DPY19L3 promotes vasculogenicmimicry by its C-mannosyltransferase activity

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.

Vasculogenic mimicry:a pivotal mechanism contributing to drug resistance in antiangiogenic therapy

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.

Molecular regulation of vasculogenic mimicry in tumors and potential tumor-target therapy

"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.

Cancer stem-like cells directly participate in vasculogenic mimicry channels in triple-negative breast cancer

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.

Vasculogenic Mimicry and Aberrant Expression of HIF-lα/E-cad Are Associated with Worse Prognosis of Esophageal Squamous Cell Carcinoma

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.

Notch4 Inhibition Suppresses Invasion and Vasculogenic Mimicry Formation of Hepatocellular Carcinoma Cells

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.

Recent advancement in diagnosis of vasculogenic impotence

Several dynamic tests with vasoactive drags are available for evaluating penile vascular inflows and outflows,ranging from simple pharmacologic test to more invasive radiologic sets. However, there is still no perfect single testto reflect the penile vascular flow. All possible efforts should be exerted to get the greatest erectile effect to avoid anunderestimation of blood flow to the corpora due to incomplete relaxation of the trabecular smooth muscle.Appreciation of the type and frequency of anatomical variations and potential collateral routes is important in interpretingpenile arterograms and in evaluating the hemodynamic significance of suspected arterial disease. Choice of the vasculartests should always depend on the purpose of testing.

Expression of Maspin in Non-small Cell Lung Cancer and Its Relationship to Vasculogenic Mimicry

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.

Downregulation of Astrocyte Elevated Gene-1 Expression Combined with All-Trans Retinoic Acid Inhibits Development of Vasculogenic Mimicry and Angiogenesis in Glioma

Objective This study aimed to investigate the effects of downregulating astrocyte elevated gene-1(AEG-1)expression combined with all-trans retinoic acid(ATRA)on vasculogenic mimicry(VM)formation and angiogenesis in glioma.Methods U87 glioma cells were transfected with AEG-1 shRNA lentiviral vectors(U87-siAEG-1)and incubated in a medium containing 20µmol/L ATRA.Matrigel-based tube formation assay was performed to evaluate VM formation,and the cell counting kit-8(CCK-8)assay was used to analyze the proliferation of glioma cells in vitro.Reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to investigate the mRNA and protein expression of related genes,respectively.Glioma xenograft models were generated via subcutaneous implantation of glioma cells in nude mice.Tumor-bearing mice received an intraperitoneal injection of ATRA(10 mg/kg per day).Immunohistochemistry was used to evaluate the expression of related genes and the microvessel density(MVD)in glioma xenograft models.CD34/periodic acid-Schiff double staining was performed to detect VM channels in vivo.The volume and weight of tumors were measured,and a tumor growth curve was drawn to evaluate tumor growth.Results A combination of ATRA intervention and downregulation of AEG-1 expression significantly inhibited the proliferation of glioma cells in vitro and glioma VM formation in vitro and in vivo.It also significantly decreased MVD and inhibited tumor growth.Further,the expression levels of matrix metalloproteinase(MMP)-2,MMP-9,vascular endothelial-cadherin(VE-cadherin),and vascular endothelial growth factor(VEGF)in glioma significantly decreased in vivo and in vivo.Conclusion Hence,a combinatorial approach might be effective in treating glioma through regulating MMP-2,MMP-9,VEGF,and VE-cadherin expression.

CircMAN1A2 promotes vasculogenic mimicry of nasopharyngeal carcinoma cells through upregulating ERBB2 via sponging miR-940

Nasopharyngeal carcinoma(NPC)is the most prevalent human primary malignancy of the head and neck,and the presence of vasculogenic mimicry(VM)renders anti-angiogenic therapy ineffective and poorly prognostic.However,the underlying mechanisms are unclear.In the present study,we used miR-940 silencing and overexpression for in vitro NPC cell EdU staining,wound healing assay and 3D cell culture assay,and in vivo xenograft mouse model and VM formation to assess miR-940 function.We found that ectopic miR-940 expression reduced NPC cell proliferation,migration and VM,as well as tumorigenesis in vivo.By bioinformatic analysis,circMAN1A2 was identified as a circRNA that binds to miR-940.Mechanistically,we confirmed that circMAN1A2 acts as a sponge for miR-940,impairs the inhibitory effect of miR-940 on target ERBB2,and then activates the PI3K/AKT/mTOR signaling pathway using RNA-FISH,dual luciferase reporter gene and rescue analysis assays.In addition,upregulation of ERBB2 expression is associated with clinical staging and poor prognosis of NPC.Taken together,the present findings suggest that circMAN1A2 promotes VM formation and progression of NPC through miR-940/ERBB2 axis and further activates the PI3K/AKT/mTOR pathway.Therefore,circMAN1A2 may become a biomarker and therapeutic target for anti-angiogenic therapy in patients with nasopharyngeal carcinoma.

The Effects of All-Trans Retinoic Acid on Vasculogenic Mimicry Formation Ability in CD133+ Glioma Stem Cells and Its Mechanisms

Objective: to investigate the effects of all-trans retinoic acid (ATRA) on vasculogenic mimicry formation in glioma stem cells. Methods: U87 stem cells were harvested through a suspension culture assay from the U87 cells, identified by CD133 and nestin, and counted by a flow cytometry. To investigate the VM formation ability of U87 stem cells with the treatment of various concentrations of ATRA, a Matrigel-based tube formation assay was used in the present study in vitro and tube-like structure (typical tube, TT;atypical tube AT) was observed and counted. Then the expressions of VEGF, VEGFR-2 and CD133 were measured throughout real time q-PCR, western blotting and immunofluorescence techniques. The data, presented as the mean ± standard deviation, were analyzed using SPSS software. One-way analysis of variance was used to compare groups and Fisher’s least significant difference tests were performed for subsequent comparisons between groups. P Results: Most of the harvested spheroid cells were positive for nestin and 88.4% were positive forCD133. The CD133+ U87 cells were cultured into tube like structure loaded on the top of Matrigel and the quantity of tubes was decreased under the treatment of ATRA. In addition, the expressions of VEGF, VEGFR-2 and CD133 were significantly reduced under the treatment of ATRA, particularly in the higher concentration groups (20 and 40 μmol, P Conclusions: ATRA may inhibit the establishment of VM differing from stem cells in glioma, and these effects may attribute to the effects of ATRA’s promotion of the differentiation of stem cells and/or down regulation of the expressions of proangiogenic factors VEGF and its receptor VEGFR-2. Thus, the results of the present study indicated a novel idea for the treatment of GBM and enriched the anti-glioma mechanisms of ARTA.

Effects of Vasculogenic Mimicry on Postoperative Recurrence and Progression of Non-Small Cell Lung Cancer

Vasculogenic mimicry(VM)in lung cancer shortens overall survival(OS)but its'associations with postoperative recurrence and progression of early non-small cell lung cancer(NSCLC)remain unclear.The purpose of this study was to analyze the association of VM with postoperative recurrence and progression of NSCLC as well as the effect of VM on postoperative recurrence-free survival(RFS).This study included NSCLC patients and detected VM in surgical specimens.The associations ofVM with the recurrence and progression were analyzed to assess the effect ofVM on postoperative RFS in NSCLC.A total of 80 NSCLC cases were followed up for 3 years.During follow-up,35 cases showed recurrence and progression where 5(6.25%)cases had simple local recurrence and the other 30(37.5%)cases had distant metastasis.The recurrence and progression rates in the first,second,and third years were 12.50%,23.75%,and 7.50%,respectively.The median RFS was 14.2 months.VM was detected in 30 out of 80 cases and was significantly correlated with tumor differentiation(r=0.365)and clinical stage(r=0.374)(both,P=0.001).Local recurrence of NSCLC was not correlated with VM,unlike distant metastasis(r=0.598,P<0.001).Average RFS was significantly longer in NSCLC patients without VM compared with the VM group 3 years post-operation(32 months versus 18 months,log-rank test P<0.001).Considering these,VM is significantly correlated with postoperative distant metastasis of NSCLC in which it is of a certain value for predicting poor prognosis in NSCLC.

A new blood supply for human primary gallbladder carcinomas:vasculogenic mimicry,and its correlation with VEGF and significance

Objective To explore if vasculogenic mimicry (VM) exists in human primary gallbladder carcinomas and evaluate the correlation between the VM and expression of vascular epithelial growth factor (VEGF) in gallbladder carcinomas and its significance. MethodsSeventy-four carcinomas, 10 adenomas and 10 chronic inflammatory lesions of the gallbladder underwent operation and confirmed histopathologically were studied. Clinical-pathological data and survival of each patient with gallbladder carcinoma were recorded and followed-up. VM in human gallbladder carcinomas was observed under light microscope by HE staining, CD31 and PAS staining; the expression of VEGF proteins in each paraffin section of each patient in vivo was determined by Envision method of immunohistochemistry; the correlation among the VM, VEGF expression and their clinical significance in the patients with gallbladder carcinomas were analyzed and compared by Kaplan-Meier actuarial survival curves and Cox multiple factors. Results①13.5% (10/74) of human gallbladder carcinomas were found to contain VM, namely intratumoral, tumor cell-lined extracellular matrix (ECM)-rich, PAS-positive and vasculogenic-like network patterns. VM was associated with histological type (χ2=10.241,P=0.017), hepatic metastasis (χ2=4.238,P=0.042) and poor overall survival (χ2=5.722 1,P=0.016). ②Expression of VEGF was increased significantly in carcinomas with or without VM than adenomas and inflammatory lesions of the gallbladder (P<0.000 1) in vivo; VEGF expression in the gallbladder carcinomas without VM was increased significantly than that with VM (P=0.018 2). ③There is positive correlation between expression of VEGF and the gallbladder carcinomas without VM in the cases of Nevin stage (P=0.003 5), invasion depth (P=0.005 9), liver metastases (P=0.037 3) and lymph node metastases (P=0.000 1), the same correlation was only observed between expression of VEGF and the gallbladder carcinomas with VM in the cases of liver metastases (P=0.032 3). When being compared the non-VM gallbladder carcinomas with the VM gallbladder carcinomas, expression of VEGF in the same conditions of Nevin stage (S3～S5, P=0.049 0) was higher significantly in the gallbladder carcinomas without VM than those with VM. ④The non-VM group underwent operation with positive expression of VEGF had longer 5-year survival than the VM group (P=0.007 2), furthermore, the non-VM group underwent operation with negative expression of VEGF had longer 5-year survival than the positive expression group (P=0.031). Also, VM, as invasive depth, lymph node metastasis, hepatic metastasis and operational method, is an independent, risk prognostic factor for patients with gallbladder carcinoma by Cox multiple factor analysis. ConclusionsVM, as a new blood supply for the growth of gallbladder carcinomas, is found to exist in the patients with gallbladder carcinomas. Increased expression of VEGF and its negative correlation with VM were observed in the gallbladder carcinomas. It is showed that VM is an independent risk prognostic factor in patients with gallbladder carcinoma, and VEGF is an important clinical marker for evaluation of Nevin stage, invasion depth, lymph node or liver metastases and prognosis in patients with gallbladder carcinoma; VM and VEGF are especially of important markers for estimating of prognosis in the gallbladder carcinoma patients.

Contribution of cancer stem cells to tumor vasculogenic mimicry

Vasculogenic mimicry(VM),a newly-defined pattern of tumor blood supply,provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis.The biological features of the tumor cells that form VM remain unknown.Cancer stem cells(CSCs)are believed to be tumorinitiating cells,capable of self-renewal and multipotent differentiation,which resemble normal stem cells in phenotype and function.Recently CSCs have been shown to contribute to VM formation as well as angiogenesis.These findings challenge the previous understanding of the cellular basis of VM formation.In this review,we present evidence for participation of CSCs in VM formation.We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche.Based on the importance of VM in tumor progression,it constitutes a novel therapeutic target for cancer.

Vasculogenic mimicry is a key prognostic factor for laryngeal squamous cell carcinoma： a new pattern of blood supply

Background Recurrence and local lymph node metastasis affected the prognosis of patients with laryngeal cancer. The aim of this study was to analyze clinical and pathological significance of vasculogenic mimicry （VM） in laryngeal squamous cell carcinoma （LSCC） and evaluate its contribution to prognosis. Methods Data of 168 cases of LSCC were reviewed retrospectively to reveal clinical pathology and prognostic significance of VM. CD31 and periodic acid-Schiff double staining was used to identify VM. Results VM in LSCC contributed to lymph node metastasis （P=0.003） and clinical progression. VM correlated to histopathology grade （P=0.001） of LSCC. VM was an adverse prognostic factor for both disease-specific survival （P=0.039） and metastasis-free survival （P=0.042） by univariate survival analyses. And it was an independent prognostic factor for only disease-specific survival （P=0.003） by multivariate survival analyses. Conclusions VM existed in LSCC. LSCC with VM has more Dotential to invasion and metastasis.

Erectile dysfunction and central obesity： an Italian perspective

Erectile dysfunction （ED） is a frequent complication of obesity. The aim of this review is to critically analyze the framework of obesity and ED, dissecting the connections between the two pathological entities. Current clinical evidence shows that obesity, and in particular central obesity, is associated with both arteriogenic ED and reduced testosterone （T） levels. It is conceivable that obesity-associated hypogonadism and increased cardiovascular risk might partially justify the higher prevalence of ED in overweight and obese individuals. Conversely, the psychological disturbances related to obesity do not seem to play a major role in the pathogenesis of obesity-related ED. However, both clinical and preclinical data show that the association between ED and visceral fat accumulation is independent from known obesity-associated comorbidities. Therefore, how visceral fat could impair penile microcirculation still remains unknown. This point is particularly relevant since central obesity in ED subjects categorizes individuals at high cardiovascular risk, especially in the youngest ones. The presence of ED in obese subjects might help healthcare professionals in convincing them to initiate a virtuous cycle, where the correction of sexual dysfunction will be the reward for improved lifestyle behavior. Unsatisfying sexual activity represents a meaningful, straightforward motivation for consulting healthcare professionals, who, in turn, should take advantage of the opportunity to encourage obese patients to treat, besides ED, the underlying unfavorable conditions, thus not only restoring erectile function, but also overall health.

The 150 most important questions in cancer research and clinical oncology series:questions 57-66

Since the beginning of 2017,Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology,which sparkle diverse thoughts,interesting communications,and potential collaborations among researchers all over the world.In this article,10 more questions are presented as followed.Question 57.What are the major stresses that drive the formation,progression,and metastasis of a cancer? Question 58.What is the mechanism responsible for altering an acidic intracellular pH and a basic extracellular pH in normal tissue cells to a basic intracellular pH and an acidic extracellular pH in cancer cells,a fundamental and yet largely ignored phenomenon? Question 59.Where are the tumor-associated plasma microRNAs from in cancer patients? Question 60.Can we identify mechanisms employed by tumor subpopulations to evade standard therapies and seed relapse/metastatic tumors before treatment? Question 61.Why are mutation rates in epidermal growth factor receptor(EGFR) and erb-b2 receptor tyrosine kinase 2(ERBB2) higher in lung cancer from never smokers than that from smokers? Question 62.Does tumor vasculogenic mimicry contribute to the resistance against antiangiogenic therapy in renal cancer? Question 63.What molecular targeted drugs would be effective for non-clear cell renal cell carcinoma(RCC),especially metastatic papillary RCC and chromophobe RCC? Question 64.Can it be more effective by targeting both the vascular endothelial growth factor receptor(VEGFR) and MET signaling pathways in sporadic metastatic papillary renal cell carcinoma(RCC)? Question 65.What are the predictive biomarkers that may be used to identify the renal cell carcinoma(RCC) patients who can benefit from immune checkpoint inhibitor treatment? Question 66.How do we identify predictive molecular biomarkers to stratify clear cell renal cell carcinoma patients for targeted therapies?

Angioarchitecture and CD133^+ tumor stem cell distribution in intracranial hemangiopericytoma A comparative study with meningioma

Angioarchitecture plays an important role in the malignant development of intracranial hemangiopericytoma. It remains poorly understood whether high frequency of hemorrhage during clinical surgery for intracranial hemangiopericytoma is associated with angioarchitecture. The present study utilized hematoxylin-eosin staining, and immunohistochemical staining with epithelial membrane antigen, vimentin, CD34, von Willebrand factor （vWF） and CD133 to observe characteristics of angioarchitecture. In addition, silver stains were used to demonstrate changes in reticular fibers in the wall of vessel channels in intracranial hemangiopericytoma and meningioma. Five patterns of angioarchitecture were identified in intracranial hemangiopericytoma, namely tumor cell islands, vasculogenic mimicry, mosaic blood vessels, sprouting angiogenesis, and intussusceptive angiogenesis. Several CD133＋ tumor cells were found to form tumor cell islands. A connection between vWF ^＋ and vWF channels was detected in the pattern of intussusceptive angiogenesis, and some vimentin^＋ tumor cells were embedded in the periodic acid-Schiff positive channel wall. Incomplete threads of reticular fibers formed the walls of larger pseudo-vascular channels and some tumor clumps or scattered tumor cells were detected ＂floating＂ in them. The angioarchitecture, specific markers and reticular fibers of intracranial hemangiopericytoma were significantly different from meningioma. Angioarchitecture provides a functional vascular network for vascular evolution in intracranial hemangiopericytoma and contributes to significant intra-operative bleeding.

Twenty years after:the beautiful hypothesis and the ugly facts

The limited clinical benefits from current antiangiogenic therapy for cancer patients have triggered some critical thoughts and insightful investigations aiming to further elucidate the relationship between vessels and cancer.Tumors need blood perfusion but there are mounting evidences that angiogenesis alone does not explain it in all the neoplasms.In this editorial,for a special issue on tumor and vessels published in the Chinese Journal of Cancer,we briefly introduce the history of the evidences that solid tumors can sometimes obtain blood perfusion by alternative approaches other than sprouting angiogenesis,i.e.,vessel co-option and vasculogenic mimicry.This editorial provides also the links to several most recently published discoveries and hypotheses on tumor interaction with blood vessels.

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

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