Risk stratification in gastric cancer lung metastasis: Utilizing an overall survival nomogram and comparing it with previous staging

BACKGROUND Gastric cancer(GC)is prevalent and aggressive,especially when patients have distant lung metastases,which often places patients into advanced stages.By identifying prognostic variables for lung metastasis in GC patients,it may be po-ssible to construct a good prediction model for both overall survival(OS)and the cumulative incidence prediction(CIP)plot of the tumour.AIM To investigate the predictors of GC with lung metastasis(GCLM)to produce nomograms for OS and generate CIP by using cancer-specific survival(CSS)data.METHODS Data from January 2000 to December 2020 involving 1652 patients with GCLM were obtained from the Surveillance,epidemiology,and end results program database.The major observational endpoint was OS;hence,patients were se-parated into training and validation groups.Correlation analysis determined va-rious connections.Univariate and multivariate Cox analyses validated the independent predictive factors.Nomogram distinction and calibration were performed with the time-dependent area under the curve(AUC)and calibration curves.To evaluate the accuracy and clinical usefulness of the nomograms,decision curve analysis(DCA)was performed.The clinical utility of the novel prognostic model was compared to that of the 7th edition of the American Joint Committee on Cancer(AJCC)staging system by utilizing Net Reclassification Improvement(NRI)and Integrated Discrimination Improvement(IDI).Finally,the OS prognostic model and Cox-AJCC risk stratification model modified for the AJCC system were compared.RESULTS For the purpose of creating the OS nomogram,a CIP plot based on CSS was generated.Cox multivariate regression analysis identified eleven significant prognostic factors(P<0.05)related to liver metastasis,bone metastasis,primary site,surgery,regional surgery,treatment sequence,chemotherapy,radiotherapy,positive lymph node count,N staging,and time from diagnosis to treatment.It was clear from the DCA(net benefit>0),time-de-pendent ROC curve(training/validation set AUC>0.7),and calibration curve(reliability slope closer to 45 degrees)results that the OS nomogram demonstrated a high level of predictive efficiency.The OS prediction model(New Model AUC=0.83)also performed much better than the old Cox-AJCC model(AUC difference between the new model and the old model greater than 0)in terms of risk stratification(P<0.0001)and verification using the IDI and NRI.CONCLUSION The OS nomogram for GCLM successfully predicts 1-and 3-year OS.Moreover,this approach can help to ap-propriately classify patients into high-risk and low-risk groups,thereby guiding treatment.

TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma

Objective:Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma(HCC).The precise prediction of post-transplant lung metastasis in the early phase is of great value.Methods:The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways.We enrolled 241 HCC patients who underwent liver transplantation from three centers.Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor(TNF),tumor necrosis factor receptor 1(TNFR1),and TNFR2,particularly for post-transplant lung metastasis.Results:Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC.The expression of TNF was degraded in comparison to that in para-tumor tissues(P<0.001).The expression of key receptors in the TNF-dependent signaling pathway,TNFR1 and TNFR2,was higher in HCC tissues than in para-tumor tissues(P<0.001).TNF and TNFR1 showed no relationship with patients’outcomes,whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival(OS)and increased recurrence risk(5-year OS rate:31.9%vs.62.5%,P<0.001).Notably,elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis(hazard ratio:1.146;P<0.001).Cox regression analysis revealed that TNFR2,Hangzhou criteria,age,and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis,and a novel nomogram was established accordingly.The nomogram achieved excellent prognostic efficiency(area under time-dependent receiver operating characteristic=0.755,concordance-index=0.779)and was superior to conventional models,such as the Milan criteria.Conclusions:TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC.A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.

What should be the future direction of development in the field of prostate cancer with lung metastasis?

BACKGROUND Since the start of the 21st century,prostate cancer with lung metastasis(PCLM)has accumulated significant scientific research output.However,a systematic knowledge framework for PCLM is still lacking.AIM To reconstruct the global knowledge system in the field of PCLM,sort out hot research directions,and provide reference for the clinical and mechanism research of PCLM.METHODS We retrieved 280 high-quality papers from the Web of Science Core Collection and conducted a bibliometric analysis of keywords,publication volume,and citation frequency.Additionally,we selected differentially expressed genes from global high-throughput datasets and performed enrichment analysis and proteinprotein interaction analysis to further summarize and explore the mechanisms of PCLM.RESULTS PCLM has received extensive attention over the past 22 years,but there is an uneven spatial distribution in PCLM research.In the clinical aspect,the treatment of PCLM is mainly based on chemotherapy and immunotherapy,while diagnosis relies on methods such as prostate-specific membrane antigen positron emission tomography/computed tomography.In the basic research aspect,the focus is on cell adhesion molecules and signal transducer and activator of transcription 3,among others.Traditional treatments,such as chemotherapy,remain the mainstay of PCLM treatment,while novel approaches such as immunotherapy have limited effectiveness in PCLM.This study reveals for the first time that pathways related to coronavirus disease 2019,cytokinecytokine receptor interaction,and ribosome are closely associated with PCLM.CONCLUSION Future research should focus on exploring and enhancing mechanisms such as cytokine-cytokine receptor interaction and ribosome and improve existing mechanisms like cadherin binding and cell adhesion molecules.

Downregulation of HNRNPK in human cancer cells inhibits lung metastasis

Background: Lung cancer frequently occurs in the clinic, leading to poor prognosis and high mortality. Markers for early diagnosis of lung cancer are scarce, and further potential therapeutic targets are also urgently needed.Method: We established a new mouse model in which the specific gene HNRNPK(heterogeneous nuclear ribonucleoprotein K) was downregulated after administration of doxycycline. The lung metastatic nodules were investigated using bioluminescence imaging, micro-CT, and autopsy quantification.Results: Compared with the short hairpin negative control group, less lung metastatic nodules were formed in the short hairpin RNA group.Conclusion: Downregulation of HNRNPK in cancer cells can inhibit lung metastasis.

Exosomes derived from pulmonary metastatic sites enhance osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS

Osteosarcoma,a prevalent primary malignant bone tumor,often presents with lung metastases,severely impacting patient survival rates.Extracellular vesicles,particularly exosomes,play a pivotal role in the formation and progression of osteosarcoma-related pulmonary lesions.However,the communication between primary osteosarcoma and exosome-mediated pulmonary lesions remains obscure,with the potential impact of pulmonary metastatic foci on osteosarcoma progression largely unknown.This study unveils an innovative mechanism by which exosomes originating from osteosarcoma pulmonary metastatic sites transport the miR-194/215 cluster to the primary tumor site.This transportation enhances lung metastatic capability by downregulating myristoylated alanine-rich C-kinase substrate(MARCKS)expression.Addressing this phenomenon,in this study we employ cationic bovine serum albumin(CBSA)to form nanoparticles(CBSA-anta-194/215)via electrostatic interaction with antagomir-miR-194/215.These nanoparticles are loaded into nucleic acid-depleted exosomal membrane vesicles(anta-194/215@Exo)targeting osteosarcoma lung metastatic sites.Intervention with bioengineered exosome mimetics(anta-194/215@Exo)not only impedes osteosarcoma progression but also significantly prolongs the lifespan of tumor-bearing mice.These findings suggest that pulmonary metastatic foci-derived exosomes initiate primary osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS,making the miR-194/215 cluster a promising therapeutic target for inhibiting the progression of patients with osteosarcoma lung metastases.

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

The p21 activated kinase 4(PAK4) is serine/threonine protein kinase that is critical for cancer progression.Guided by X-ray crystallography and structure-based optimization,we report a novel subseries of C-3-substituted 6-ethynyl-1 H-indole derivatives that display high potential and specificity towards group Ⅱ PAKs.Among these inhibitors,compound 55 exhibited excellent inhibitory activity and kinase selectivity,displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16.Compound 55 exhibited potent in vivo antitumor metastatic efficacy,with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models,respectively.Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition(EMT).

Efficacy and safety of radiotherapy combined with zoledronic acid in the treatment of lung cancer with bone metastasis: a meta-analysis

Objective: To evaluate the efficacy and safety of radiotherapy combined with zoledronic acid fOr the treatment of bone metastases. Methods: Use Pubmed, Cochrane Library, Embase, CBM, CNKI, Wanfang, Weipu tools to search-related databases at home and abroad. From 2013.1 to March 2019, radiotherapy combined with zoledronic acid and radiotherapy alone for bone metastasis of lung cancer were collected. Experimental studies;quality evaluation and data extraction for each of the included studies, and Cochrane risk bias assessment tools for quality evaluation of the literature. Data processing was performed using RevMan 5.3 and Stata 15.0 software, including risk ratio (OR), 95% CI, I2, and P values. Line sensitivity test, publication bias evaluation is using Egger's, Bgge's method quantitative calculation using Revman 5.3 and Stata 15.0 software for statistical analysis. Results: The total of 8 articles was included, and the number of cases was 703. The results of the meta-analysis showed that the radiotherapy, combined with the zoledronic acid group was effective in the treatment of lung cancer with bone metastasis. The meta-analysis was Z = 6.31 (P < 0.00001), OR (95% CI = 3.57, (2.41, 5.30)), the difference was statistically significant. The combined effect of bone metastases was better than that of the single-stage group. The meta-analysis results were Z = 3.18 (P = 0.001) and OR (95% CI = 3.21, (1.57, 6.59)), indicating the therapeutic effect of the two groups in the treatment of bone metastases. The difference is statistically significant. Adverse reactions include: (1) bone marrow suppression, blood toxicity;(2) fever and rash;(3) nausea, vomiting, and fatigue;(4) liver damage and loss of appetite, meta-analysis results are: bone marrow suppression, blood toxicity: Z =0.73 ( P = 0.47), OR (95% CI = 0.58 (0.13, 2.54));fever, rash: Z = 0.36 (P = 0.36), OR (95% CI = 1.3 (0.31, 5.38));nausea, vomiting, Weakness: Z = 0.29 (P = 0.77), OR (95% CI = 0.85 (0.27, 2.62));liver function damage and loss of appetite: Z = 0.00 (P = 1.00), OR (95% CI = 1.00 (0.17, 6.00)). The P values of the four meta-analyses were all greater than 0.05, and the difference was not statistically significant, indicating that the addition of zoledronic acid to the bone metastasis of lung cancer did not aggravate the changes of the above four adverse reactions. Conclusion: Radiotherapy combined with the zoledronic acid group is better than the single radiotherapy group in treating pain caused by bone metastasis. It can effectively treat bone metastasis and will not aggravate the occurrence of adverse reactions.

Clinical Study of Recombinant Human Endostatin Combined with Iressa in Targeted Treatment of Patients with Lung Adenocarcinoma with Pleural Metastasis

Objective:To evaluate and comprehensively analyze the clinical efficacy of recombinant human endostatin combined with Iressa targeted therapy in patients with pleural metastasis of lung adenocarcinoma.Methods:The interval of the selected study period span was from January 2017 to April 2021.The sample source of the study was 42 patients with lung adenocarcinoma admitted to hospital.The random number table method was used for study grouping,and they were further divided into study groups(n=21,14 cases with pleural metastasis)and control group(n=21,13 cases with pleural metastasis),all patients received systemic chemotherapy with pemetrexed and cisplatin.Patients with pleural metastases in the control group were injected with 60 mg cisplatin into the thoracic cavity.Patients in the study group were treated with Iressa(gefitinib)targeted therapy if genetic testing showed epidermal growth factor receptor(EGRF)mutations,and patients with pleural metastases were treated with pleural metastasis with Endo(recombinant human endostatin YH-16)to control pleural effusion.Two sets of related indicators were compared and analyzed.Results:Comparing the short-term disease control rate,treatment effectiveness and long-term survival rate between the two groups shows that the study group has more advantages(P<0.05).In the comparison between the two groups of serum markers and related indicators,the study group has more advantages(P<0.05),whereas in the comparison between the two groups in the incidence of adverse reactions,there is no significant difference(P>0.05).Based on statistics of the recurrence rate of pleural fluid in the two groups,the study group is significantly lower than the control group(P<0.05).Conclusion:Recombinant human endostatin combined with Iressa targeted therapy for patients with lung adenocarcinoma with pleural metastasis has significant short-term and long-term effects without serious adverse reactions.It can be fully promoted in medical institutions at all levels.

Implication of serum levels of interleukin-18 and nitric oxide in tumor growth and metastasis of non-small cell lung cancer

To study the effect of IL-18 and nitric oxide(NO) on the growth and metastasis of non-small cell lung cancer (NSCLC).Methods Serum IL-18 and nitrate and nitrite levels in 82 patients with NSCLC and 20 healthy control subjects were measured by using ELISA and Griess.Results The levels of serum IL-18 were (334.2±31.0)ng/L in NSCLC patients and (151.3±22.0)ng/L in control subjects,respectively.The levels of nitrate and nitrite were (237.1±21.0)μmol/L in NSCLC patients and (44.2±15.0)μmol/L in control subjects.The levels of serum IL-18 and nitrate and nitrite were not related with age,gender,histological types in patients with NSCLC.The levels of serum IL-18 was closely associated with TNM stage,lymph node metastasis and distal metastasis,but not with its degree and organ types of metastasis.There was a negative correlation between the levels of serum IL-18 and nitrate and nitrite.Conclusion Serum IL-18 and nitrate and nitrite levels may be useful to evaluate the prognosis of the patients with NSCLC.16 refs,2 tabs.

Dietary crocin reverses melanoma metastasis

Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models.However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16 F-10 cells in to C57 BL/6 mice. Metastatic mice treated with two different doses of crocin（250 and 500 μg/kg of bodyweight） for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment. Then blood was collected and serum gamma glutamyl transpeptidase（γ-GGT）, sialic acid,tumor necrosis factor alpha（TNF-a）, interleukin 10（IL-10）, IL-6, IL-2, and TIMP-1 levels were measured. Further, a lung histological examination was done in crocin treated metastatic mice. Subsequently hallmark metastatic parameters such as matrix metalloproteinases（MMPs）, extracellular regulated kinase 2（ERK2）, vascular endothelial growth factor（VEGF）, and K-ras gene expression were investigated in the lungs of crocin treated metastatic mice.Further, in-vitro adhesion, invasion and migration of B16 F-10 cells were examined after 24 hours of crocin（5 and 10μg/mL） treatment. Administration of crocin to tumor bearing C57 BL/6 mice reduced the lung metastasis by 85%.Elevated levels of hydroxyproline, uronic acid, hexosamine, serum sialic acid and y-GGT in metastatic control were found to be significantly reduced in crocin treated mice. Crocin also inhibited expression of MMP-2, MMP-9, ERK-2,K-ras, and VEGF. Crocin reduced the ability of B16 F-10 cells invasion（P〈0.05）, migration（P〈0.05） and adhesion by upregulating E-cadherin expression. In conclusion, crocin elicited marked anti-metastatic potential by regulating the metastasis induced biomarkers.

Mechanisms and anatomical risk factors of pneumothorax after Bevacizumab use:A case report

BACKGROUND Bevacizumab is an antiangiogenic agent,and that synergizes with chemotherapeutic drugs.When used in combination therapies,Bevacizumab is associated with adverse events such as hemorrhage,gastrointestinal perforation,delayed wound healing,and pneumothorax.However,the molecular mechanisms underlying these adverse events are not fully understood.CASE SUMMARY A 45-year-old female with multiple lung metastases that were derived from primary breast cancer,was placed on Bevacizumab+paclitaxel therapy,since this combination has a potent antitumor effect.She reported dyspnea before cycle 3,day 1 and we therefore ran a chest X-ray,which detected a right pneumothorax.The coronal plane computed tomography revealed that one solid mass rapidly necrosed and was replaced by a cavity that passed through the bronchus in the right lower lobe.The cavity eventually ruptured the pleura and made the bronchopleural fistula that led to this pneumothorax.Thoracic cavity drainage using an intercostal catheter was performed.On the 7th day of drainage,the patient was discharged from our hospital on recovery.Recurrence of pneumothorax was not reported,and continuation of chemotherapy was made possible by changing the regimen.CONCLUSION Patients with lung metastases surrounding the bronchi and on the pleura should be monitored for pneumothorax by Bevacizumab-containing chemotherapies.

Case Report:Metastasis of gastric carcinoma to the thyroid and lung:a case report and review of literature

Cancer metastasis to the thyroid is extremely rare. The more commonly reported primary sites for metastasis to the thyroid are the kidney, breast, lung, colon, esophagus, and uterus. Thyroid metastasis from the stomach has only been reported in three cases. Herein, we report a 71-year-old man presenting with bilateral thyroid multinodular lesions. Bilateral near-total thyroidectomy was performed due to airway compression with related symptoms. Wedge resection of a suspicious pulmonary nodule, detected on CT, was performed for diagnosis. Polypoid lesions in the stomach were examined by trans-scopic biopsy. Poorly differentiated adenocarcinomas with the same histological profiles were noted at these three sites. The immunohistochemical staining for thyroglobulin of these specimens was negative. We conclude that a new thyroid mass appearing in a patient with present or prior malignancies should raise the concern of metastatic disease.

Co-delivery of TRAIL and paclitaxel by fibronectin-targeting liposomal nanodisk for effective lung melanoma metastasis treatment

Melanoma is a highly aggressive cancer which often forms metastatic tumors in the lung,leading to sharply reduced patients'survival rate.Effectively treating these tumors thus could improve late stage melanoma with lung metastasis.In this study,we fabricated a Cys-Arg-Glu-Lys-Ala with N-methylated Glu(CR(NMe)EKA)decorated disk shaped nano vehicle to co-deliver tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)and paclitaxel(PTX)to lung melanoma tumor sites(TRAIL-[ND-PTX]^(CR(NMe)EKA)).These nanodisks displayed better tumor-targeting and penetration capability than spherical nanoparticles,while the fibronectin-targeting CR(NMe)EKA motif also increased the tumor accumulation of loaded drugs.The combined usage of TRAIL and PTX both killed tumor cells and reduced local nutrition supply,leading to stronger overall anti-tumor effect.This TRAIL-[ND-PTX]^(CR(NMe)EKA)system performed remarkably better than free paclitaxel and also significantly elongated survival rate of melanoma lung metastasis bearing mice,without displaying significant toxicity.Hence,this designing strategy and the fabricated nanoplatform possess potential for further development.

THE SIGNIFICANCE OF IMMUNO-STAIN WITH HLC_3-AB IN CEREBRAL METASTATIC TUMOR

By using the immunohistochemical technique(ABCmethod), 186 cases of cerebral metastatic tumors labeled with McAb against human lung carcinoma are reported. They were divided into two groups: primary site determined group and undetermined group. In determined group(59 cases) . 33/36 cases( 91. 6 % ) of lung carcinomas showed HLC3 positive reactions, but among 23 cases of other cancers, only two cases showed weak positive reactions.This result indicated that the HLC3 have strong specific reaction to the lung carcinomas. In undetermined group( 127 cases), 68 cases of metastatic tumors reacted to HLC3 positively. In all 186 cases of cerebral metastatic tumor, there were 101 cases( 53. 5%) showing positive reaction to HLC3- AB. Among 125 cases of cerebral metastatic adenocarcinoma, 76 cases( 61 %) showed positive reactions with HLC3-AB. The result in this paper proved that the lung carcinoma was the important primary site of the cerebral metastatic tumor operated neurosurggically. The specifity of McAb HLC3- AB, the incidance of the cerebral metastatic lung carcinoma and its metastatic course were discaussed.

Tumorigenesis and spontaneous metastasis by luciferase-labeled human xenograft osteosarcoma cells in nude mice

Background Osteosarcoma （OS） is the most common primary malignant tumor of bone. Mouse models of human OS can invariably provide greater insight into the complex mechanisms that underlie the development and pathogenesis of this aggressive tumor. Bioluminescence technology favored tracing cancer cells in vivo. In this study, an OS model was described and evaluated using human OS cell line, Saos2, labeled with luciferase （Saos2-1uc）. Methods Saos2 cells were infected by lentivirus loading a firefly luciferase gene. Luciferase expression of Saos2-1uc cells was characterized both in vitro and in vivo. Specific biologic and oncologic features of Saos2-1uc cells were analyzed. The OS was established as orthotopic xenografts in nude mice. Both orthotopic tumors and spontaneous lung metastasis were analyzed. Results Tumorigenesis and spontaneous lung metastasis in nude mice could be monitored in vivo through in vivo imaging system. The enhancement in proliferation, migration and invasion abilities and the attenuation in adhesion ability were observed in Saos2-1uc cells compared with Saos2 cells. Furthermore, there were the up-regulation of Osteocalcin, CCRIO, CXCR1 and ID1 and the down-regulation of ALP, collagen I, CCR1, CCR3, CXCR3, NID and N-cadherin in Saos2-1uc cells compare to Saos2 cells. The rate of spontaneous lung metastasis in Saos2-1uc cells was higher than that in Saos2 cells, although without significant difference. Conclusions Lentivirus transfection may cause alteration of gene expression profiles and further biological functions. This model can be used in the elucidation of molecular mechanisms of tumorigenesis and the screening of new therapeutic agents.

Inhibiting collagen Ⅰ production and tumor cell colonization in the lung via miR-29a-3p loading of exosome-/liposome-based nanovesicles

The lung is one of the most common sites for cancer metastasis.Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells.Therefore,down-regulating the production of collagens may contribute to the inhibition of lung metastasis.It has been suggested that mi R-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens.Indeed,our clinical lung tumor data shows that mi R-29 a-3 p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients’outcomes.However,suitable carriers need to be selected to deliver this therapeutic mi RNA to the lungs.In this study,we found that the chemotherapy drug cisplatin facilitated mi R-29 a-3 p accumulation in the exosomes of lung tumor cells,and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation.To scale up the preparation and simplify the delivery system,we designed a lung-targeting liposomal nanovesicle(by adjusting the molar ratio of DOTAP/cholesterol-mi RNAs to 4:1)to carry mi R-29 a-3 p and mimic the exosomes.This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo,thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.

Cancer-specific calcium nanoregulator suppressing the generation and circulation of circulating tumor cell clusters for enhanced anti-metastasis combinational chemotherapy

Tumor metastasis is responsible for chemotherapeutic failure and cancer-related death.Moreover,circulating tumor cell(CTC)clusters play a pivotal role in tumor metastasis.Herein,we develop cancer-specific calcium nanoregulators to suppress the generation and circulation of CTC clusters by cancer membrane-coated digoxin(DIG)and doxorubicin(DOX)co-encapsulated PLGA nanoparticles(CPDDs).CPDDs could precisely target the homologous primary tumor cells and CTC clusters in blood and lymphatic circulation.Intriguingly,CPDDs induce the accumulation of intracellular Ca^(2+) by inhibiting Na^(+)/K^(+)-ATPase,which help restrain cellecell junctions to disaggregate CTC clusters.Meanwhile,CPDDs suppress the epithelialemesenchymal transition(EMT)process,resulting in inhibiting tumor cells escape from the primary site.Moreover,the combination of DOX and DIG at a mass ratio of 5:1 synergistically induces the apoptosis of tumor cells.In vitro and in vivo results demonstrate that CPDDs not only effectively inhibit the generation and circulation of CTC clusters,but also precisely target and eliminate primary tumors.Our findings present a novel approach for anti-metastasis combinational chemotherapy.

ROR2 regulates the survival of murine osteosarcoma cells in lung capillaries

Aim:Lung metastasis is a leading cause of death in patients with osteosarcoma(OS).No effective therapy exists that improves the five-year overall survival rate of OS patients with metastasis.Therefore,finding novel therapeutic targets will help develop new treatment strategies for OS patients with lung metastasis.Methods:Based on analysis of gene expression profiles between sublines of the Dunn OS LM8 cell line with high(LM8-H)and low(LM8-L)metastatic ability,we have identified Wnt signal-related genes that play an important role in lung metastasis of OS.Function of the genes was investigated by establishing sublines of gene knockout and assessing their metastatic ability using a mouse lung metastasis model.The molecular mechanism underlying the function of the genes was further investigated by in vitro experiments.Results:We have identified that receptor tyrosine kinase-like orphan receptor 2(ROR2),a receptor of the non-canonical Wnt signaling pathway,was involved in OS cell survival in lung capillaries during metastasis.LM8-H knocked out of Ror2(H/Ror2-KO)significantly reduced lung metastasis by decreasing the viability in lung capillaries 48 h after intravenous injection.In vitro study revealed that ROR2 increased anoikis resistance through AKT activation.Reconstitution of ROR2 expression in H/Ror2-KO cells restored their metastatic ability and viability in lung capillaries.Conclusion:The results demonstrate a novel ROR2 function in OS lung metastasis and may inform new treatment strategies for OS patients.

Clinical significance of co-expression of VEGF-C and VEGFR-3 in non-small cell lung cancer

Objective To investigate the relationship between vascular endothelial growth factor C (VEGF-C) expression, VEGFR-3 expression, lymphangiogenesis and angiogenesis in human non-small cell lung cancer (NSCLC).Methods Seventy-six NSCLC samples were stained for VEGF-C, VEGFR-3 and CD34 with immunohistochemical methods. Assessment of lymphatic vessel density (LVD) and microvessel density (MVD) was performed. The expressions of VEGF-C in 24 fresh NSCLC samples were determined with Western blot assay.Results Of the 76 NSCLC cases, 55 were VEGF-C positive and 40 were VEGFR-3 positive in cancer cells. A significant positive correlation was found between VEGF-C expression and VEGFR-3 expression in cancer cells (P<0.05). VEGF-C expression was negatively associated with differentiation of tumor cells (P<0.05). VEGF-C expression and VEGFR-3 expression were positively associated with lymph node metastasis and lymphatic invasion (P<0.05). LVD was positively related to VEGF-C expression, lymph node metastasis, lymphatic invasion and clinical stage (P<0.05). There was a significant correlation between LVD and MVD (R=0.732, P<0.05). Patients with positive VEGF-C expression had worse outcomes than those with negative VEGF-C expression (P<0.01).Conclusions In NSCLC, VEGF-C and VEGFR-3 are related to the lymphangiogenesis, angiogenesis, and occurrence and development of lung cancers. VEGF-C expression could be a useful predictor of poor prognosis in NSCLC.

Gold nanorods-mediated efficient synergistic immunotherapy for detection and inhibition of postoperative tumor recurrence

Tumor recurrence after surgery is the main cause of treatment failure.However,the initial stage of recurrence is not easy to detect,and it is difficult to cure in the late stage.In order to improve the life quality of postoperative patients,an efficient synergistic immunotherapy was developed to achieve early diagnosis and treatment of post-surgical tumor recurrence,simultaneously.In this paper,two kinds of theranostic agents based on gold nanorods(AuNRs)platform were prepared.AuNRs and quantum dots(QDs)in one agent was used for the detection of carcinoembryonic antigen(CEA),using fluorescence resonance energy transfer(FRET)technology to indicate the occurrence of in situ recurrence,while AuNRs in the other agent was used for photothermal therapy(PTT),together with antiPDL1 mediated immunotherapy to alleviate the process of tumor metastasis.A series of assays indicated that this synergistic immunotherapy could induce tumor cell death and the increased generation of CD3;/CD4;T-lymphocytes and CD3+;CD8;T-lymphocytes.Besides,more immune factors(IL-2,IL-6,and IFN-γ)produced by synergistic immunotherapy were secreted than mono-immunotherapy.This cooperative immunotherapy strategy could be utilized for diagnosis and treatment of postoperative tumor recurrence at the same time,providing a new perspective for basic and clinical research.