Background:Vasculogenic mimicry refers to a specialized tumor microvasculature independently formed by tumor cells,which facilitates the recurrence,metastasis,and therapeutic resistance in esophageal cancer.Within the...Background:Vasculogenic mimicry refers to a specialized tumor microvasculature independently formed by tumor cells,which facilitates the recurrence,metastasis,and therapeutic resistance in esophageal cancer.Within the framework of traditional Chinese medicine(TCM)theory,there is currently no clear conceptual classification or diagnostic-therapeutic principles for this phenomenon.Objective:To explore traditional Chinese medicine(TCM)herbs and syndrome factors related to the treatment of vasculogenic mimicry in esophageal cancer,and to provide a reference for clarifying the TCM clinical syndromes of vasculogenic mimicry in esophageal cancer.Methods:Based on public databases such as TCMSP,CNKI,and PubMed,TCM herbs related to esophageal cancer,clinical medications,and herbs inhibiting vasculogenic mimicry were retrieved.The herbs collected from multiple databases were standardized,collated,and cross-analyzed,and core herbs were screened for further analysis.Results:Among the public databases,herbs inhibiting vasculogenic mimicry and commonly used clinical herbs for esophageal cancer were mainly of the blood-activating and stasis-resolving type(Huoxue Huayu).In contrast,esophageal cancer-related herbs in the TCMSP database were mainly of the heat-clearing and toxin-resolving type(Qingre Jiedu).A total of 22 TCM herbs related to vasculogenic mimicry in esophageal cancer were identified,mainly blood-activating and stasis-resolving herbs,involving three syndrome factors:“blood stasis(Xueyu),Qi deficiency(Qixu),and Qi stagnation(Qizhi).”Conclusion:Vasculogenic mimicry can promote the progression of esophageal cancer,and blood-activating and stasis-resolving herbs may improve the prognosis of patients with esophageal cancer.展开更多
Melanoma,the most aggressive form of skin cancer,remains a significant clinical challenge due to the high metastatic potential and drug resistance.This review explores the pivotal roles of angiogenesis and vasculogeni...Melanoma,the most aggressive form of skin cancer,remains a significant clinical challenge due to the high metastatic potential and drug resistance.This review explores the pivotal roles of angiogenesis and vasculogenic mimicry in melanoma progression and treatment resistance.Angiogenesis,driven primarily by VEGF/VEGFR signaling,is critical for tumor sustenance but is often insufficient under hypoxic conditions,prompting melanoma cells to adapt by forming vascular-like structures(i.e.,vasculogenic mimicry).These structures enable melanoma cells to mimic endothelial functions and are linked to increased metastasis and poor prognosis.Molecular drivers,including VE-cadherin,EphA2,and hypoxia-inducible factors,have been identified as key regulators of these processes.Current anti-angiogenic agents have limited efficacy in advanced/metastatic melanoma due to tumor plasticity and the interplay between angiogenesis and vasculogenic mimicry.The review highlights the need for therapeutic strategies targeting both mechanisms,emphasizing the importance of combination treatments to overcome resistance.Future research should aim to elucidate the molecular underpinnings of angiogenesis and vasculogenic mimicry to improve melanoma management and patient outcomes.展开更多
Glioblastoma(GBM)is a highly vascularized malignant brain tumor with poor clinical outcomes.Vasculogenic mimicry(VM)formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to t...Glioblastoma(GBM)is a highly vascularized malignant brain tumor with poor clinical outcomes.Vasculogenic mimicry(VM)formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to the failure of anti-angiogenic therapy.To date,there is still a lack of effective drugs that target VM formation in GBM.In the present study,we evaluated the effects of the plant cyclopeptide moroidin on VM formed by GBM cells and investigated its underlying molecular mechanisms.Moroidin significantly suppressed cell migration,tube formation,and the expression levels ofα-smooth muscle actin and matrix metalloproteinase-9 in human GBM cell lines at sublethal concentrations.The RNA sequencing data suggested the involvement of the epithelialmesenchymal transition(EMT)pathway in the mechanism of moroidin.Exposure to moroidin led to a concentration-dependent decrease in the expression levels of the EMT markers N-cadherin and vimentin in GBM cells.Moreover,moroidin significantly reduced the level of phosphorylated extracellular signal-regulated protein kinase(p-ERK)and inhibited the activation of β-catenin.Finally,we demonstrated that the plant cyclopeptide moroidin inhibited VM formation by GBM cells through inhibiting the ERK/β-catenin-mediated EMT.Therefore,our study indicates a potential application of moroidin as an anti-VM agent in the treatment of GBM.展开更多
The growth of solid tumors relies on establishing a robust blood supply,with angiogenesis playing a key role in this intricate process.Based on this understanding,therapeutic strategies targeting tumor angiogenesis ha...The growth of solid tumors relies on establishing a robust blood supply,with angiogenesis playing a key role in this intricate process.Based on this understanding,therapeutic strategies targeting tumor angiogenesis have been developed.However,the clinical effectiveness of antiangiogenic therapy(AAT)in treating tumors has not lived up to expectations.In recent years,vasculogenic mimicry(VM)has attracted increasing attention from the academic community as a longstanding but often overlooked mechanism of nonangiogenic tumor vascularization.Within the tumor microenvironment,neoplastic cells can autonomously form vessel-like structures,creating a blood supply that does not rely on endothelial cells.This phenomenon,known as VM,is a critical marker of aggressive tumors and may play a significant role in conferring resistance to AAT.In this review,we thoroughly examine the evidence,clinical characteristics,and mechanisms of VM across various tumor types and explore its potential role and importance in resistance to AAT and the development of new antitumor therapies.展开更多
Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counter...Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counteract antiviral response.Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus.However,the distribution,characteristics,and functions of HM in eukaryotic viruses remain obscure.Herein,we developed a bioinformatic pipeline,Histone Motif Scan(HiScan),to identify HM motifs in viral proteins and predict their functions in silico.By analyzing 592,643 viral proteins using HiScan,we found that putative HM motifs were widely distributed in most viral proteins.Among animal viruses,the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1,and viruses with smaller genomes had a higher density of HM motifs.Notably,coronaviruses exhibited an uneven distribution of HM motifs,with betacoronaviruses(including most human pathogenic coronaviruses)harboring more HM motifs than other coronaviruses,primarily in the NSP3,S,and N proteins.In summary,our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins,with a preference in DNA viruses.Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions,making it an attractive area of research in virology and antiviral medication.展开更多
Objective Vasculogenic mimicry(VM)is a novel vasculogenic process integral to glioma stem cells(GSCs)in glioblastoma(GBM).However,the relationship between VM and ataxia-telangiectasia mutated(ATM)serine/threonine kina...Objective Vasculogenic mimicry(VM)is a novel vasculogenic process integral to glioma stem cells(GSCs)in glioblastoma(GBM).However,the relationship between VM and ataxia-telangiectasia mutated(ATM)serine/threonine kinase activation,which confers chemoradiotherapy resistance,remains unclear.Methods We investigated VM formation and phosphorylated ATM(pATM)levels by CD31/GFAPperiodic acid-Schiff dual staining and immunohistochemical staining in 145 GBM specimens.Glioma stem-like cells(GSLCs)derived from the formatted spheres of U87 and U251 cell lines and their pATM level and VM formation ability were examined using western blot and three-dimensional culture.For the examination of the function of pATM in VM formation by GSLCs,ATM knockdown by shRNAs and deactivated via ATM phosphorylation inhibitor KU55933 were studied.Results VM and high pATM expression occurred in 38.5% and 41.8% of tumors,respectively,and were significantly associated with reduced progression-free and overall survival.Patients with VM-positive GBMs exhibited higher pATM levels(r_(s)=0.425,P=0.01).The multivariate analysis established VM as an independent negative prognostic factor(P=0.002).Furthermore,GSLCs expressed high levels of pATM and formed vascular-like networks in vitro.ATM inactivation or knockdown hindered VM-like network formation concomitant with the downregulation of pVEGFR-2,VE-cadherin,and laminin B2.Conclusion VM may predict a poor GBM prognosis and is associated with pATM expression.We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin/pVEGFR-2 activation,thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM.展开更多
C-mannosylation is a post-translational modification that occurs intracellularly in the endoplasmic reticulum.In humans,biosynthesis of C-mannosylation in proteins containing thrombospondin type 1 repeat is catalyzed ...C-mannosylation is a post-translational modification that occurs intracellularly in the endoplasmic reticulum.In humans,biosynthesis of C-mannosylation in proteins containing thrombospondin type 1 repeat is catalyzed by the DPY19 family;nonetheless,biological functions of protein C-mannosylation are not yet fully understood,especially in tumor progression.Vasculogenic mimicry(VM)is the formation of fluid-conducting channels by highly invasive and genetically deregulated tumor cells,enabling the tumors to form matrix-embedded vasculogenic structures,containing plasma and blood cells to meet the metabolic demands of rapidly growing tumors.In this study,we focused on DPY19L3,a C-mannosyltransferase,and aimed to unravel its role in VM.Knockout of DPY19L3 inhibited the formation of VM in HT1080 human fibrosarcoma cells.Re-expression of wild-type DPY19L3 recovered VM formation;however,DPY19L3 isoform2,an enzymatic activity-defect mutant,did not restore it,suggesting that the C-mannosyltransferase activity of DPY19L3 is crucial to its function.Furthermore,the knockdown of DPY19L3 in MDA-MB-231 breast cancer cells hindered its network formation ability.Altogether,our findings suggest that DPY19L3 is required for VM formation and stipulate the relevance of C-mannosylation in oncogenesis.展开更多
Objective: To investigate the role of collagen IV and PAS positive substancesecreted by tumor cells in vasculogenic mimicry (VM) and the effects of VM on tumor cells expressingVEGF. Methods: 158 cases of bi-direction ...Objective: To investigate the role of collagen IV and PAS positive substancesecreted by tumor cells in vasculogenic mimicry (VM) and the effects of VM on tumor cells expressingVEGF. Methods: 158 cases of bi-direction differential malignant tumor specimens withparaffin-embedded were enrolled into our study and made tissue microarray which were dual-stainedwith CD31-PAS and stained with collagen IV. The difference of the areas and distribution withpattern surrounded by between CD31 and PAS positive respectively were identified via grid-counting,as well as the difference of VEGF expression with VE absent and present. Results: The basementmembrane of VM was both PAS and collagen IV positive. VEGF expression in the bi-directiondifferential malignant tumor was higher VM-absent than VM-present and the difference wasstatistically significance in malignant melanoma and alveolar rhabdomyosarcoma (P 【 0.05).Conclusion: PAS positive substance and collagen IV compose the wall of VE and VE could provide theoxygen and nutrition for tumor growth and progression.展开更多
Objective: To observe whether there is evidence for vascular channel formation by osteosarcoma cellsin vitro and to illustrate mechanism of vasculogenic mimicry in osteosarcoma.Methods: Osteosarcoma cell lines (U-2OS)...Objective: To observe whether there is evidence for vascular channel formation by osteosarcoma cellsin vitro and to illustrate mechanism of vasculogenic mimicry in osteosarcoma.Methods: Osteosarcoma cell lines (U-2OS) were tested for their ability to form tubular networks in three-dimensional culture containing type I collagen. The structures of the tubular networks were observed under a phase contrast microscope and an electron microscope.Results: Observation under light microscopy and electron microscopy showed that high aggressive osteosarcoma cells line (U-2OS) formed networks containing channels when grown in three-dimensional culture containing type I collagen in the absence of endothelial cells or fibroblasts.Conclusion: These observations strongly suggest that aggressive osteosarcoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis and have the ability of vasculogenic mimicry. Key words osteosarcoma cells line - vasculogenesis mimicry - angiogenesis - 3-dimensional cultures This study was supported in part by the National Natural Sciences Foundation of China (No. 30271314).展开更多
Mimicry is widely used to exemplify natural selection＇s power in promoting adaptation. Nonetheless, it has become increasingly clear that mimicry is frequently imprecise. Indeed, the phenotypic match is often poor be...Mimicry is widely used to exemplify natural selection＇s power in promoting adaptation. Nonetheless, it has become increasingly clear that mimicry is frequently imprecise. Indeed, the phenotypic match is often poor between mimics and models in many Batesian mimicry complexes and among co-mimics in many Mtillerian mimicry complexes. Here, we consider whether such imperfect mimicry represents an evolutionary compromise between predator-mediated selection favoring mimetic conver- gence on the one hand and competitively mediated selection favoring divergence on the other hand. Specifically, for mimicry to be effective, mimics and their models/co-mimics should occur together. Yet, co-occurring species that are phenotypically similar often compete for resources, successful reproduction, or both. As an adaptive response to minimize such costly interactions, in-teracting species may diverge phenotypically through an evolutionary process known as character displacement. Such divergence between mimics and their models/co-mimics may thereby result in imperfect mimicry. We review the various ways in which character displacement could promote imprecise mimicry, describe the conditions under which this process may be especially likely to produce imperfect mimicry, examine a possible case study, and discuss avenues for future research. Generally, character displacement may play an underappreciated role in fostering inexact mimicry .展开更多
AIM: To investigate whether malignant esophageal stromal tumors contain PAS-positive patterned matrix-associated vascular channels, which are lined by tumor cells, but not vascular endothelial cells. That is vasculoge...AIM: To investigate whether malignant esophageal stromal tumors contain PAS-positive patterned matrix-associated vascular channels, which are lined by tumor cells, but not vascular endothelial cells. That is vasculogenic mimicry (VM) independent of tumor angiogenesis. METHODS: Thirty-six tissue samples of malignant esophageal stromal tumors were analyzed. Tissue sections were stained for Vascular endothelial growth factor (VEGF), CD31 and periodic acid Schiff (PAS). The level of VEGF, the microvascular density (MVD) and the vasculogenic mimicry density (VMD) were determined. RESULTS: PAS-positive patterned matrix-associated vascular channels were detected in 33.3% (12/36) of tumor samples. Within these patterned channels, red blood cells were found. The level of VEGF and the MVD in tumors containing patterned channels were significantly higher than those in tumors not containing patterned channels (P < 0.05). At the same time, the malignant degree of tumors was higher, the proportions of tumors containing patterned channels were not only more, but also in the each kind of tumors containing patterned channels. CONCLUSION: In malignant esophageal stromal tumors, a VM mechanism causes some tumor cells to deform themselves and secrete extracellular matrix; thus, PAS-positive patterned matrix-associated vascular channels appear and supplying blood to the tumors to sustain their growth and metastasis.展开更多
Gram-negative bacteria Helicobacter pylori(H. pylori) colonize gastric mucosa in humans and increase the risk of serious diseases such as gastric and duodenal ulcers, stomach cancers and mucosa associated lymphoid tis...Gram-negative bacteria Helicobacter pylori(H. pylori) colonize gastric mucosa in humans and increase the risk of serious diseases such as gastric and duodenal ulcers, stomach cancers and mucosa associated lymphoid tissue lymphoma. The role of H. pylori infection in the pathogenesis of several extragastric diseases has been suggested including immune thrombocytopenic purpura, iron deficiency anemia, vitamin D deficiency, cardiovascular diseases,diabetes mellitus and dermatological disorders. Also neurological diseases and even lung cancer have attracted researchers concern. The relation between H. pylori infection and a growth retardation in children has also been suggested. Many mechanisms of molecular mimicry between H. pylori and the host have been proposed as a pathogen strategy to manipulate the immune system of the host in order to remain unrecognized and avoid eradication. A lot of effort has been put into the demonstration of homologous sequences between H. pylori and host compounds. However, knowledge about how often autoantibodies or autoreactive T lymphocytes induced during H. pylori infections cause pathological disorders is insufficient. This review provides data on H. pylori antigenic mimicry and possible deleterious effects due to the induction of immune response to the components common to these bacteria and the host.展开更多
"Vasculogenic mimicry(VM)",is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in t..."Vasculogenic mimicry(VM)",is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in threedimensional culture.As an angiogenesis-independent pathway,VM and/or periodic acid-schiff-positive patterns are associated with poor prognosis in tumor patients.Moreover,VM is resistant to angiogenesis inhibitors.Here,we will review the advances in research on biochemical and molecular signaling pathways of VM in tumors and on potential anti-VM therapy strategy.展开更多
Maspin belongs to the serine protease inhibitor （serpin） family and has been proven to be a suppressor of tumor growth and metastasis in many types of tumors. The purpose of this study was to investigate the express...Maspin belongs to the serine protease inhibitor （serpin） family and has been proven to be a suppressor of tumor growth and metastasis in many types of tumors. The purpose of this study was to investigate the expression of maspin in non-small cell lung cancer （NSCLC） and its relationship to vasculogenic mimicry （VM）. A total of 160 specimens of NSCLC were involved in this study and 20 specimens of normal lung tissue served as controls. VM, microvessel density （MVD） and the expression of maspin were detected by using immunohistochemical staining. The results showed that the positive rates of maspin and VM in the NSCLC group were 48.1% （77/160） and 36.9% （59/160）, respectively, which were significantly different from those in the control group with the positive rates of maspin and VM being 100% and 0% respectively （P〈0.05）. VM, MVD and the expression level of maspin were significantly related to tumor differentiation, lymph node metastasis, clinical stages and postoperative survival time （all P〈0.05）. The maspin expression in patients with squamous cell carcinoma was significantly higher than that in those with adenocarcinoma （P〈0.05）. The maspin expression was negatively correlated with VM and MVD, and there was a positive correlation between VM and MVD. Maspin-negative expression, VM and high MVD score were negatively related to the 5-year-survival rate. PTNM stages, VM, MVD and maspin expression were independent prognostic factors for NSCLC （P〈0.05）. It was suggested that the loss of expression of maspin may participate in the invasion and metastasis of NSCLC and it has a positive relationship to VM in NSCLC. Combined detection of maspin, VM and MVD may help predict the progression and prognosis of NSCLC.展开更多
Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(C...Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.展开更多
Summary： This study aims to find good markers for predicting the prognosis of patients with eso- phageal squamous cell carcinoma （ESCC）. Vasculogenic mimicry （VM） and the expression of hy- poxia inducible factor-...Summary： This study aims to find good markers for predicting the prognosis of patients with eso- phageal squamous cell carcinoma （ESCC）. Vasculogenic mimicry （VM） and the expression of hy- poxia inducible factor-1α（HIF-1α）/E-cad protein in ESCC were investigated by immunostaining. The association between VM, HIF-1α/E-cad and clinicopathologic characteristics and 5-year-survival rate of patients with ESCC was analyzed. A total of 160 ESCC specimens were involved in this study and 28 specimens of normal esophageal mucosa served as controls. VM channels were identified in 78 （48.75%） of the 160 ESCC specimens and none of the normal esophageal mucosa was found to have VM. The rates of high-expression of HIF-1αand E-cad in ESCC were 43.75% and 38.75%, while the rates in control were 17.86% and 71.43%, respectively （P〈0.05 for all）. VM and the expression levels of HIF-1α and E-cad were significantly related to lymph node metastasis, serosa infiltration, PTNM staging and 5-year-survival rates of patients with ESCC （P〈0.05 for all）. VM was positively corre- lated with HIF-1α but negatively with E-cad, and HIF-let was negatively correlated with E-cad （P〈0.001 for all）. The 5-year-survival rate of patients with ESCC was 6.41% （5/78） in VM group and 65% （52/82） in non-VM group, 7.14% （5/70） in high HIF-1α expression group and 57.78% （52/90） in low HIF-1α expression group. Oppositely, the 5-year-survival rate in high E-cad expression group was 80.65% （50/62） and that in low E-cad expression group was 7.37% （7/98） （P〈0.05 for all）. Cox multifactor regression analysis indicated that lymph node metastasis, PTNM stage, VM and expres- sion levels of HIF-1α and E-cad were independent risk factors of patients with ESCC （P〈0.05 for all）. Combined detection ofVM, HIF-1α and E-cad plays an important role in predicting the invasion, me- tastasis and prognosis of patients with ESCC.展开更多
Vasculogenic mimicry（VM） is a process by which aggressive tumor cells generate non-endothelial cell-lined channels in malignant tumors including hepatocellular carcinoma（HCC）. It has provided new insights into tum...Vasculogenic mimicry（VM） is a process by which aggressive tumor cells generate non-endothelial cell-lined channels in malignant tumors including hepatocellular carcinoma（HCC）. It has provided new insights into tumor behavior and has surfaced as a potential target for drug therapy. The molecular events underlying the process of VM formation are still poorly understood. In this study, we attempted to elucidate the relationship between Notch4 and VM formation in HCC. An effective si RNA lentiviral vector targeting Notch4 was constructed and transfected into Bel7402, a HCC cell line. VM networks were observed with a microscope in a 3 dimensional cell culture system. Cell migration and invasion were evaluated using wound healing and transwell assays. Matrix metalloproteinases（MMPs） activity was detected by gelatin zymography. Furthermore, the role of Notch4 inhibition in Bel7402 cells in vivo was examined in subcutaneous xenograft tumor model of mice. The results showed that downregulation of Notch4 destroyed VM network formation and inhibited migration and invasion of tumor cells in vitro（P〈0.05）. In vivo, tumor growth was also inhibited in subcutaneous xenograft model（P〈0.05）. The potential mechanisms might be related with down-regulation of MT1-MMP, MMP-2, MMP-9 expression and inhibition of the activation of MMP2 and MMP9. These results indicated that Notch4 may play an important role in VM formation and tumor invasion in HCC. Related molecular pathways may be used as novel therapeutic targets for HCC antiangiogenesis therapy.展开更多
基金National Natural Science Foundation of China(Project No.:82474597)Key Project of Jiangsu Traditional Chinese Medicine Science and Technology Development(Project No.:ZD202330)+1 种基金Major Project of Natural Science Research in Jiangsu Universities(Project No.:22KJA360009)Graduate Innovation Project of Jiangsu Province(Project No.:KYCX25-4103)。
文摘Background:Vasculogenic mimicry refers to a specialized tumor microvasculature independently formed by tumor cells,which facilitates the recurrence,metastasis,and therapeutic resistance in esophageal cancer.Within the framework of traditional Chinese medicine(TCM)theory,there is currently no clear conceptual classification or diagnostic-therapeutic principles for this phenomenon.Objective:To explore traditional Chinese medicine(TCM)herbs and syndrome factors related to the treatment of vasculogenic mimicry in esophageal cancer,and to provide a reference for clarifying the TCM clinical syndromes of vasculogenic mimicry in esophageal cancer.Methods:Based on public databases such as TCMSP,CNKI,and PubMed,TCM herbs related to esophageal cancer,clinical medications,and herbs inhibiting vasculogenic mimicry were retrieved.The herbs collected from multiple databases were standardized,collated,and cross-analyzed,and core herbs were screened for further analysis.Results:Among the public databases,herbs inhibiting vasculogenic mimicry and commonly used clinical herbs for esophageal cancer were mainly of the blood-activating and stasis-resolving type(Huoxue Huayu).In contrast,esophageal cancer-related herbs in the TCMSP database were mainly of the heat-clearing and toxin-resolving type(Qingre Jiedu).A total of 22 TCM herbs related to vasculogenic mimicry in esophageal cancer were identified,mainly blood-activating and stasis-resolving herbs,involving three syndrome factors:“blood stasis(Xueyu),Qi deficiency(Qixu),and Qi stagnation(Qizhi).”Conclusion:Vasculogenic mimicry can promote the progression of esophageal cancer,and blood-activating and stasis-resolving herbs may improve the prognosis of patients with esophageal cancer.
基金supported by the European Union-Next Generation EU-PNRR M6C2-Investment 2.1 Enhancement and Strengthening of Biomedical Research in the NHS-Project:PNRR-MCNT2-2023-12377670(Grant No.CUP F93C24000250007).
文摘Melanoma,the most aggressive form of skin cancer,remains a significant clinical challenge due to the high metastatic potential and drug resistance.This review explores the pivotal roles of angiogenesis and vasculogenic mimicry in melanoma progression and treatment resistance.Angiogenesis,driven primarily by VEGF/VEGFR signaling,is critical for tumor sustenance but is often insufficient under hypoxic conditions,prompting melanoma cells to adapt by forming vascular-like structures(i.e.,vasculogenic mimicry).These structures enable melanoma cells to mimic endothelial functions and are linked to increased metastasis and poor prognosis.Molecular drivers,including VE-cadherin,EphA2,and hypoxia-inducible factors,have been identified as key regulators of these processes.Current anti-angiogenic agents have limited efficacy in advanced/metastatic melanoma due to tumor plasticity and the interplay between angiogenesis and vasculogenic mimicry.The review highlights the need for therapeutic strategies targeting both mechanisms,emphasizing the importance of combination treatments to overcome resistance.Future research should aim to elucidate the molecular underpinnings of angiogenesis and vasculogenic mimicry to improve melanoma management and patient outcomes.
基金This work was supported by the National Key Research and Development Program of China(Grant No.2022YFE0104800 to Feng Han)the National Natural Science Foundation of China(Grant No.82003764 to Lili Feng)the Project supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.19KJB350001 to Lili Feng).
文摘Glioblastoma(GBM)is a highly vascularized malignant brain tumor with poor clinical outcomes.Vasculogenic mimicry(VM)formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to the failure of anti-angiogenic therapy.To date,there is still a lack of effective drugs that target VM formation in GBM.In the present study,we evaluated the effects of the plant cyclopeptide moroidin on VM formed by GBM cells and investigated its underlying molecular mechanisms.Moroidin significantly suppressed cell migration,tube formation,and the expression levels ofα-smooth muscle actin and matrix metalloproteinase-9 in human GBM cell lines at sublethal concentrations.The RNA sequencing data suggested the involvement of the epithelialmesenchymal transition(EMT)pathway in the mechanism of moroidin.Exposure to moroidin led to a concentration-dependent decrease in the expression levels of the EMT markers N-cadherin and vimentin in GBM cells.Moreover,moroidin significantly reduced the level of phosphorylated extracellular signal-regulated protein kinase(p-ERK)and inhibited the activation of β-catenin.Finally,we demonstrated that the plant cyclopeptide moroidin inhibited VM formation by GBM cells through inhibiting the ERK/β-catenin-mediated EMT.Therefore,our study indicates a potential application of moroidin as an anti-VM agent in the treatment of GBM.
基金supported by grants from the Scientific and Technological Project of Henan Province(grant no.232102311024 and 222102310001)the Henan Provincial Key Projects of Medical Science and Technology Project(grant no.SBGJ202103002 and SBGJ202103010).
文摘The growth of solid tumors relies on establishing a robust blood supply,with angiogenesis playing a key role in this intricate process.Based on this understanding,therapeutic strategies targeting tumor angiogenesis have been developed.However,the clinical effectiveness of antiangiogenic therapy(AAT)in treating tumors has not lived up to expectations.In recent years,vasculogenic mimicry(VM)has attracted increasing attention from the academic community as a longstanding but often overlooked mechanism of nonangiogenic tumor vascularization.Within the tumor microenvironment,neoplastic cells can autonomously form vessel-like structures,creating a blood supply that does not rely on endothelial cells.This phenomenon,known as VM,is a critical marker of aggressive tumors and may play a significant role in conferring resistance to AAT.In this review,we thoroughly examine the evidence,clinical characteristics,and mechanisms of VM across various tumor types and explore its potential role and importance in resistance to AAT and the development of new antitumor therapies.
基金funded by the National Natural Science Foundation of China(No.U2002218,32270170 and 81902070)the Fund of Hunan University(521119400156)the Science and Technology Innovation Program of Hunan Province(2024RC1028).
文摘Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counteract antiviral response.Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus.However,the distribution,characteristics,and functions of HM in eukaryotic viruses remain obscure.Herein,we developed a bioinformatic pipeline,Histone Motif Scan(HiScan),to identify HM motifs in viral proteins and predict their functions in silico.By analyzing 592,643 viral proteins using HiScan,we found that putative HM motifs were widely distributed in most viral proteins.Among animal viruses,the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1,and viruses with smaller genomes had a higher density of HM motifs.Notably,coronaviruses exhibited an uneven distribution of HM motifs,with betacoronaviruses(including most human pathogenic coronaviruses)harboring more HM motifs than other coronaviruses,primarily in the NSP3,S,and N proteins.In summary,our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins,with a preference in DNA viruses.Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions,making it an attractive area of research in virology and antiviral medication.
基金supported by the Natural Science Foundation of Anhui Province(2208085MH250,2308085MH272)National Key Research and Development Program of China(2021YFF1201000)+2 种基金Natural Science Research Project of the Anhui Educational Committee(2023AH040404,2023AH053402)Anhui Provincial Health and Medical Research Project(AHWJ2023A10143)Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM(2023IHM01043)。
文摘Objective Vasculogenic mimicry(VM)is a novel vasculogenic process integral to glioma stem cells(GSCs)in glioblastoma(GBM).However,the relationship between VM and ataxia-telangiectasia mutated(ATM)serine/threonine kinase activation,which confers chemoradiotherapy resistance,remains unclear.Methods We investigated VM formation and phosphorylated ATM(pATM)levels by CD31/GFAPperiodic acid-Schiff dual staining and immunohistochemical staining in 145 GBM specimens.Glioma stem-like cells(GSLCs)derived from the formatted spheres of U87 and U251 cell lines and their pATM level and VM formation ability were examined using western blot and three-dimensional culture.For the examination of the function of pATM in VM formation by GSLCs,ATM knockdown by shRNAs and deactivated via ATM phosphorylation inhibitor KU55933 were studied.Results VM and high pATM expression occurred in 38.5% and 41.8% of tumors,respectively,and were significantly associated with reduced progression-free and overall survival.Patients with VM-positive GBMs exhibited higher pATM levels(r_(s)=0.425,P=0.01).The multivariate analysis established VM as an independent negative prognostic factor(P=0.002).Furthermore,GSLCs expressed high levels of pATM and formed vascular-like networks in vitro.ATM inactivation or knockdown hindered VM-like network formation concomitant with the downregulation of pVEGFR-2,VE-cadherin,and laminin B2.Conclusion VM may predict a poor GBM prognosis and is associated with pATM expression.We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin/pVEGFR-2 activation,thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM.
文摘C-mannosylation is a post-translational modification that occurs intracellularly in the endoplasmic reticulum.In humans,biosynthesis of C-mannosylation in proteins containing thrombospondin type 1 repeat is catalyzed by the DPY19 family;nonetheless,biological functions of protein C-mannosylation are not yet fully understood,especially in tumor progression.Vasculogenic mimicry(VM)is the formation of fluid-conducting channels by highly invasive and genetically deregulated tumor cells,enabling the tumors to form matrix-embedded vasculogenic structures,containing plasma and blood cells to meet the metabolic demands of rapidly growing tumors.In this study,we focused on DPY19L3,a C-mannosyltransferase,and aimed to unravel its role in VM.Knockout of DPY19L3 inhibited the formation of VM in HT1080 human fibrosarcoma cells.Re-expression of wild-type DPY19L3 recovered VM formation;however,DPY19L3 isoform2,an enzymatic activity-defect mutant,did not restore it,suggesting that the C-mannosyltransferase activity of DPY19L3 is crucial to its function.Furthermore,the knockdown of DPY19L3 in MDA-MB-231 breast cancer cells hindered its network formation ability.Altogether,our findings suggest that DPY19L3 is required for VM formation and stipulate the relevance of C-mannosylation in oncogenesis.
基金This work was partially supported by a grant from the National Natural Science Foundation of China (No. 30370378)
文摘Objective: To investigate the role of collagen IV and PAS positive substancesecreted by tumor cells in vasculogenic mimicry (VM) and the effects of VM on tumor cells expressingVEGF. Methods: 158 cases of bi-direction differential malignant tumor specimens withparaffin-embedded were enrolled into our study and made tissue microarray which were dual-stainedwith CD31-PAS and stained with collagen IV. The difference of the areas and distribution withpattern surrounded by between CD31 and PAS positive respectively were identified via grid-counting,as well as the difference of VEGF expression with VE absent and present. Results: The basementmembrane of VM was both PAS and collagen IV positive. VEGF expression in the bi-directiondifferential malignant tumor was higher VM-absent than VM-present and the difference wasstatistically significance in malignant melanoma and alveolar rhabdomyosarcoma (P 【 0.05).Conclusion: PAS positive substance and collagen IV compose the wall of VE and VE could provide theoxygen and nutrition for tumor growth and progression.
基金This study was supported in part by the National Natural Sciences Foundation of China(No.30271314).
文摘Objective: To observe whether there is evidence for vascular channel formation by osteosarcoma cellsin vitro and to illustrate mechanism of vasculogenic mimicry in osteosarcoma.Methods: Osteosarcoma cell lines (U-2OS) were tested for their ability to form tubular networks in three-dimensional culture containing type I collagen. The structures of the tubular networks were observed under a phase contrast microscope and an electron microscope.Results: Observation under light microscopy and electron microscopy showed that high aggressive osteosarcoma cells line (U-2OS) formed networks containing channels when grown in three-dimensional culture containing type I collagen in the absence of endothelial cells or fibroblasts.Conclusion: These observations strongly suggest that aggressive osteosarcoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis and have the ability of vasculogenic mimicry. Key words osteosarcoma cells line - vasculogenesis mimicry - angiogenesis - 3-dimensional cultures This study was supported in part by the National Natural Sciences Foundation of China (No. 30271314).
基金We thank Karin Pfennig, the members of the Pfennig lab, and two anonymous referees for helpful comments. We also thank Zhi-Yun Jia for inviting us to submit this paper and the U.S. National Science Foundation for fund-ing our research on mimicry and character displacement.
文摘Mimicry is widely used to exemplify natural selection＇s power in promoting adaptation. Nonetheless, it has become increasingly clear that mimicry is frequently imprecise. Indeed, the phenotypic match is often poor between mimics and models in many Batesian mimicry complexes and among co-mimics in many Mtillerian mimicry complexes. Here, we consider whether such imperfect mimicry represents an evolutionary compromise between predator-mediated selection favoring mimetic conver- gence on the one hand and competitively mediated selection favoring divergence on the other hand. Specifically, for mimicry to be effective, mimics and their models/co-mimics should occur together. Yet, co-occurring species that are phenotypically similar often compete for resources, successful reproduction, or both. As an adaptive response to minimize such costly interactions, in-teracting species may diverge phenotypically through an evolutionary process known as character displacement. Such divergence between mimics and their models/co-mimics may thereby result in imperfect mimicry. We review the various ways in which character displacement could promote imprecise mimicry, describe the conditions under which this process may be especially likely to produce imperfect mimicry, examine a possible case study, and discuss avenues for future research. Generally, character displacement may play an underappreciated role in fostering inexact mimicry .
基金Grant from the Natural Science Foundation of Shandong Province, No. Q2005C05
文摘AIM: To investigate whether malignant esophageal stromal tumors contain PAS-positive patterned matrix-associated vascular channels, which are lined by tumor cells, but not vascular endothelial cells. That is vasculogenic mimicry (VM) independent of tumor angiogenesis. METHODS: Thirty-six tissue samples of malignant esophageal stromal tumors were analyzed. Tissue sections were stained for Vascular endothelial growth factor (VEGF), CD31 and periodic acid Schiff (PAS). The level of VEGF, the microvascular density (MVD) and the vasculogenic mimicry density (VMD) were determined. RESULTS: PAS-positive patterned matrix-associated vascular channels were detected in 33.3% (12/36) of tumor samples. Within these patterned channels, red blood cells were found. The level of VEGF and the MVD in tumors containing patterned channels were significantly higher than those in tumors not containing patterned channels (P < 0.05). At the same time, the malignant degree of tumors was higher, the proportions of tumors containing patterned channels were not only more, but also in the each kind of tumors containing patterned channels. CONCLUSION: In malignant esophageal stromal tumors, a VM mechanism causes some tumor cells to deform themselves and secrete extracellular matrix; thus, PAS-positive patterned matrix-associated vascular channels appear and supplying blood to the tumors to sustain their growth and metastasis.
基金Supported by the National Science Center grants,No.UMO-2013/09/N/NZ6/00805 and No.UMO-2015/17/N/NZ6/03490
文摘Gram-negative bacteria Helicobacter pylori(H. pylori) colonize gastric mucosa in humans and increase the risk of serious diseases such as gastric and duodenal ulcers, stomach cancers and mucosa associated lymphoid tissue lymphoma. The role of H. pylori infection in the pathogenesis of several extragastric diseases has been suggested including immune thrombocytopenic purpura, iron deficiency anemia, vitamin D deficiency, cardiovascular diseases,diabetes mellitus and dermatological disorders. Also neurological diseases and even lung cancer have attracted researchers concern. The relation between H. pylori infection and a growth retardation in children has also been suggested. Many mechanisms of molecular mimicry between H. pylori and the host have been proposed as a pathogen strategy to manipulate the immune system of the host in order to remain unrecognized and avoid eradication. A lot of effort has been put into the demonstration of homologous sequences between H. pylori and host compounds. However, knowledge about how often autoantibodies or autoreactive T lymphocytes induced during H. pylori infections cause pathological disorders is insufficient. This review provides data on H. pylori antigenic mimicry and possible deleterious effects due to the induction of immune response to the components common to these bacteria and the host.
基金Supported by National Natural Science Foundation of China,No.30770991 and No.30800511Esophageal Carcinoma Innovative Research Program of Jiangsu Provincial Hospitals
文摘AIM: To investigate whether hypoxia inducible factor (HIF)-1α modulates vasculogenic mimicry (VM) by upregulating VE-cadherin expression in esophageal squamous cell carcinoma (ESCC).
基金Supported by A grant from the National Nature Science Foundation of China,No. 30672073
文摘"Vasculogenic mimicry(VM)",is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in threedimensional culture.As an angiogenesis-independent pathway,VM and/or periodic acid-schiff-positive patterns are associated with poor prognosis in tumor patients.Moreover,VM is resistant to angiogenesis inhibitors.Here,we will review the advances in research on biochemical and molecular signaling pathways of VM in tumors and on potential anti-VM therapy strategy.
文摘Maspin belongs to the serine protease inhibitor （serpin） family and has been proven to be a suppressor of tumor growth and metastasis in many types of tumors. The purpose of this study was to investigate the expression of maspin in non-small cell lung cancer （NSCLC） and its relationship to vasculogenic mimicry （VM）. A total of 160 specimens of NSCLC were involved in this study and 20 specimens of normal lung tissue served as controls. VM, microvessel density （MVD） and the expression of maspin were detected by using immunohistochemical staining. The results showed that the positive rates of maspin and VM in the NSCLC group were 48.1% （77/160） and 36.9% （59/160）, respectively, which were significantly different from those in the control group with the positive rates of maspin and VM being 100% and 0% respectively （P〈0.05）. VM, MVD and the expression level of maspin were significantly related to tumor differentiation, lymph node metastasis, clinical stages and postoperative survival time （all P〈0.05）. The maspin expression in patients with squamous cell carcinoma was significantly higher than that in those with adenocarcinoma （P〈0.05）. The maspin expression was negatively correlated with VM and MVD, and there was a positive correlation between VM and MVD. Maspin-negative expression, VM and high MVD score were negatively related to the 5-year-survival rate. PTNM stages, VM, MVD and maspin expression were independent prognostic factors for NSCLC （P〈0.05）. It was suggested that the loss of expression of maspin may participate in the invasion and metastasis of NSCLC and it has a positive relationship to VM in NSCLC. Combined detection of maspin, VM and MVD may help predict the progression and prognosis of NSCLC.
基金supported by the Student’s Platform for Innovation and Entrepreneurship Training Program, China (Grant No. 201510062001)
文摘Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.
基金supported by grants from the National Natural Science Foundation of China (No. 81171465)Natural Science Research Program of Education Bureau of Anhui Province (No. KJ2013B141)
文摘Summary： This study aims to find good markers for predicting the prognosis of patients with eso- phageal squamous cell carcinoma （ESCC）. Vasculogenic mimicry （VM） and the expression of hy- poxia inducible factor-1α（HIF-1α）/E-cad protein in ESCC were investigated by immunostaining. The association between VM, HIF-1α/E-cad and clinicopathologic characteristics and 5-year-survival rate of patients with ESCC was analyzed. A total of 160 ESCC specimens were involved in this study and 28 specimens of normal esophageal mucosa served as controls. VM channels were identified in 78 （48.75%） of the 160 ESCC specimens and none of the normal esophageal mucosa was found to have VM. The rates of high-expression of HIF-1αand E-cad in ESCC were 43.75% and 38.75%, while the rates in control were 17.86% and 71.43%, respectively （P〈0.05 for all）. VM and the expression levels of HIF-1α and E-cad were significantly related to lymph node metastasis, serosa infiltration, PTNM staging and 5-year-survival rates of patients with ESCC （P〈0.05 for all）. VM was positively corre- lated with HIF-1α but negatively with E-cad, and HIF-let was negatively correlated with E-cad （P〈0.001 for all）. The 5-year-survival rate of patients with ESCC was 6.41% （5/78） in VM group and 65% （52/82） in non-VM group, 7.14% （5/70） in high HIF-1α expression group and 57.78% （52/90） in low HIF-1α expression group. Oppositely, the 5-year-survival rate in high E-cad expression group was 80.65% （50/62） and that in low E-cad expression group was 7.37% （7/98） （P〈0.05 for all）. Cox multifactor regression analysis indicated that lymph node metastasis, PTNM stage, VM and expres- sion levels of HIF-1α and E-cad were independent risk factors of patients with ESCC （P〈0.05 for all）. Combined detection ofVM, HIF-1α and E-cad plays an important role in predicting the invasion, me- tastasis and prognosis of patients with ESCC.
基金supported by grants from the Sci-Tech Research Foundation of Fujian Province(No.2011J05067)the National Clinical Key Specialty Construction Project(General Surgery)of China(No.[2012]649)
文摘Vasculogenic mimicry（VM） is a process by which aggressive tumor cells generate non-endothelial cell-lined channels in malignant tumors including hepatocellular carcinoma（HCC）. It has provided new insights into tumor behavior and has surfaced as a potential target for drug therapy. The molecular events underlying the process of VM formation are still poorly understood. In this study, we attempted to elucidate the relationship between Notch4 and VM formation in HCC. An effective si RNA lentiviral vector targeting Notch4 was constructed and transfected into Bel7402, a HCC cell line. VM networks were observed with a microscope in a 3 dimensional cell culture system. Cell migration and invasion were evaluated using wound healing and transwell assays. Matrix metalloproteinases（MMPs） activity was detected by gelatin zymography. Furthermore, the role of Notch4 inhibition in Bel7402 cells in vivo was examined in subcutaneous xenograft tumor model of mice. The results showed that downregulation of Notch4 destroyed VM network formation and inhibited migration and invasion of tumor cells in vitro（P〈0.05）. In vivo, tumor growth was also inhibited in subcutaneous xenograft model（P〈0.05）. The potential mechanisms might be related with down-regulation of MT1-MMP, MMP-2, MMP-9 expression and inhibition of the activation of MMP2 and MMP9. These results indicated that Notch4 may play an important role in VM formation and tumor invasion in HCC. Related molecular pathways may be used as novel therapeutic targets for HCC antiangiogenesis therapy.
