BACKGROUND Colorectal cancer(CRC) is a common malignant tumor. Alcohol consumption is positively correlated with CRC malignant metastasis;however, the mechanism is unclear. The interaction between laminin-γ2(LAMC2) a...BACKGROUND Colorectal cancer(CRC) is a common malignant tumor. Alcohol consumption is positively correlated with CRC malignant metastasis;however, the mechanism is unclear. The interaction between laminin-γ2(LAMC2) and integrin-β1(ITGB1) plays a role in premetastatic niche signaling, which may induce epithelial mesenchymal transformation(EMT) and lead to metastasis.AIM To investigate the effects of alcohol on CRC metastasis from the molecular mechanism of the premetastatic niche.METHODS The interaction between LAMC2 and ITGB1 was measured by Duolink assay, and the expression levels of LAMC2, ITGB1 and focal adhesion kinase(FAK), snail, fibronectin, N-cadherin and special AT-rich sequence binding protein 1(SATB1) were measured by quantitative real-time polymerase chain reaction, immunohistochemistry and western blotting. Interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α) and IL-6 levels were measured via enzyme-linked immunosorbent assay, histopathological assessment via hematoxylin eosin staining, and determination of aberrant crypt foci via methylene blue.RESULTS The lymph node metastasis rate was higher in the alcohol group than non-alcohol group. There was a significant increase in interaction signals between LAMC2 and ITGB1, and an increase in phosphorylate-FAK/FAK, snail, fibronectin, N-cadherin and SATB1, whereas E-cadherin was reduced in the alcohol group compared to the non-alcohol group in both animal and clinical samples. Serum IL-1β, TNF-α and IL-6 were higher in alcohol group than in non-alcohol group. Alcohol may promote CRC metastasis by influencing the molecular mechanism of the premetastatic niche.CONCLUSION Our study suggests that alcohol promotes EMT-mediated premetastatic niche formation of CRC by activating the early interaction between LAMC2 and ITGB1 and lead to CRC metastasis.展开更多
The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,whic...The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,which is becoming increasingly important.At present,there is a lack of in-depth understanding of the cellular and molecular characteristics of the PMN.Here,we summarize current research advances on the cellular and molecular characteristics of the PMN.We emphasize that PMN intervention is a potential therapeutic strategy for early prevention of tumor metastasis,which provides a promising basis for future research and clinical application.展开更多
Background:Shuangshen granule s(SSGs) are extensively utilized for the treatment of lung cancer in China and have been reported to possess tumor-protective and anti-metastatic effects.Therefore,it is crucial to unders...Background:Shuangshen granule s(SSGs) are extensively utilized for the treatment of lung cancer in China and have been reported to possess tumor-protective and anti-metastatic effects.Therefore,it is crucial to understand the precise mechanism.Building upon the findings of our previous study,the objective of the present study was to explore the impact of S SGs on the sphingosine-1-phosphate receptor-1(S1PR1)/signal transducer and activator of transcription 3(STAT3) axis,as well as the recruitment of myeloid-derived suppressor cells(MDSCs) during the formation of the premetastatic niches(PMNs).Methods:In a mouse xenograft model utilizing Lewis lung carcinoma(LLC) cells that express green fluorescent protein(GFP),the initiation of lung metastasis was monitored every three days until day 35 following transplantation.Lung metastasis,MD SC recruitment,the expression of PMN and S1PR1/STAT3 axis biomarkers,as well as the blood levels of granulocyte-mac rophage colony-stimulating factor(GM-CSF) and transforming growth factor-β(TGF-β) were assessed in the SSG treatment and control groups.Results:The LLC cells did not reach the lung until 14-17 days following subcutaneous implantation,which was concurrent with the formation of lung PMNs.S SG significantly postponed the initiation of lung metastasis and reduced the recruitment of MDSCs to the lung PMNs.S SG also suppre ssed the S1PR1/STAT3 axis in tumor tissue s,bone marrow,and lung PMNs.Additionally,SSG suppres sed the blood levels of GM-CSF and TGF-β,as well as the PMN markers,matrix metalloproteinase-9 and versican.Conclusion:Our findings suggested that SSG suppressed the development of MD SC-mediated PMNs by inhibiting the S1PR1/STAT3 axis,consequently postponing the initiation of lung metastasis.展开更多
Gastric cancer(GC) is one of the most frequentlydiagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally ...Gastric cancer(GC) is one of the most frequentlydiagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC.展开更多
After reading the review by An et al“Biological factors driving colorectal cancer metastasis”,which covers the problem of the metastasis of colorectal cancer(CRC),I had a desire to discuss with readers one of the ex...After reading the review by An et al“Biological factors driving colorectal cancer metastasis”,which covers the problem of the metastasis of colorectal cancer(CRC),I had a desire to discuss with readers one of the exciting problems associated with dormant metastases.Most deaths from CRCs are caused by metastases,which can be detected both at diagnosis of the primary tumor and several years or even decades after treatment.This is because tumor cells that enter the bloodstream can be destroyed by the immune system,cause metastatic growth,or remain dormant for a long time.Dormant tumor cells may not manifest themselves throughout a person’s life or,after some time and under appropriate conditions,may give rise to the growth of metastases.In this editorial,we will discuss the most important features of dormant metastases and the mechanisms of premetastatic niche formation,as well as factors that contribute to the activation of dormant metastases in CRCs.We will pay special attention to the possible mechanisms involved in the formation of circulating tumor cell complexes and the choice of therapeutic strategies that promote the dormancy or destruction of tumor cells in CRCs.展开更多
Objective:Tumor-derived exosomes(TDEs)play crucial roles in intercellular communication.Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis.Jiedu recipe(JR),a traditional ...Objective:Tumor-derived exosomes(TDEs)play crucial roles in intercellular communication.Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis.Jiedu recipe(JR),a traditional Chinese medicinal formula,has demonstrated efficacy in preventing the metastasis of hepatocellular carcinoma(HCC).However,the underlying mechanism remains largely unknown.Methods:Animal experiments were performed to investigate the metastasis-preventing effects of JR.Bioinformatics analysis and in vitro assays were conducted to explore the potential targets and active components of JR.TDEs were assessed using nanoparticle tracking analysis(NTA)and Western blotting(WB).Exosomes derived from normoxic or hypoxic HCC cells(H-TDEs)were collected to establish premetastatic mouse models.JR was intragastrically administered to evaluate its metastasis-preventive effects.WB and lysosomal staining were performed to investigate the effects of JR on lysosomal function and autophagy.Bioinformatics analysis,WB,NTA,and immunofluorescence staining were used to identify the active components and potential targets of JR.Results:JR effectively inhibited subcutaneous-tumor-promoted lung premetastatic niche development and tumor metastasis.It inhibited the release of exosomes from tumor cells under hypoxic condition.JR treatment promoted both lysosomal acidification and suppressed secretory autophagy,which were dysregulated in hypoxic tumor cells.Quercetin was identified as the active component in JR,and the epidermal growth factor receptor(EGFR)was identified as a potential target.Quercetin inhibited EGFR phosphorylation and promoted the nuclear translocation of transcription factor EB(TFEB).Hypoxia-impaired lysosomal function was restored,and secretory autophagy was alleviated by quercetin treatment.Conclusion:JR suppressed HCC metastasis by inhibiting hypoxia-stimulated exosome release,restoring lysosomal function,and suppressing secretory autophagy.Quercetin acted as a key component of JR and regulated TDE release through EGFR-TFEB signaling.Our study provides a potential strategy for retarding tumor metastasis by targeting H-TDE secretion.展开更多
Despite considerable progresses in cancer treatment,tumor metastasis is still a thorny issue,which leads to majority of cancer-related deaths.In hematogenous metastasis,the concept of"seed and soil"suggests ...Despite considerable progresses in cancer treatment,tumor metastasis is still a thorny issue,which leads to majority of cancer-related deaths.In hematogenous metastasis,the concept of"seed and soil"suggests that the crosstalk between cancer cells(seeds)and premetastatic niche(soil)facilitates tumor metastasis.Considerable efforts have been dedicated to inhibit the tumor metastatic cascade,which is a highly complicated process involving various pathways and biological events.Nonetheless,satisfactory therapeutic outcomes are rarely observed,since it is a great challenge to thwart this multi-phase process.Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis,especially compared with conventional treatment methods,which are limited by serious side effects and poor efficacy.In this review,we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization.Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade,including modulating primary tumor microenvironment,targeting circulating tumor cells,regulating premetastatic niche and eliminating established metastasis.Additionally,we highlighted the multiphase targeted drug delivery systems,which hold a better chance to inhibit metastasis.Besides,we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.展开更多
基金Supported by the National Natural Science Foundation of China,No.81673944
文摘BACKGROUND Colorectal cancer(CRC) is a common malignant tumor. Alcohol consumption is positively correlated with CRC malignant metastasis;however, the mechanism is unclear. The interaction between laminin-γ2(LAMC2) and integrin-β1(ITGB1) plays a role in premetastatic niche signaling, which may induce epithelial mesenchymal transformation(EMT) and lead to metastasis.AIM To investigate the effects of alcohol on CRC metastasis from the molecular mechanism of the premetastatic niche.METHODS The interaction between LAMC2 and ITGB1 was measured by Duolink assay, and the expression levels of LAMC2, ITGB1 and focal adhesion kinase(FAK), snail, fibronectin, N-cadherin and special AT-rich sequence binding protein 1(SATB1) were measured by quantitative real-time polymerase chain reaction, immunohistochemistry and western blotting. Interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α) and IL-6 levels were measured via enzyme-linked immunosorbent assay, histopathological assessment via hematoxylin eosin staining, and determination of aberrant crypt foci via methylene blue.RESULTS The lymph node metastasis rate was higher in the alcohol group than non-alcohol group. There was a significant increase in interaction signals between LAMC2 and ITGB1, and an increase in phosphorylate-FAK/FAK, snail, fibronectin, N-cadherin and SATB1, whereas E-cadherin was reduced in the alcohol group compared to the non-alcohol group in both animal and clinical samples. Serum IL-1β, TNF-α and IL-6 were higher in alcohol group than in non-alcohol group. Alcohol may promote CRC metastasis by influencing the molecular mechanism of the premetastatic niche.CONCLUSION Our study suggests that alcohol promotes EMT-mediated premetastatic niche formation of CRC by activating the early interaction between LAMC2 and ITGB1 and lead to CRC metastasis.
基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-013)the National Key Research and Development Program of China(2021YFF0702801,2022YFF0710705)+1 种基金the Special Research Fund for Central Universities,Peking Union Medical College(No.3332022182)Seed Fund for Youth Talent Training Program of Beijing Tongren Hospital Affiliated to Capital Medical University(2020-YJJ-ZZL-034).
文摘The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,which is becoming increasingly important.At present,there is a lack of in-depth understanding of the cellular and molecular characteristics of the PMN.Here,we summarize current research advances on the cellular and molecular characteristics of the PMN.We emphasize that PMN intervention is a potential therapeutic strategy for early prevention of tumor metastasis,which provides a promising basis for future research and clinical application.
基金supported by the Special Training of Scientific and Technological Talents,China Academy of Chinese Medical Sciences (grant number ZZ13-YQ-023,ZZ13-YQ-028)the National Natural Science Foundation of China(grant number 82174465,82074338,82274609,82104961,82174463)+7 种基金the Beijing Municipal Science and Technology Commission (grant number Z181100001618006)Scientificand Technological Innovation Project of China Academy of Chinese Medical Sciences (grant number CI2021A01810,CI2021A01814,CI2021A01808,CI2021B009)Traditional Chinese Medicine Innovation Team Project of the National Administration of Traditional Chinese Medicine(grant number ZYYCXTD-C-202205)Central High-Level Traditional Chinese Medicine Hospital Clinical Research and Achievement Transformation Capacity Enhancement Project-Special Project Inheriting the Academic Experienceof Renowned Traditional Chinese Medicine Experts(HLCMHPP2023012)China Academy of Chinese Medical Sciences Special Project for Research and Development of Superior Diseases,Hospital Preparations,New Drugs(ZZ15-XY-PT-01)Xu Hang Project for Cultivating Young Top Talents at Guang'anmen Hospital (CZ40908)The Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ17XRZ-023)Clinical Research Expenses of the Central High-level Hospital of Traditional Chinese Medicine (HLCMHPP2023101)
文摘Background:Shuangshen granule s(SSGs) are extensively utilized for the treatment of lung cancer in China and have been reported to possess tumor-protective and anti-metastatic effects.Therefore,it is crucial to understand the precise mechanism.Building upon the findings of our previous study,the objective of the present study was to explore the impact of S SGs on the sphingosine-1-phosphate receptor-1(S1PR1)/signal transducer and activator of transcription 3(STAT3) axis,as well as the recruitment of myeloid-derived suppressor cells(MDSCs) during the formation of the premetastatic niches(PMNs).Methods:In a mouse xenograft model utilizing Lewis lung carcinoma(LLC) cells that express green fluorescent protein(GFP),the initiation of lung metastasis was monitored every three days until day 35 following transplantation.Lung metastasis,MD SC recruitment,the expression of PMN and S1PR1/STAT3 axis biomarkers,as well as the blood levels of granulocyte-mac rophage colony-stimulating factor(GM-CSF) and transforming growth factor-β(TGF-β) were assessed in the SSG treatment and control groups.Results:The LLC cells did not reach the lung until 14-17 days following subcutaneous implantation,which was concurrent with the formation of lung PMNs.S SG significantly postponed the initiation of lung metastasis and reduced the recruitment of MDSCs to the lung PMNs.S SG also suppre ssed the S1PR1/STAT3 axis in tumor tissue s,bone marrow,and lung PMNs.Additionally,SSG suppres sed the blood levels of GM-CSF and TGF-β,as well as the PMN markers,matrix metalloproteinase-9 and versican.Conclusion:Our findings suggested that SSG suppressed the development of MD SC-mediated PMNs by inhibiting the S1PR1/STAT3 axis,consequently postponing the initiation of lung metastasis.
文摘Gastric cancer(GC) is one of the most frequentlydiagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC.
文摘After reading the review by An et al“Biological factors driving colorectal cancer metastasis”,which covers the problem of the metastasis of colorectal cancer(CRC),I had a desire to discuss with readers one of the exciting problems associated with dormant metastases.Most deaths from CRCs are caused by metastases,which can be detected both at diagnosis of the primary tumor and several years or even decades after treatment.This is because tumor cells that enter the bloodstream can be destroyed by the immune system,cause metastatic growth,or remain dormant for a long time.Dormant tumor cells may not manifest themselves throughout a person’s life or,after some time and under appropriate conditions,may give rise to the growth of metastases.In this editorial,we will discuss the most important features of dormant metastases and the mechanisms of premetastatic niche formation,as well as factors that contribute to the activation of dormant metastases in CRCs.We will pay special attention to the possible mechanisms involved in the formation of circulating tumor cell complexes and the choice of therapeutic strategies that promote the dormancy or destruction of tumor cells in CRCs.
基金supported by the grants from National Natural Science Foundation of China(No.82030117,82074203,82170033,and 82374540)Special Fund for Research on Community Medicine and Health Management in Shanghai(No.2023SQ01)+2 种基金Medical Research Project of Health Commission of Shanghai Hongkou District(No.HW2302-43)Special Medical Basic Research Project of the First Affiliated Hospital of Naval Medical University(No.2021JCMS12)Wild Goose Array Project of Zhengzhou Center of Chinese People’s Liberation Army Joint Logistic Support Force。
文摘Objective:Tumor-derived exosomes(TDEs)play crucial roles in intercellular communication.Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis.Jiedu recipe(JR),a traditional Chinese medicinal formula,has demonstrated efficacy in preventing the metastasis of hepatocellular carcinoma(HCC).However,the underlying mechanism remains largely unknown.Methods:Animal experiments were performed to investigate the metastasis-preventing effects of JR.Bioinformatics analysis and in vitro assays were conducted to explore the potential targets and active components of JR.TDEs were assessed using nanoparticle tracking analysis(NTA)and Western blotting(WB).Exosomes derived from normoxic or hypoxic HCC cells(H-TDEs)were collected to establish premetastatic mouse models.JR was intragastrically administered to evaluate its metastasis-preventive effects.WB and lysosomal staining were performed to investigate the effects of JR on lysosomal function and autophagy.Bioinformatics analysis,WB,NTA,and immunofluorescence staining were used to identify the active components and potential targets of JR.Results:JR effectively inhibited subcutaneous-tumor-promoted lung premetastatic niche development and tumor metastasis.It inhibited the release of exosomes from tumor cells under hypoxic condition.JR treatment promoted both lysosomal acidification and suppressed secretory autophagy,which were dysregulated in hypoxic tumor cells.Quercetin was identified as the active component in JR,and the epidermal growth factor receptor(EGFR)was identified as a potential target.Quercetin inhibited EGFR phosphorylation and promoted the nuclear translocation of transcription factor EB(TFEB).Hypoxia-impaired lysosomal function was restored,and secretory autophagy was alleviated by quercetin treatment.Conclusion:JR suppressed HCC metastasis by inhibiting hypoxia-stimulated exosome release,restoring lysosomal function,and suppressing secretory autophagy.Quercetin acted as a key component of JR and regulated TDE release through EGFR-TFEB signaling.Our study provides a potential strategy for retarding tumor metastasis by targeting H-TDE secretion.
基金the financial support of the National Natural Science Foundation of China(Nos.81690261 and 81974499)Sichuan Science and Technology Program(2018RZ0136,China)
文摘Despite considerable progresses in cancer treatment,tumor metastasis is still a thorny issue,which leads to majority of cancer-related deaths.In hematogenous metastasis,the concept of"seed and soil"suggests that the crosstalk between cancer cells(seeds)and premetastatic niche(soil)facilitates tumor metastasis.Considerable efforts have been dedicated to inhibit the tumor metastatic cascade,which is a highly complicated process involving various pathways and biological events.Nonetheless,satisfactory therapeutic outcomes are rarely observed,since it is a great challenge to thwart this multi-phase process.Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis,especially compared with conventional treatment methods,which are limited by serious side effects and poor efficacy.In this review,we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization.Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade,including modulating primary tumor microenvironment,targeting circulating tumor cells,regulating premetastatic niche and eliminating established metastasis.Additionally,we highlighted the multiphase targeted drug delivery systems,which hold a better chance to inhibit metastasis.Besides,we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.
