma with metastasis to subcutaneous soft tissue is a rare finding.CASE SUMMARY In this report,the clinical data,diagnosis and treatment process,and postope-rative pathological features of a patient with left waist subcutaneous soft tissue masses were retrospectively analyzed.The patient underwent surgical treatment after admission and recovered well after surgery.The final pathological diagnosis was rectal MAC with left waist subcutaneous soft tissue metastasis.CONCLUSION Subcutaneous soft tissue metastasis of rectal MAC is rare,and it can suggest that the tumor is disseminated,and it can appear even earlier than the primary ma-lignant tumor,which is occult and leads to a missed diagnosis and misdiagnosis clinically.When a subcutaneous soft tissue mass of unknown origin appears in a patient with rectal cancer,a ma-lignant tumor should be considered.

Prognostic role of serum carcinoembryonic antigen in patients receiving liver resection for colorectal cancer liver metastasis:A meta-analysis

BACKGROUND Carcinoembryonic antigen(CEA)is a broad-spectrum tumor marker for differential diagnosis,monitoring,and response assessment of a variety of malignancies.AIM To evaluate whether serum CEA could predict the prognosis in patients with colorectal cancer liver metastasis(CRCLM)before and after liver resection(LR).METHODS PubMed,Embase,Cochrane,and Web of Science were systematically searched to retrieve literature,with a search cut-off date of February 27,2023.Articles were strictly screened for inclusion according to pre-specified inclusion and exclusion criteria.Data were pooled and analyzed using Stata 16.0.RESULTS This meta-analysis included 36 studies involving a total of 11143 CRCLM patients.The results showed that a high pre-LR serum CEA level was correlated with poor overall survival(OS)[hazard ratio(HR)=1.61,95%confidence interval(CI):1.49-1.75,P<0.001]and recurrence-free survival(HR=1.27,95%CI:1.11-1.45,P<0.001)in CRCLM patients.A high post-LR serum CEA level predicted poor OS(HR=2.66,95%CI:2.10-3.38,P<0.001).A comparison by treatment modality,analysis modality,patient source,and cutoff-value showed that overall,high preoperative and postoperative serum CEA levels remained correlated with a poor prognosis.CONCLUSION This study concluded that high pre-LR and post-LR serum CEA levels were significantly correlated with a poor prognosis in CRCLM patients.

Establishment of Risk Prediction Model and Nomogram for Lymph Node Metastasis of Cervical Cancer: Based on SEER Database

Objective: To predict the risk factors of lymph node metastasis in cervical cancer by using large sample clinical data, and to construct and verify the nomogram for predicting lymph node metastasis. Methods: A total of 5940 patients with cervical cancer from 2004 to 2015 in the National Cancer Institute Surveillance Epidemiology and End Results database were retrospectively screened and randomly assigned to training group (n = 4172) and validation group (n = 1768). Multivariate Logistic regression analysis was used, and the optimal model was selected according to AIC or BIC and likelihood ratio test, and a nomogram was drawn. The accuracy and robustness of the prediction model were evaluated in three aspects: discrimination, calibration and clinical net benefit. Results: The prediction model based on race, tumor tissue differentiation degree, tumor histopathological type, distant metastasis of tumor, tumor diameter and other risk factors was successfully established and a nomogram was constructed. The AUCs of training group and validation group were: 0.736 and 0.714, respectively. And the p-values of the Hosmer-Lemeshow test were 0.28 and 0.11, respectively. The calibration curve was in good agreement with the ideal curve. It had high accuracy and applicability after internal verification. Conclusion: A prediction model is constructed based on the risk factors of lymph node metastasis of cervical cancer. The nomogram has a good effective prediction and can provide a theoretical basis for clinicians to assess the disease quickly before surgery.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Identification of metastasis-associated genes in colorectal cancer through an integrated genomic and transcriptomic analysis

Objective： Identification of colorectal cancer （CRC） metastasis genes is one of the most important issues in CRC research. For the purpose of mining CRC metastasis-associated genes, an integrated analysis of mJcroarray data was presented, by combined with evidence acquired from comparative genornic hybridization （CGH） data. Methods： Gene expression profile data of CRC samples were obtained at Gene Expression Omnibus （GEO） website. The 15 important chromosomal aberration sites detected by using CGH technology were used for integrated genomic and transcriptomic analysis. Significant Analysis of Microarray （SAM） was used to detect significantly differentially expressed genes across the whole genome. The overlapping genes were selected in their corresponding chromosomal aberration regions, and analyzed by using the Database for Annotation, Visualization and Integrated Discovery （DAVID）. Finally, SVM-T-RFE gene selection algorithm was applied to identify ted genes in CRC. Results： A minimum gene set was obtained with the minimum number [14] of genes, and the highest classification accuracy （100%） in both PRI and META datasets. A fraction of selected genes are associated with CRC or its metastasis. Conclusions- Our results demonstrated that integration analysis is an effective strategy for mining cancer- associated genes.

MAGE-C3 promotes cancer metastasis by inducing epithelial-mesenchymal transition and immunosuppression in esophageal squamous cell carcinoma

Background:Evading immune surveillance is necessary for tumor metastasis.Thus,there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion.In this study,we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma(ESCC).Methods:The expression of melanoma-associated antigen C3(MAGE-C3)was detected using immunohistochemistry.Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma(ESCC)cells.Metastasis assays in mice were used to evaluate metastatic ability in vivo.Lymphocyte-mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells.RNA sequencing was performed to identify differentially expressed genes between MAGE-C3 overexpressing ESCC cells and control cells.Gene ontology(GO)enrichment analyses was performed to identify the most altered pathways influenced by MAGE-C3.The activation of the interferon-γ(IFN-γ)pathway was analyzed using Western blotting,GAS luciferase reporter assays,immunofluorescence,and flow cytometry.The role of MAGE-C3 in the IFN-γpathway was determined by Western blotting and immunoprecipitation.Furthermore,immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases.Results:MAGE-C3 was overexpressed in ESCC tissues.High expression of MAGE-C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC.Functional experiments revealed that MAGE-C3 promoted tumor metastasis by activating the epithelial-mesenchymal transition(EMT).MAGE-C3 repressed antitumor immunity and regulated cytokine secretion of T cells,implying an immunosuppressive function.Mechanistically,MAGE-C3 facilitated IFN-γsignaling and upregulated programmed cell death ligand 1(PDŋL1)by binding with IFN-γreceptor 1(IFNGR1)and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1(STAT1).Interestingly,MAGE-C3 displayed higher tumorigenesis in immune-competent mice than in immune-deficient nude mice,confirming the immunosuppressive role of MAGE-C3.Furthermore,mice bearing MAGE-C3-overexpressing tumors showed worse survival and more lung metastases with decreased CD8+infiltrated T cells and increased programmed cell death 1(PD-1)^(+)CD8^(+) infiltrated T cells.Conclusion:MAGE-C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance,and could be a potential prognostic marker and therapeutic target.

Upregulation of PIP3-Dependent Rac Exchanger 1(P-Rex1) Promotes Prostate Cancer Metastasis

Excessive activation of G-protein coupled receptor (GPCR) and receptor tyrosine kinase (RTK) pathways has been linked to prostate cancer metastasis. Rac activation

Exosomal long non-coding RNAs:Emerging players in cancer metastasis and potential diagnostic biomarkers for personalized oncology

Metastasis is a major challenge in the treatment of cancer.Exosomes are a class of small extracellular vesicles(EVs)that play critical roles in several human diseases,especially cancer,by transferring information(e.g.,DNA,RNA,and protein)via cell-to-cell communication.Numerous recent studies have shown that exosomal long non-coding RNAs(lncRNAs)play crucial regulatory roles in cancer metastasis in the tumor microenvironment by altering the expression of several key signaling pathways and molecules.Due to their specificity and sensitivity,exosomal lncRNAs have potential as novel tumor markers and therapeutic targets in the treatment of cancer metastasis.In this review,we aim to summarize the roles of exosomal lncRNAs in cancer metastasis,the mechanisms underlying their roles,and their potential clinical applications.

Long non-coding RNAs as key regulators of cancer metastasis

The recent advances in functional genomics have discovered that a large number of long non-coding RNAs(lncRNAs)are pervasively transcribed from the human genome.Increasing evidence further indicates that lncRNAs are important for gene expression during cell differentiation and development through various mechanisms such as nuclear organization,post-transcription regulation,alternative splicing,and epigenetic regulation.Thus,aberrant expression of lncRNAs can cause abnormality in those cellular functions and lead to various pathological conditions.One of such fatal consequences is cancer metastasis which is responsible for more than 90%of cancer-related deaths.A good understanding of how lncRNAs regulate different genetic and epigenetic changes during different stages of cancer metastasis is important not only for general cancer biology but also for identification of novel biomarkers and therapeutic targets for treatment of metastatic cancer.A significant progress has been made regarding the role of lncRNAs in cancer for past several years.In this study,we first discuss general functions of lncRNAs and then highlight recent findings of how lncRNAs impact cancer metastasis,and finally we provide our perspectives on clinical implications of lncRNAs.