Estimation of cancer cell migration in biomimetic random/oriented collagen fiber microenvironments

Increasing data indicate that cancer cell migration is regulated by extracellular matrixes and their surrounding biochemical microenvironment,playing a crucial role in pathological processes such as tumor invasion and metastasis.However,conventional two-dimensional cell culture and animal models have limitations in studying the influence of tumor microenvironment on cancer cell migration.Fortunately,the further development of microfluidic technology has provided solutions for the study of such questions.We utilize microfluidic chip to build a random collagen fiber microenvironment(RFM)model and an oriented collagen fiber microenvironment(OFM)model that resemble early stage and late stage breast cancer microenvironments,respectively.By combining cell culture,biochemical concentration gradient construction,and microscopic imaging techniques,we investigate the impact of different collagen fiber biochemical microenvironments on the migration of breast cancer MDA-MB-231-RFP cells.The results show that MDA-MB-231-RFP cells migrate further in the OFM model compared to the RFM model,with significant differences observed.Furthermore,we establish concentration gradients of the anticancer drug paclitaxel in both the RFM and OFM models and find that paclitaxel significantly inhibits the migration of MDA-MB-231-RFP cells in the RFM model,with stronger inhibition on the high concentration side compared to the low concentration side.However,the inhibitory effect of paclitaxel on the migration of MDA-MB-231-RFP cells in the OFM model is weak.These findings suggest that the oriented collagen fiber microenvironment resembling the late-stage tumor microenvironment is more favorable for cancer cell migration and that the effectiveness of anticancer drugs is diminished.The RFM and OFM models constructed in this study not only provide a platform for studying the mechanism of cancer development,but also serve as a tool for the initial measurement of drug screening.

Mechanical microenvironments of living cells: a critical frontier in mechanobiology

The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanical environment very close to cells–the cell microenvironment–plays the most important role in determining what a cell feels and how it responds to tissue-level stimuli. To complicate matters further, cells can actively manipulate their microenvironments through pathways of recursive mechanobiological feedback. Harnessing this recursive behavior to understand and control cell physiology and pathophysiology is a critical frontier in the field of mechanobiology. Recent results suggest that the key to opening this scientific frontier to investigation and engineering application is understanding a different frontier: the physical frontier that cells face when probing their mechanical microenvironments.

The EuroLifeNet Study: How Different Microenvironments Influence Personal Exposure to PM_2.5among High-School Students in Milan

Epidemiological studies show that long-term exposure to PM is associated with an increased risk of cancer. The EuroLifeNet study measured the personal exposure to PM2.5 in 90 pupils attending three schools in Milan, using a portable nephelometer, over a three-week period spanning November and December 2006. Background levels explained 40% of the variability of the exposure. Methods: As a second part of that study we analyzed the role of different microenvironments as determinants of personal exposure to PM2.5. Results: Exposure was influenced by the time of day, zone of the city and different microenvironments. Exposure was higher indoors than out, and indoors it was higher in the kitchen, particularly during cooking. In outdoor environments exposure was higher at bus stops where road traffic was heavy. Conclusions: Even though background concentration can be a good predictor of personal exposure to PM, students’ personal exposure is strongly influenced by different microenvironments and should be considered in population studies. The EuroLifeNet experience gives a contribution to personal exposure measure methodology.

Promising key genes associated with tumor microenvironments and prognosis of hepatocellular carcinoma

BACKGROUND Despite significant advances in multimodality treatments,hepatocellular carcinoma(HCC)remains one of the most common malignant tumors.Identification of novel prognostic biomarkers and molecular targets is urgently needed.AIM To identify potential key genes associated with tumor microenvironments and the prognosis of HCC.METHODS The infiltration levels of immune cells and stromal cells were calculated and quantified based on the ESTIMATE algorithm.Differentially expressed genes(DEGs)between high and low groups according to immune or stromal scores were screened using the gene expression profile of HCC patients in The Cancer Genome Atlas and were further linked to the prognosis of HCC.These genes were validated in four independent HCC cohorts.Survival-related key genes were identified by a LASSO Cox regression model.RESULTS HCC patients with a high immune/stromal score had better survival benefits than patients with a low score.A total of 899 DEGs were identified and found to be involved in immune responses and extracellular matrices,147 of which were associated with overall survival.Subsequently,52 of 147 survival-related DEGs were validated in additional cohorts.Finally,ten key genes(STSL2,TMC5,DOK5,RASGRP2,NLRC3,KLRB1,CD5L,CFHR3,ADH1C,and UGT2B15)were selected and used to construct a prognostic gene signature,which presented a good performance in predicting overall survival.CONCLUSION This study extracted a list of genes associated with tumor microenvironments and the prognosis of HCC,thereby providing several valuable directions for the prognostic prediction and molecular targeted therapy of HCC in the future.

Dental mesenchymal stromal/stem cells in different microenvironments— implications in regenerative therapy

Current research data reveal microenvironment as a significant modifier of physical functions,pathologic changes,as well as the therapeutic effects of stem cells.When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering,mesenchymal stem cells(MSCs)are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use.The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs,indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration.Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues,MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years.This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions,giving additional insight into the current clinical application of these cells.

Tungsten oxide-anchored Ru clusters with electron-rich and anti-corrosive microenvironments for efficient and robust seawater splitting

Ruthenium(Ru)has been recognized as a prospective candidate to substitute platinum catalysts in water-splitting-based hydrogen production.However,minimizing the Ru contents,optimizing the water dissociation energy of Ru sites,and enhancing the long-term stability are extremely required,but still face a great challenge.Here,we report on creating tungsten oxide-anchored Ru clusters(Ru-WO_(x))with electron-rich and anti-corrosive microenvironments for efficient and robust seawater splitting.Benefiting from the abundant oxygen vacancy structure in tungsten oxide support,the Ru-WO_(x)exhibits strong Ru-O and Ru-W bonds at the interface.Our study elucidates that the strong Ru-O bonds in Ru-WO_(x)may accelerate the water dissociation kinetics,and the Ru-W bonds will lead to the strong metal-support interaction and electrons transfer fromWto Ru.The optimal Ru-WO_(x)catalysts exhibit a low overpotential of 29 and 218mVat the current density of 10 mA cm^(−2) in alkaline and seawater media,respectively.The outstanding long-term stability discloses that the Ru-WO_(x)catalysts own efficient corrosion resistance in seawater electrolysis.We believe that thiswork offers new insights into the essential roles of electron-rich and anti-corrosivemicroenvironments in Ru-based catalysts and provide a new pathway to design efficient and robust cathodes for seawater splitting.

Radiation-induced tumor immune microenvironments and potential targets for combination therapy

As one of the four major means of cancer treatment including surgery,radiotherapy(RT),chemotherapy,immunotherapy,RT can be applied to various cancers as both a radical cancer treatment and an adjuvant treatment before or after surgery.Although RT is an important modality for cancer treatment,the consequential changes caused by RT in the tumor microenvironment(TME)have not yet been fully elucidated.RT-induced damage to cancer cells leads to different outcomes,such as survival,senescence,or death.During RT,alterations in signaling pathways result in changes in the local immune microenvironment.However,some immune cells are immunosuppressive or transform into immunosuppressive phenotypes under specific conditions,leading to the development of radioresistance.Patients who are radioresistant respond poorly to RT and may experience cancer progression.Given that the emergence of radioresistance is inevitable,new radiosensitization treatments are urgently needed.In this review,we discuss the changes in irradiated cancer cells and immune cells in the TME under different RT regimens and describe existing and potential molecules that could be targeted to improve the therapeutic effects of RT.Overall,this review highlights the possibilities of synergistic therapy by building on existing research.

Modulating microenvironments to enhance CO_(2) electroreduction performance

Microenvironments of the catalytic center,which play a vital role in adjusting electrocatalytic CO_(2) reduction reaction(ECO_(2) RR)activity,have received increasing attention during the past few years.However,controllable microenvironment construction and the effects of multi-microenvironment variations for improving ECO_(2) RR performance remain unclear.Herein,we summarize the representative strategies for tuning the catalyst and local microenvironments to enhance ECO_(2) RR selectivity and activity.The multifactor synergetic effects of microen-vironment regulation for enhancing CO_(2) accessibility,stabilizing key intermediates,and improving the performance of ECO_(2) RR catalysts are discussed in detail,as well as perspectives on the challenges when investigating ECO_(2) RR microenvironments.We anticipate that the discussions in this review will inspire further research in microenvironment engineering to accelerate the development of the ECO 2 RR for practical application.

Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Microbiome changes in esophageal cancer:implications for pathogenesis and prognosis

Esophageal cancer(EC)is an aggressive malignancy with a poor prognosis.Various factors,including dietary habits,and antacid and antibiotic use,have been shown to influence the esophageal microbiome.Conversely,enrichment and diversity of the esophageal microbiome can also impact its function.Recent studies have revealed prevalent changes in the esophageal microbiome among patients with EC,thus suggesting the potential contribution of the esophageal microbiome to EC development.Additionally,distinct microbiome compositions have been observed in patients with different responses to radiotherapy and chemotherapy,indicating the role of the esophageal microbiome in modulating treatment outcomes.In this review,we have examined previous studies on the esophageal microbiome in healthy individuals and patients with EC or other esophageal diseases,with a focus on identifying microbial communities associated with EC pathogenesis and prognosis.Understanding the role of the microbiome in EC may aid in early detection and optimized treatment strategies,ultimately leading to better outcomes for patients.

Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism,and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-βexpression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.

Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment.Here,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury.Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model.Basso,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion core.Examination of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the microenvironment.Altogether,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion site.Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status

Hepatocellular carcinoma(HCC)is the most common primary tumor of the liver and has a high mortality rate.The Barcelona Clinic Liver Cancer staging system in addition to tumor staging also links the modality of treatment available to a particular stage.The recent description of the tumor microenvironment(TME)in HCC has provided a new concept of immunogenicity within the HCC.Virusrelated HCC has been shown to be more immunogenic with higher expression of cytotoxic T lymphocytes and decreased elements for immunosuppression such as regulatory T cells.This immunogenic milieu provides a better response to immunotherapy especially immune checkpoint inhibitors(ICIs).In addition,the recent data on combining locoregional therapies and other strategies may convert the less immunogenic state of the TME towards higher immunogenicity.Therefore,data are emerging on the use of combinations of locoregional therapy and ICIs in unresectable or advanced HCC and has shown better survival outcomes in this difficult population.

New roles of tumor-derived exosomes in tumor microenvironment

Throughout tumorigenesis, the co-evolution of tumor cells and their surrounding microenvironment leads to the development of malignant phenotypes. Cellular communication within the tumor microenvironment(TME) plays a critical role in influencing various aspects of tumor progression, including invasion and metastasis. The release of exosomes, a type of extracellular vesicle, by most cell types in the body, is an essential mediator of intercellular communication. A growing body of research indicates that tumor-derived exosomes(TDEs) significantly expedite tumor progression through multiple mechanisms, inducing epithelial-mesenchymal transition and macrophage polarization, enhancing angiogenesis, and aiding in the immune evasion of tumor cells. Herein, we describe the formation and characteristics of the TME, and summarize the contents of TDEs and their diverse functions in modulating tumor development. Furthermore, we explore potential applications of TDEs in tumor diagnosis and treatment.

Exosomal microRNAs in hepatocellular carcinoma,expanding research field

In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023.Small extracellular vesicles(exosomes)play important roles in the tumor microenvironment.In this review,the authors introduce the following points:(1)The composition and function of exosomal microRNAs(miRNAs)of different cell origins in hepatocellular carcinoma(HCC);(2)the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC;and(3)the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.In addition,the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced.In this review,the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC,which provides a deeper understanding of exosomal miRNAs to the readers.

MicroRNAs in hepatocellular carcinoma treatment:Charting the path forward

MicroRNAs(miRNAs)are recognized for their involvement in the regulation of gene expression and exhibit significant potential in both the prognostic assessment and treatment of hepatocellular carcinoma(HCC).HCC,like other tumors,seldom occurs in isolation;instead,it evolves within a microenvironment featuring oncogenic and tumor-suppressive elements.When combined with suitable delivery vehicles,miRNA technology provides the capability to directly engage with these elements,thereby hindering tumor formation and progression.Ongoing research in this domain holds the promise of enabling a more efficacious and multi-modal treatment approach for HCC in the near future.

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment

BACKGROUND Pancreatic cancer is one of the most lethal malignancies,characterized by poor prognosis and low survival rates.Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy,often failing to capture the complexity of the disease.The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment.This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer.AIM To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules.METHODS This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2,PLAU,and CCNA2.The results were validated in an independent dataset.This study also examined the correlations between the model risk score and various clinical features,components of the immune microenvironment,chemotherapeutic drug sensitivity,and metabolism-related pathways.Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines.RESULTS The prognostic model demonstrated significant predictive value,with the risk score showing a strong correlation with clinical features:It was significantly associated with tumor grade(G)(bP<0.01),moderately associated with tumor stage(T)(aP<0.05),and significantly correlated with residual tumor(R)status(bP<0.01).There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs.Furthermore,the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer.CONCLUSION The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Lipid metabolism-related long noncoding RNA RP11-817I4.1 promotes fatty acid synthesis and tumor progression in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common types of tumors.The influence of lipid metabolism disruption on the development of HCC has been demonstrated in published studies.AIM To establish an HCC prognostic model for lipid metabolism-related long non-coding RNAs(LMR-lncRNAs)and conduct in-depth research on the specific role of novel LMR-lncRNAs in HCC.METHODS Correlation and differential expression analyses of The Cancer Genome Atlas data were used to identify differentially expressed LMR-lncRNAs.Quantitative real-time polymerase chain reaction analysis was used to evaluate the expression of LMR-lncRNAs.Nile red staining was employed to observe intracellular lipid levels.The interaction between RP11-817I4.1,miR-3120-3p,and ATP citrate lyase(ACLY)was validated through the performance of dual-luciferase reporter gene and RIP assays.RESULTS Three LMR-lncRNAs(negative regulator of antiviral response,RNA transmembrane and coiled-coil domain family 1 antisense RNA 1,and RP11-817I4.1)were identified as predictive markers for HCC patients and were utilized in the construction of risk models.Additionally,proliferation,migration,and invasion were reduced by RP11-817I4.1 knockdown.An increase in lipid levels in HCC cells was significantly induced by RP11-817I4.1 through the miR-3120-3p/ACLY axis.CONCLUSION LMR-lncRNAs have the capacity to predict the clinical characteristics and prognoses of HCC patients,and the discovery of a novel LMR-lncRNAs,RP11-817I4.1,revealed its role in promoting lipid accumulation,thereby accelerating the onset and progression of HCC.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.

Tumor microenvironments self-activated nanoscale metal-organic frameworks for ferroptosis based cancer chemodynamic/photothermal/chemo therapy

Ferroptosis,as a newly discovered cell death form,has become an attractive target for precision cancer therapy.Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione(GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4(GPX4).However,the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported.Herein,novel tumor microenvironments(TME)-activated metal-organic frameworks involving Fe&Cu ions bridged by disulfide bonds with PEGylation(FCSP MOFs)were developed,which would be degraded specifically under the redox TME,simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction,therefore causing ferroptosis.More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs.The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy.Better tumor therapeutic efficiency could be achieved by doxorubicin(DOX)loading since it can not only cause apoptosis,but also indirectly produce H2O2 to amplify Fenton reaction.Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.