Crosstalk between the tumor microenvironment and tumor cells through exosomes:Roles in tumor metabolism and progression

Tumor proliferation,metabolism,metastasis,and chemoresistance are intimately related to the tumor microenvironment(TME).The metabolic reprogramming of tumor cells is a hallmark of their adaptation to hypoxic and nutrient-deficient TMEs.Exosomes,a type of extracellular vesicle,have been found to regulate the crosstalk between tumor cells and the TME,affecting tumor metabolic reprogramming.In this review,we introduce the metabolic characteristics of tumor cells;describe the crosstalk between tumor cells and the TME in terms of glucose metabolism,lipid metabolism,and amino acid metabolism through exosomes;and provide an overview of the diagnostic and therapeutic potential of exosomes.A better understanding of tumor metabolism would provide a broader perspective about the mechanisms underlying tumor pathology and would facilitate the search for therapeutic targets and guide more individualized tumor treatment.

Evaluation of brain tumor metabolism with [^(11)C] choline PET and ~1H-MRS.

BACKGROUND:The signal of choline containing compounds（Cho）in proton magnetic resonance spectroscopy（1H-MRS）is elevated in brain tumors.[11C]choline uptake as assessed using positron emission tomography（PET）has also been suggested to be higher in brain tumors than in the normal brain.We examined whetherquantitative analysis of choline accumulation and content using these 1wo novel techniques would be helpful innon-invasive,preoperative evaluation of suspected brain tumors and tumor malignancy grade.METHODS:12patients with suspected brain tumor were studied using[11C]choline PET,gadolinium enhanced 3-D magneticresonance imaging and1H-MRS prior to diagnostic biopsy or resection.Eleven normal subjects served as

Nuclear Magnetic Resonance technique in tumor metabolism

Cancer is one of the most serious diseases that cause an enormous number of deaths all over the world.Tumor metabolism has great discrimination from that of normal tissues.Exploring the tumor metabolism may be one of the best ways to find biomarkers for cancer detection,diagnosis and to provide novel insights into internal physiological state where subtle changes may happen in metabolite concentrations.Nuclear Magnetic Resonance(NMR)technique nowadays is a popular tool to analyze cell extracts,tissues and biological fluids,etc,since it is a relatively fast and an accurate technique to supply abundant biochemical information at molecular levels for tumor research.In this review,approaches in tumor metabolism are discussed,including sample collection,data profiling and multivariate data analysis methods etc.Some typical applications of NMR are also summarized in tumor metabolism.

Proteins moonlighting in tumor metabolism and epigenetics

Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment.High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells.To respond to nutrient stress and to meet the requirements for rapid cell proliferation,cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis.Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes.The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

Prognostic value of metabolic tumor burden in lung cancer

Accurate prognosis in patients with lung cancer is important for clinical decision making and treatment selection. The TNM staging system is currently the main method for establishing prognosis. Using this system, patients are grouped into one of four stages based on primary tumor extent, nodal disease, and distant metastases. However, each stage represents a range of disease extent and may not on its own be the best reflection of individual patient prognosis. 18F-fluorodeoxyglucose_positron emission tomography （18F-FDG-PET） can be used to evaluate the metabolic tumor burden affecting the whole body with measures such as metabolic rumor volume （MTV） and total lesion glycolysis （TLG）. MTV and TLG have been shown to be significant prognostic factors in patients with lung cancer, independent of TNM stage. These metabolic tumor burden measures have the potential to make lung cancer staging and prognostication more accurate and quantitative, with the goal of optimizing treatment choices and outcome predictions.

Incorporation of circulating tumor cells and whole-body metabolic tumor volume of 18F-FDG PET/CT improves prediction of outcome inⅢB stage small-cell lung cancer

Objective: We investigated the correlation between the number of circulating tumor cells(CTCs) and wholebody metabolic tumor volume(WBMTV) measured by 18 F-fluorodeoxyglucose(FDG) positron emission tomography/computed tomography(PET/CT).The aim was to evaluate the value of the incorporation of CTC number and WBMTV in the prognostic prediction of stage III small-cell lung cancer(SCLC).Methods: One hundred and twenty-nine patients were enrolled in this study.All patients were treated with four cycles of a platinum-based regimen and concurrent chest irradiation,followed by prophylactic cranial irradiation.Blood samples for CTC analysis were obtained from 112 patients before the initiation of chemotherapy(as a baseline),after cycle 1 and after cycle 4.CTCs were measured using the CELLSEARCH? system.The patients underwent pretreatment FDG PET/CT WBMTV,which included all malignant lesions.The Spearman rank test was used to determine the correlation among CTC counts,WBMTV and disease stage.Overall survival(OS) and progression-free survival(PFS) curves were produced using the Kaplan-Meier method,and survival differences between groups were assessed by the log-rank test.Results: The number of CTCs at baseline did not correlate with WBMTV before the initiation of therapy(P=0.241).The number of CTCs at baseline and the WBMTV before the initiation of therapy were independent relevant factors for PFS and OS.The subgroup analysis(Group A: CTC count >19.5 and a WBMTV >266.5cm~3;Group B: CTC count >19.5 and a WBMTV ≤266.5cm~3; Group C: CTC count ≤19.5 and a WBMTV >266.5cm~3;Group D: CTC count ≤19.5 and a WBMTV ≤266.5cm~3) showed that the differences were statistically significant in the median PFS(Group A vs.D,P<0.001; Group B vs.D,P=0.018; Group C vs.D,P=0.029) and in the median OS(Group A vs.D,P<0.001; Group B vs.D,P=0.012).Conclusions: CTC number and WBMTV are related to progression and death in patients with SCLC.The incorporation of CTC number and WBMTV scans can provide a detailed prognostic prediction for SCLC.

Value of metabolic parameters in distinguishing primary mediastinal lymphomas from thymic epithelial tumors

Objective:A high rate of unnecessary thymectomies has been reported.This study aimed to distinguish primary mediastinal lymphomas(PMLs)from thymic epithelial tumors(TETs)by evaluating volumetric and metabolic parameters with l8F-FDG PET/CT.Methods:A total of 136 patients who were pathologically diagnosed with TETs or PMLs were enrolled,and 18F-FDG PET/CT was performed before therapy.Volumetric parameters,including the mean SUV(SUVmean),metabolic tumor volume(MTV),total lesion glycolysis(TLG),and SUVmax,were determined and compared between the 2 subtypes.The diagnostic performance of these parameters was evaluated with receiver operating characteristic(ROC)curve analysis.Results:All parameters significantly differed between patients with PMLs and TETs.Patients with lymphomas were younger and had higher SUVmean,SUVmax,TLG,and MTV values than patients with TETs.The MTV and TLG values had similar diagnostic performance.ROC analysis indicated that the areas under the curves of the SUVmean and SUVmax values performed similarly(approximately 0.76)in differentiating patients with PMLs from TETs,and both values were better than the MTV and TLG values.When age was included with the SUVmax in differentiating TETs from PMLs,the AUC was 0.91,and the sensitivity and specificity increased to 80%and 93%,respectively.Conclusions:The SUVmax and volumetric parameters of 18F-FDG PET/CT can be used to distinguish patients with PMLs versus TETs,and thus may aid in preventing unnecessary thymectomies or other invasive operations.

Applied Value of Monitoring Serum Hepcidin in Differential Diagnosis of Infection versus Tumor Fevers

The applied value of serum hepcidin in differential diagnosis of infection fevers versus tumor fevers was explored.A total of 432 fever patients were selected according to the domestic fever of unknown origin（FUO） diagnostic criteria from our hospital between June 2010 and November 2013.Venous blood samples were taken on the day 1,5,10 after admission.The infection group（98 cases） and the tumor group（50 cases） were set up based on the clinical and laboratory findings.ELISA was used to determine the serum hepcidin and IL-6 levels.SPSS 13.0 was used for statistical analysis.Hepcidin showed obvious descending trend on the 10 th day in both the bacterial infection group（66 cases） and the virus infection group（32 cases）,and the descending trend was similar to that of inflammatory indexes such as procalcitonin（PCT）,hypersensitive C-reactive protein（h-CRP）,erythrocyte sedimentation rate（ESR）,white blood cell（WBC）,and ferritin.Serum hepcidin showed no obvious differences in the tumor group on the day 1,5,10 after admission.In the infection groups,serum hepcidin was positively correlated with IL-6（r=0.687,P=0.000） and CRP（r=0.487,P=0.026）,but had a poor correlation with blood sedimentation,ferritin,PCT and WBC（P〉0.05）.Monitoring dynamic changes of hepcidin and related inflammatory factors in patients with fever is expected to be used for clinical identification of infection fever and tumor fever.

Prognostic Value of Semi-Quantitative 18F-FDG PET/CT Parameters in Hodgkin’s Lymphoma

Objective:To assess the prognostic value of maximum standardized uptake value(SUVmax),metabolic tumor volume(MTV),and total lesion glycolysis(TLG)determined by 18F-fluorodeoxyglucose positron emission tomography-computed tomography(18F-FDG PET/CT)imaging in Hodgkin’s lymphoma patients.Methods:A total of 148 Hodgkin’s lymphoma patients diagnosed with lymph node biopsy from October 2014 to October 2015 were retrospectively analyzed followed by categorizing into good(125 cases)and poor(23 cases)prognosis groups.The chi-squared test was used to analyze the clinicopathological characteristics of Hodgkin’s lymphoma patients with the semi-quantitative 18F-FDG PET/CT parameters;the Spearman method was used to analyze the correlation between the semi-quantitative parameters and clinicopathological features of Hodgkin’s lymphoma;receiver operating characteristic curve was used to analyze the predictive value of the semi-quantitative parameters for poor prognosis of Hodgkin’s lymphoma patients.Results:Mean SUVmax,MTV,and TLG of the 148 cases of Hodgkin’s lymphoma were 7.26±2.38,12.46±3.14 cm3,and 76.83±18.56 g,respectively.Significant variations in the Ann Arbor stage and clinical classification were observed with different levels of semi-quantitative parameters(P<0.05).The semi-quantitative parameters were not correlated with age and gender(P>0.05)but positively correlated with Ann Arbor stage and clinical classification(P<0.05).These parameters in the poor prognosis group were higher than those in the good prognosis group(P<0.05).The area under the curve(AUC)of SUVmax,MTV,and TLG in predicting the poor prognosis group was 0.881,0.875,and 0.838,with cut-off values of 7.264,12.898 cm3,and 74.580g,as well as specificity of 88.8%,84.0%,and 78.4%,and sensitivity of 87.0%,87.0%,and 78.3%,respectively;the AUC of the combined prediction was 0.986,with a specificity of 97.6%and sensitivity of 86.3%.Conclusion:The semi-quantitative 18F-FDG PET/CT parameters provide valuable insights for Hodgkin’s lymphoma prognosis assessment.

CHOP THER APY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS

We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival.The redox state can be imaged by the redox scanner that collects the fuorescence signals from both the oxidized-fAavoproteins(Fp)and the reduced form of nicotinamide adenine dinucleotide(NADH)in snap frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses.Here,with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B.cell lymphoma cell line(DLCL2).The mice were treated with CHOP therapy,i.e,cyclophosphamide(C)+hydroxydoxorubicin(H)+Oncovin(O)+prednisone(P)with CHO administration on day 1 and prednisone administration on days 1-5.The Fp content of the treated group was significantly decreased(p=0.033)on day 5,and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group(p=0.048).The decrease of the Fp heterogeneity(measured by the mean st andard deviation)had a border-line statistical significance(p=0.071).The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.

Overexpression of AMPD2 indicates poor prognosis in colorectal cancer patients via the Notch3 signaling pathway

BACKGROUND AMPD2 is a critical enzyme catalyzing smooth muscle energy supply and metabolism;however,its cellular biological function and clinical implication in colorectal cancer(CRC)are largely unknown.AIM To clarify the role of AMPD2 in CRC and study the pathway and prognostic value of its role.METHODS AMPD2 expression was analyzed by integrated bioinformatics analysis based on TCGA data sets and immunohistochemistry in tissue microarrays,and the correlation between AMPD2 expression and clinicopathological parameters,Notch3 expression,and prognostic features was assessed.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were then performed to investigate the regulatory pathway involved.The effects of AMPD2 expression on CRC cells and Notch3 protein expression were investigated by downregulation and overexpression of AMPD2.RESULTS AMPD2 mRNA was significantly overexpressed in tumor tissue when compared with normal tissue in a cohort of the TCGA-COAD data set.Biological function enrichment analysis indicated that the Notch pathway strongly correlated with AMPD2 expression,and that the expression of Notch3 and JAG2 mRNA was positively associated with AMPD2 in CRC tissues.In vitro,AMPD2 overexpression markedly reduced Notch3 protein expression in CRC cells,while knockdown of AMPD2 showed the opposite findings.In addition,protein expression was significantly up-regulated in our CRC cohort as indicated by tissue microarray analysis.High expression of AMPD2 protein correlated with advanced depth of tumor and poor differentiation.Furthermore,high AMPD2 expression in CRC tissues was an indicator of poor outcome for CRC patients.CONCLUSION AMPD2 is commonly overexpressed in CRC,and acts as a metabolism oncogene to induce CRC progression through the Notch signaling pathway.Thus,AMPD2 may be a novel prognostic biomarker for CRC.

The role of glutamine metabolism in castration-resistant prostate cancer

Reprogramming of metabolism is a hallmark of tumors,which has been explored for therapeutic purposes.Prostate cancer(PCa),particularly advanced and therapy-resistant PCa,displays unique metabolic properties.Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes.Among the many nutrients,glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa.In addition to amino acid metabolism,glutamine is also widely involved in the synthesis of other macromolecules and biomasses.Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients.This review summarizes the metabolic landscape of PCa,with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa,and suggests novel therapeutic strategies.

A metabolic acidity-activatable calcium phosphate probe with fluorescence signal amplification capabilities for non-invasive imaging of tumor malignancy

Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer.Tumor cells,which are characterized by abnormal glycolysis,exhibit a lower extracellular pH(6.5–7.0)than nor-mal tissues(7.2–7.4),providing a promising target for tumor-specific imaging and therapy.However,most pH-sensitive materials are unable to distinguish such a subtle pH difference owing to their wide and continuous pH-responsive range.In this study,we developed an efficient strategy for the fabrication of a tumor metabolic acidity-activatable calcium phosphate(CaP)fluorescent probe(termed MACaP9).Unlike traditional CaP-based biomedical nanomaterials,which only work within more acidic organelles,such as endosomes and lysosomes(pH 4.0–6.0),MACaP9 could not only specifically respond to the tumor extra-cellular pH but also rapidly convert pH variations into a distinct fluorescence signal to visually dis-tinguish tumor from normal tissues.The superior sensitivity and specificity of MACaP9 enabled high-contrast visualization of a broad range of tumors,as well as small tumor lesions.

Self-shrinking supramolecular nanoparticles syndicate energy suppression and NIR-II mild photothermal amplification of mitochondrial oxidative stress for breast cancer therapy

Photothermal therapy(PTT)may lead to healthy tissue damage,tumor metastasis,and recurrence,which makes mild photothermal therapy(mild PTT)stand out.However,overcoming heat resistance,insufficient therapeutic effect,and poor photothermal conversion efficiency has become new challenge.Herein,we report a dynamic supramolecular nanocarrier formed from amide-sericin and aldehyde-polyhydroxy glucan(denoted as SDA),the loose cavity of which can be filled by using the pharmaceutical combination of lonidamine(LND)and NIR-II photothermal agent of IR-1061,producing SDLI with a tighter inner hole,smaller and uniform particle size and excellent stability due to multiple pulling forces.Moreover,the intricate internal network structure prevents the hydrophobic IR-1061 from forming aggregates in the small cavity,and the photothermal conversion efficiency(PCE)can reach 48.9%.At the acidic tumor microenvironment of pH 6.5,the controlled release of LND can solve the problem of heat resistance of NIR-II mild PTT and significantly improve the therapeutic effect of NIR-II mild PTT.Meanwhile,SDLI also shows a reasonable tumor inhibition rate,so the synergistic strategy of inhibiting tumor energy metabolism and NIR-II mild PTT to magnify mitochondrial oxidative stress,continuous cell stress state-induced immunogenic cell death to promote the induction of tumor apoptosis is proposed to achieve more effective cancer treatment.

Review of pharmacological inhibition of thyroid cancer metabolism

Thyroid cancer(TC)is the most common malignancy of the endocrine system and has been rapidly increasing in incidence over the past few decades.Aggressive TCs metastasize quickly and often levy poor prognoses,as they are frequently resistant to first-line treatment options.Patients diagnosed with aggressive,dedifferentiated TC have a prognosis of under a year with the most current treatment modalities.Like many cancers,TCs also exhibit altered cell metabolism,which enhances the cell’s ability to generate energy,protect against reactive oxygen species,and synthesize macromolecules such as lipids,proteins,and nucleotides for proliferation.Genetic and enzyme profiling of TC tissues and cell lines have uncovered several dysregulated metabolic pathways such as glycolysis,the pentose phosphate pathway,glutamine metabolism,and pyrimidine synthesis.These aberrations are most often due to overexpression of rate-limiting enzymes or metabolite transporters.Metabolic pathways pose attractive therapeutic targets in aggressive TC and may serve to work in tandem with standard therapeutics such as kinase inhibitors depending on the genetic,metabolic,and signaling backgrounds of individual tumors.Further studies are needed to clearly delineate altered metabolic targets across TC subtypes for implementing therapeutic metabolic inhibitors that have shown success in other aggressive tumors.

An update on the molecular biology of glioblastoma,with clinical implications and progress in its treatment

Glioblastoma multiforme(GBM)is the most aggressive and common malig-nant primary brain tumor.Patients with GBM often have poor prognoses,with a median survival of∼15 months.Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications,the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system.This review aims to give a panoramic view of the last 3 years’findings in glioblastoma characterization,its heterogeneity,and current advances in its treatment.Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients,including epigenetic,genetic,transcriptomic and metabolic features,as well as age-and sex-related patterns and the involvement of several noncoding RNAs in glioblastoma progression.Astrocyte-like neural stem cells and outer radial glial-like cells from the subven-tricular zone have been proposed as agents involved in GBM of IDH-wildtype origin,but this remains controversial.Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway,promotion of the gly-colytic flux,maintenance of lipid storage,and other features.This metabolism also contributes to glioblastoma’s resistance to conventional therapies.Tumor heterogeneity,a hallmark of GBM,has been shown to affect the genetic expresion,modulation of metabolic pathways,and immune system evasion.GBM’s aggressive invasion potential is modulated by cell-to-cell crosstalk within the tumor microenvironment and altered expressions of specific genes,such as ANXA2,GBP2,FN1,PHIP,and GLUT3.Nevertheless,the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy.Immunotherapy is still relevant for research purposes,given the amount of ongoing clinical trials based on this strategy to treat GBM,and neoantigen and nucleic acid-based vaccines are gaining importance due to their antitumoral activity by inducing the immune response.Furthermore,there are clinical trials focused on the PI3K/Akt/mTOR axis,angiogenesis,and tumor heterogeneity for developing molecular-targeted therapies against GBM.Other strategies,such as nanodelivery and computational models,may improve the drug pharmacokinetics and the prognosis of patients with GBM.

Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China

Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(mIDH2),which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate(2-HG),resulting in poor prognosis.Thus,global institutions have been working to develop mIDH2 inhibitors.SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised.We have conducted a comprehensive study on its pharmacodynamics,pharmacokinetics and safety.First,SH1573 exhibited a strong selective inhibition of mIDH2 R140 Q protein,which could effectively reduce the production of 2-HG in cell lines,serum and tumors of an animal model.It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models.Then,it was confirmed that SH1573 possessed characteristics of high bioavailability,good metabolic stability and wide tissue distribution.Finally,toxicological data showed that SH1573 had no effects on the respiratory system,cardiovascular system and nervous system,and was genetically safe.This research successfully promoted the approval of SH1573 for clinical trials(CTR20200247).All experiments demonstrated that,as a potential drug against mIDH2 R140 Q acute myeloid leukaemia,SH1573 was effective and safe.

The 150 most important questions in cancer research and clinical oncology series: questions 86-93

Since the beginning of 2017,Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology,which spark diverse thoughts,interesting communications,and potential collabora-tions among researchers all over the world.In this article,8 more questions are presented as follows.Question 86.In which circumstances is good supportive care associated with a survival advantage in patients with cancer?Question 87.Can we develop animal models to mimic immunotherapy response of cancer patients?Question 88.What are the mechanisms underlying hepatitis B virus-associated non-hepatocellular cancers?Question 89.Can we more pre-cisely target tumor metabolism by identifying individual patients who would benefit from the treatment?Question 90.What type of cranial irradiation-based prophylactic therapy combination can dramatically improve the survival of patients with extensive small-cell lung cancer?Question 91.How can postoperative radiotherapy prolong overall survival of the patients with resected pIIIA-N2 non-small cell lung cancer?Question 92.What are the key molecular events that drive oral leukoplakia or erythroplakia into oral cancer?Question 93.How could we track the chemothera-peutics-driven evolution of tumor genome in non-small cell lung cancer for more effective treatment?