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

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World Journal of Gastrointestinal Surgery 2024年第2期16卷 357-381页

作者： Zhi-Ren Chen Mei-Fang Yang Zhi-Yuan Xie Pei-An Wang Liang Zhang Ze-Hua Huang Yao Luo Department of Science and Education Xuzhou Medical UniversityXuzhou Clinical CollegeXuzhou 221000Jiangsu ProvinceChina Department of Neurology Xuzhou Medical UniversityXuzhou 221000Jiangsu ProvinceChina Department of Neurology Clinical LaboratoryGastrointestinal SurgeryCentral Hospital of XuzhouCentral Hospital of XuzhouXuzhou 221000Jiangsu ProvinceChina Department of Public Health Xuzhou Central HospitalXuzhou 221000Jiangsu ProvinceChina Department of Gastroenterology Xuzhou Centre HospitalXuzhou 221000Jiangsu ProvinceChina Department of Public Health Xuzhou Medical UniversityXuzhou 221000Jiangsu ProvinceChina

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(Pmetastasis,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(rel

关键词： Gastric cancer lung metastasis Nomograms Surveillance Epidemiology Surveillance epidemiology and end results program database Overall survival Prognosis

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

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2039-2056页

作者： Pei Yu Yubao Han Lulu Meng Yanyuan Tian Zhiwei Jin Jun Luo Chao Han Wenjun Xu Lingyi Kong Chao Zhang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Bioactive Natural Product ResearchSchool of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 211198China

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.

关键词： lung–bone transmission miR-194/215 cluster Exosome lung metastasis Epithelial–mesenchymal transition Vasculogenic mimicry Bioengineered exosome mimetics Osteosarcoma

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

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2905-2922页

作者： Peilu Song Fan Zhao Dahong Li Jiqiang Qu Miao Yao Yuan Su Hanxun Wang Miaomiao Zhou Yujie Wang Yinli Gao Feng Li Dongmei Zhao Fengjiao Zhang Yu Rao Mingyu Xia Haitao Li Jian Wang Maosheng Cheng Key Laboratory of Structure-Based Drug Design&Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China MOE Key Laboratory of Protein Sciences School of Pharmaceutical SciencesMOE Key Laboratory of Bioorganic Phosphorus Chemistry Chemical BiologyTsinghua UniversityBeijing 100084China MOE Key Laboratory of Protein Sciences Beijing Advanced Innovation Center for Structural BiologyTsinghua-Peking Joint Center for Life SciencesSchool of Life Sciences and School of MedicineTsinghua UniversityBeijing 100084China School of Traditional Chinese Materia Medica Shenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShengyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Department of Cell Biology Key Laboratory of Cell BiologyMinistry of Public Healthand Key Laboratory of Medical Cell BiologyMinistry of EducationChina Medical UniversityShenyang 110001China

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).

关键词： Anti-cancer PAK4 inhibitor Kinase selectivity Cocrystallization lung metastasis EMT

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

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Chinese Journal of Cancer Research 2023年第1期35卷 66-80页

作者： Huigang Li Zuyuan Lin Jianyong Zhuo Modan Yang Wei Shen Zhihang Hu Yichen Ding Hao Chen Chiyu He Xinyu Yang Siyi Dong Xuyong Wei Beicheng Sun Shusen Zheng Ren Lang Di Lu Xiao Xu Zhejiang University School of Medicine Hangzhou 310058China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou 310006China The Institute for Organ Repair and Regenerative Medicine of Hangzhou Hangzhou 310006China Institute of Organ Transplantation Zhejiang UniversityHangzhou 310003China National Center for Healthcare Quality Management in Liver Transplant Hangzhou 310003China Department of Hepatobiliary Surgery the Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhou 311112China NHC Key Laboratory of Combined Multi-organ Transplantation Hangzhou 31003China Department of Hepatobiliary Surgery Beijing Chaoyang Hospital Affiliated to Capital Medical UniversityBeijing 100020China

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(Plung metastasis(hazard ratio:1.146;Plung 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.

关键词： lung metastasis hepatocellular carcinoma liver transplantation nomogram

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

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World Journal of Clinical Oncology 2023年第10期14卷 420-439页

作者： Zhi-Guang Huang Yi Chen Tong Wu Bin-Tong Yin Xiao Feng Sheng-Hua Li Dong-Ming Li Gang Chen Ji-Wen Cheng Juan He Department of Pathology First Affiliated Hospital of Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina Department of Radiology First Affiliated Hospital of Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina Department of Urology First Affiliated Hospital of Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina

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.

关键词： Prostate cancer lung metastasis Chemotherapy Immunotherapy Bibliometric analysis Enrichment analysis

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Downregulation of HNRNPK in human cancer cells inhibits lung metastasis

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Animal Models and Experimental Medicine 2019年第4期2卷 291-296页

作者： Mengyuan Li Wenlong Zhang Xingjiu Yang Hongfei Liu Lin Cao Weisha Li Le Wang Guoxin Zhang Ran Gao Key Laboratory of Human Disease Comparative Medicine(National Health and Family Planning Commission) The Institute of Laboratory Animal ScienceChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingP.R.China Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases BeijingP.R.China

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.

关键词： HNRNPK lung metastasis mouse model

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Palladium nanoplates scotch breast cancer lung metastasis by constraining epithelial-mesenchymal transition

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National Science Review 2021年第7期8卷 124-136页

作者： Shunhao Wang Jingchao Li Mei Chen Liting Ren Wenya Feng Lining Xu Xiaolan Chen Tian Xia Nanfeng Zheng Sijin Liu State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental Sciences Chinese Academy of Sciences University of Chinese Academy of Sciences State Key Laboratory for Physical Chemistry of Solid Surfaces Collaborative Innovation Center of Chemistry for Energy Materials Department of Chemistry Xiamen University College of Materials Science and Engineering Hunan University Division of Nanomedicine Department of Medicine California Nano Systems Institute University of CaliforniaLos Angeles

metastasis accounts for the majority of cancer deaths in many tumor types including breast cancer.Epithelial-mesenchymal transition(EMT) is the driving force for the occurrence and progression of metastasis, however, no targeted strategies to block the EMT program are currently available to combat metastasis. Diverse engineered nanomaterials(ENMs) have been reported to exert promising anti-cancer effects, however, no ENMs have been designed to target EMT. Palladium(Pd) nanomaterials, a type of ENM, have received substantial attention in nanomedicine due to their favorable photothermal performance for cancer therapeutics. Herein, Pd nanoplates(Pd PL) were found to be preferentially biodistributed to both primary tumors and metastatic tumors. Importantly, Pd PL showed a significant inhibition of lung metastasis with and without near-infrared(NIR) irradiation. Mechanistic investigations revealed that EMT was significantly compromised in breast cancer cells upon the Pd PL treatment, which was partially due to the inhibition of the transforming growth factor-beta(TGF-β) signaling. Strikingly, the Pd PL was found to directly interact with TGF-β proteins to diminish TGF-β functions in activating its downstream signaling, as evidenced by the reduced phosphorylation of Smad2. Notably,TGF-β-independent pathways were also involved in undermining EMT and other important biological processes that are necessary for metastasis. Additionally, NIR irradiation elicited synergistic effects on PdPL-induced inhibition of primary tumors and metastasis. In summary, these results revealed that the Pd PL remarkably curbed metastasis by inhibiting EMT signaling, thereby indicating the promising potential of Pd PL as a therapeutic agent for treating breast cancer metastasis.

关键词： palladium nanoplates tumor targeting lung metastasis epithelial-mesenchymal transition TGF-β

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

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2010年第7期11卷 542-546页

作者： Hwa-chan LEE Fen-fen CHEN Ching-chu LO Chung-jing WANG Wei-chun LO Shi-ping LUH Department of Surgery St. Martin de Porres Hospital Chia-Yi City 60069 Taiwan China 2Department of Emergency Medicine St Martin de Porres Hospital Chia-Yi City 60069 Taiwan China Department of Pathology St. Martin de Porres Hospital Chia- Yi City 60069 Taiwan. China Department of Gastroenterology St. Martin de PorresHospital Chia-Yi City 60069 Taiwan China

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.

关键词： Gastric carcinoma Thyroid metastasis lung metastasis

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

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Acta Pharmaceutica Sinica B 2022年第2期12卷 939-951页

作者： Yan Yan Cancan Du Xixi Duan Xiaohan Yao Jiajia Wan Ziming Jiang Zhongyu Qin Wenqing Li Longze Pan Zhuoyu Gu Fazhan Wang Ming Wang Zhihai Qin Medical Research Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Academy of Medical Sciences Zhengzhou UniversityZhengzhou 450052China Department of Urology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Changzhi Medical College Changzhi 046000China Institute of Biophysics Chinese Academy of SciencesBeijing 100101China

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.

关键词： lung metastasis miR-29a-3p CollagenⅠ Liposomal nanovesicle Exosomes Fibroblasts Pre-metastatic niche

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

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Acta Pharmaceutica Sinica B 2021年第10期11卷 3262-3271页

作者： Dan Li Yingli Wang Chang Li Qiu Wang Bingjun Sun Haotian Zhang Zhonggui He Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China

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.

关键词： Cell-cell junctions Digoxin Doxorubicin Homologous targeting Circulating tumor cell clusters Epithelial-mesenchymal transition Breast cancer lung metastasis

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