Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC ...Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.展开更多
OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(Lo...OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(LoVo)xenografts were treated with SMI 10 mL·kg^-1 daily for 1 or 8 d.Multidimensional PK profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.For PD studies,the tumor-bearing mice Intravital multi-photon imaging and CD31 immunofluorescence staining were used to evaluate the number of microves⁃sels and braches.Double staining of CD31 and α-SMA was performed to evaluate pericytes coverage ratios around vessels.ELISA was performed to determine the concentrations of VEGF and FGF in tumor tissues.For synergistic anti-tumor study,the tumor-bearing mice were treated with SMI 10 mL·kg^-1 daily,Rd 5 mg·kg^-1 daily with or without 5-FU 15 mg·kg^-1 every 3 d for 20 d.HPLC-MS/MS was used to determine the concentrations of 5-FU in plasma and tumor tissues.RESULTS SMI decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and improved vascular pericytes coverage(P<0.05).PK studies showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both,plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In fact,the proportion of Rd in the detectable components of SMI gradually increased in the following order:SMI formula(2.8%),plasma(16.0%),tumor tissues(34.3%),and TECs(40.3%).In vivo bioactivity results showed that Rd 5 mg·kg^-1 daily significantly decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and increased pericytes coverage(P<0.05)while Rd 0.5 mg·kg^-1 daily,Rb1 and Rg1 had no significant effect on them.Rd 5 mg·kg^-1 suppressed the expression of VEGF and FGF simultaneously.Rd 5 mg·kg^-1 enhanced the antitumor effect of 5-FU via increasing the distribution of 5-FU in tumor tissues(P<0.05)in xenograft mice.CONCLUSION Ginsenoside Rd may be the major bioactive anti-angiogenic constituent targeting TECs after SMI treatment.展开更多
Colorectal cancer(CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality i...Colorectal cancer(CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various antiangiogenic agents in patients with metastatic CRC(m CRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in m CRC patients. Despite the discovery of several promising anti-angiogenic agents, m CRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.展开更多
Shenmai injection(SMI)is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer.Previously,we found that SMI synergistically enhanced the activity of chemotherapy on col...Shenmai injection(SMI)is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer.Previously,we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors.However,the underlying mechanisms and bioactive constituents remained unknown.In the present work,the regulatory effects of SMI on tumor vasculature were determined,and the potential anti-angiogenic components targeting tumor endothelial cells(TECs)were identified.Multidimensional pharmacokinetic profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.The results showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD-type ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In vivo bioactivity results showed that Rd suppressed neovascularization in tumors,normalized the structure of tumor vessels,and improved the anti-tumor effect of 5-fluorouracil(5 FU)in xenograft mice.Furthermore,Rd inhibited the migration and tube formation capacity of endothelial cells in vitro.In conclusion,Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.展开更多
Angiogenesis is a crucial process in the development of inflammatory diseases,including cancer,psoriasis and rheumatoid arthritis.Recently,several alkaloids from Picrasma quassioides had been screened for angiogenic a...Angiogenesis is a crucial process in the development of inflammatory diseases,including cancer,psoriasis and rheumatoid arthritis.Recently,several alkaloids from Picrasma quassioides had been screened for angiogenic activity in the zebrafish model,and the results indicated that 1-methoxycarbony-β-carboline(MCC) could effectively inhibit blood vessel formation.In this study,we further confirmed that MCC can inhibit,in a concentration-dependent manner,the viability,migration,invasion,and tube formation of human umbilical vein endothelial cells(HUVECs) in vitro,as well as the regenerative vascular outgrowth of zebrafish caudal fin in vivo.In the zebrafish xenograft assay,MCC inhibited the growth of tumor masses and the metastatic transplanted DU145 tumor cells.The proteome profile array of the MCC-treated HUVECs showed that MCC could down-regulate several angiogenesis-related self-secreted proteins,including ANG,EGF,b FGF,GRO,IGF-1,PLG and MMP-1.In addition,the expression of two key membrane receptor proteins in angiogenesis,TIE-2 and u PAR,were also down-regulated after MCC treatment.Taken together,these results shed light on the potential therapeutic application of MCC as a potent natural angiogenesis inhibitor via multiple molecular targets.展开更多
Cancer is a group of diseases with significant morbidity and mortality.In cancer cells,where energy requirements are exceptionally high,angiogenesis,which is the sprouting of new blood vessels from pre-existing ones,i...Cancer is a group of diseases with significant morbidity and mortality.In cancer cells,where energy requirements are exceptionally high,angiogenesis,which is the sprouting of new blood vessels from pre-existing ones,is an important process for tumour survival and progression.Hence,extensive research in recent years focuses on the discovery of new anticancer drugs that target angiogenesis.Several methodologies have been developed preclinically,including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones.The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years.Many new anticancer drugs targeting angiogenesis are identified in the literature.The results of the in vitro and in vivo evaluation of these drugs show that,apart from inhibiting angiogenesis,they also affect cancer cell proliferation and tumour growth.Recent clinical studies show that these drugs increase the overall or disease-free survival of patients,even those with persistent,chemotherapy-resistant and metastatic types of cancer,although treatment-related side effects are not uncommon.Drugs that target the process of angiogenesis are likely to be the future of anticancer therapy,especially in cases where more traditional treatments do not produce the desired results and where combination regimens of anti-angiogenic agents with standard chemotherapeutics increase patient survival.展开更多
Deoxyactein(DA)is a triterpenoid isolated from the root of Cimicifuga foetida which is a source of traditional Chinese herb'shengma'and is traditionally used as an antipyretic and analgesic agent.Previous stud...Deoxyactein(DA)is a triterpenoid isolated from the root of Cimicifuga foetida which is a source of traditional Chinese herb'shengma'and is traditionally used as an antipyretic and analgesic agent.Previous studies showed that DA exhibited anti-proliferative effect in human breast cancer cells.Hence,the objectives of this study were to展开更多
Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenome...Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenomenon of resistance was based on the fact that was targeting normal vessels rather than tumour cells prone to mutation and subject to drug induced selection.However,reality turned out to be more complex and since 1997,several mechanisms of resistance have been described to the point that the study of resistance to these drugs is now a very large field.Far from being exhaustive,this paper presents the main mechanisms discovered trough some examples.展开更多
Angiogenesis affects both wound healing and malignant cell growth through nutrients and oxygen.Vascular endothelial growth factor(VEGF) is the most important element involved in this complex process.Inhibition of VEGF...Angiogenesis affects both wound healing and malignant cell growth through nutrients and oxygen.Vascular endothelial growth factor(VEGF) is the most important element involved in this complex process.Inhibition of VEGF influences angiogenesis and may restrict tumor growth and metastatic ability.Modern antiangiogenic therapy is based on this theory.Bevacizumab is a recombinant humanized monoclonal antibody(immunoglobulin G1) which binds with VEGF-A forming a large molecule.It can not be bound with VEGF tyrosine kinase receptors preventing VEGF-A incorporation;thus its activity is inhibited inducing blockage of VEGFmediated angiogenesis.Bevacizumab,in combination with chemotherapy or other novel targeted therapeutic agents,is currently used more frequently in clinical practice,mainly for managing advanced colorectal cancer.It is also used for managing other malignancies,such as breast cancer,pancreatic cancer,prostate cancer,non small-cell lung cancer,metastatic renal carcinoma and ovarian tumors.Although it is generally considered a safe treatment,there are reports of some rare side effects which should be taken into account.Recent experiments in rats and mice show promising results with a wider therapeutic range.展开更多
Various imaging modalities are available for the diagnosis, staging and response evaluation of patients with renal cell carcinoma(RCC). While contrast enhanced computed tomography(CT) is used as the standard of imagin...Various imaging modalities are available for the diagnosis, staging and response evaluation of patients with renal cell carcinoma(RCC). While contrast enhanced computed tomography(CT) is used as the standard of imaging for size, morphological evaluation and response assessment in RCC, a new functional imaging technique like perfusion CT(p CT), goes down to the molecular level and provides new perspectives in imaging of RCC. p CT depicts regional tumor perfusion and vascular permeability which are indirect parameters of tumor angiogenesis and thereby provides vital information regarding tumor microenvironment. Also response evaluation using p CT may predate the size criteria used in Response Evaluation Criteria in Solid Tumors, as changes in the perfusion occurs earlier following tissue kinase inhibitors before any actual change in size. This may potentially help in predicting prognosis, better selection of therapy and more accurate and better response evaluation in patients with RCC. This article describes the techniques and role of p CT in staging and response assessment in patients with RCCs.展开更多
In this study, a fucoidan-based theranostic nanogel(CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve acti-vatable near-infrared fluorescence ima...In this study, a fucoidan-based theranostic nanogel(CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve acti-vatable near-infrared fluorescence imaging of tumor sites and an enhanced photodynamic therapy(PDT) to induce the com-plete death of cancer cells. A CFN-gel has nanomolar a nity for P-selectin, which is overexpressed on the surface of tumor neovascular endothelial cells as well as many other cancer cells. Therefore, a CFN-gel can enhance tumor accumulation through P-selectin targeting and the enhanced permeation and retention e ect. Moreover, a CFN-gel is non-fluorescent and non-phototoxic upon its systemic administration due to the aggregation-induced self-quenching in its fluorescence and singlet oxygen generation. After internalization into cancer cells and tumor neovascular endothelial cells, its photoactivity is recovered in response to the intracellular redox potential, thereby enabling selective near-infrared fluorescence imaging and an enhanced PDT of tumors. Since a CFN-gel also shows nanomolar a nity for the vascular endothelial growth factor, it also provides a significant anti-tumor e ect in the absence of light treatment in vivo. Our study indicates that a fucoidan-based theranostic nanogel is a new theranostic material for imaging and treating cancer with high e cacy and specificity.展开更多
Hepatocellular carcinoma(HCC)is the most common primary liver cancer.For advanced HCC,sorafenib was considered the standard of care for more than ten years.Recently the atezolizumab and bevacizumab combination has bec...Hepatocellular carcinoma(HCC)is the most common primary liver cancer.For advanced HCC,sorafenib was considered the standard of care for more than ten years.Recently the atezolizumab and bevacizumab combination has become standard of care for these patients without contraindications to either immune checkpoint inhibitors or antiangiogenic therapy.We now review the practical aspects of the atezolizumab and bevacizumab combination,including current evidence,indications,contraindications,management of adverse events,sequencing of this combination,areas of current knowledge gaps and future areas of active clinical research of this combination for busy clinicians in clinical practice.展开更多
Angiogenesis, the growth of new vessels from pre-existing ones, is an important feature of tumor growth that has been exploited as a therapeutic target in oncology. Given its key role in facilitating blood vessel spro...Angiogenesis, the growth of new vessels from pre-existing ones, is an important feature of tumor growth that has been exploited as a therapeutic target in oncology. Given its key role in facilitating blood vessel sprouting, VEGF has been a major focus of anti-angiogenic strategies, but the observation of resistance in some clinical trials utilizing such agents has led to a search for new or complementary targets in angiogenesis process. The Angiopoietin/Tie2 pathway and in particular the Angiopoietin-2 (Ang-2) ligand which is critically involved in the destabilization of normal vasculature, has been identified as one such target. The current study investigated the potential benefits of combining an Ang-2 targeted therapy with small molecule VEGF targeted agents (Sunitinib, Cediranib) in a human renal cell carcinoma model. The results showed that while both Ang-2 and VEGF interference on their own impaired tumor growth and new blood vessel formation, the combination of agents that targeted both pathways resulted in significantly superior anti-tumor and anti-angiogenic effects.展开更多
In recent years,seeking effective anti-angiogenic components and therapeutic methods from traditional Chinese Medicine(TCM)has been a hot spot in the treatment of malignant tumors.In particular,the active ingredients ...In recent years,seeking effective anti-angiogenic components and therapeutic methods from traditional Chinese Medicine(TCM)has been a hot spot in the treatment of malignant tumors.In particular,the active ingredients found in Chinese herbal extracts have shown strong inhibition of tumor neovascularization.展开更多
BACKGROUND Pseudomyxoma peritonei(PMP)is a rare benign,but progressive,disease according to myxoma histopathology.Surgical resection is the preferred and most effective treatment,but the outcomes are often unsatisfact...BACKGROUND Pseudomyxoma peritonei(PMP)is a rare benign,but progressive,disease according to myxoma histopathology.Surgical resection is the preferred and most effective treatment,but the outcomes are often unsatisfactory.CASE SUMMARY A 63-year-old Chinese woman with PMP received apatinib at a daily dose of 0.5 mg for 15 d per cycle and at a daily dose of 0.4 mg to date for recurrent abdominal distension after surgical treatment and hyperthermic intraperitoneal chemotherapy.During the follow-up period,apatinib was the maintenance treatment with a progression-free period of 10 mo and the toxicity of apatinib was controllable and tolerable.Unfortunately,recurrence occurred 10 mo after administration.After two operations,the patient gave up treatment at the 18th mo and eventually died of intestinal obstruction and multiple organ failure.CONCLUSION Apatinib may be an option for recurrent PMP after surgical treatment,but this conclusion remains to be confirmed.展开更多
Among collagen members in the collagen superfamily,type XIX collagen has raised increasing interest in relation to its structural and biological roles.Type XIX collagen is a Fibril-Associated Collagen with Interrupted...Among collagen members in the collagen superfamily,type XIX collagen has raised increasing interest in relation to its structural and biological roles.Type XIX collagen is a Fibril-Associated Collagen with Interrupted Triple helices member,one main subclass of collagens in this superfamily.This collagen contains a triple helix composed of three polypeptide segments aligned in parallel and it is associated with the basement membrane zone in different tissues.The molecular structure of type XIX collagen consists of five collagenous domains,COL1 to COL5,interrupted by six non-collagenous domains,NCI to NC6.The most relevant domain by which this collagen exerts its biological roles is NCI domain that can be cleavage enzymatically to release matricryptins,exerting anti-tumor and anti-angiogenic effect in murine and human models of cancer.Under physiological conditions,type XIX collagen expression decreases after birth in different tissues although it is necessary to keep its basal levels,mainly in skeletal muscle and hippocampal and telencephalic interneurons in brain.Notwithstanding,in amyotrophic lateral sclerosis,altered transcript expression levels show a novel biological effect of this collagen beyond its structural role in basement membranes and its anti-tumor and anti-angiogenic properties.Type XIX collagen can exert a compensatory effect to ameliorate the disease progression under neurodegenerative conditions specific to amyotrophic lateral sclerosis in transgenic SOD1 G93 A mice and amyotrophic lateral sclerosis patients.This novel biological role highlights its nature as prognostic biomarker of disease progression in and as promising therapeutic target,paving the way to a more precise prognosis of amyotrophic lateral sclerosis.展开更多
Liver cancer,mostly hepatocellular carcinoma(HCC),is the second leading cause of cancer mortality globally.Most patients were diagnosed at an advanced stage,and systemic therapy is the standard of care.All the approve...Liver cancer,mostly hepatocellular carcinoma(HCC),is the second leading cause of cancer mortality globally.Most patients were diagnosed at an advanced stage,and systemic therapy is the standard of care.All the approved systemic therapies for HCC are molecular targeted therapies with anti-angiogenic effects targeting the vascular endothelial growth factor signaling pathway.Sorafenib and lenvatinib are the first-line treatment,and regorafenib,ramucirumab,and cabozantinib are second-line treatment options.Although anti-PD-1 antibodies,including nivolumab and pembrolizumab,demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials,both failed in phase III studies.Anti-angiogenic treatment remains the backbone of systemic therapy for HCC.In this review,we summarized the approved anti-angiogenic medicines and discussed the potential strategies to improve the efficacy of anti-angiogenic therapy,including combination therapy with other treatments,and discussed the approaches to overcome the drawbacks of anti-angiogenic therapies.展开更多
Sarcomatoid carcinoma is a rare tumor that is composed of a mixture of malignant epithelial cells and mesenchymal cells.Many studies have reported that sarcomatoid carci-noma occurs in multiple organs including the li...Sarcomatoid carcinoma is a rare tumor that is composed of a mixture of malignant epithelial cells and mesenchymal cells.Many studies have reported that sarcomatoid carci-noma occurs in multiple organs including the liver.Sarco-matoid intrahepatic cholangiocarcinoma(S-iCCA)is an ex-tremely rare tumor that primarily occurs in the liver.This case occurred in a middle-aged man who was admitted to our hospital with abdominal pain.Enhanced computed to-mography of the abdomen showed a low-density mass in the upper right posterior lobe of the liver with enhancement in the periphery.Histological and immunohistochemical examination indicated that the tumor was malignant,with both cancer and sarcoma components,and was positive for cytokeratin and vimentin.The patient was diagnosed with S-iCCA.Metastases appeared in the liver and lung 4 months after surgery.Two cycles of chemotherapy were adminis-tered.Because of enlargement of the tumor,anti-angiogen-ic agents combined with immunotherapy were subsequently given to achieve disease control.To the best of our knowl-edge,this is the first reported case of a programmed cell death-1 inhibitor used in a S-iCCA patient.The purpose of this case report and literature review is to enhance clinician understanding of S-iCCA and to explore safe and effective treatment methods.展开更多
基金supported by the National Key Research and Development Program of China(Grant No.2020YFA0803700)the National Natural Science Foundation of China(Grant Nos.91639108,81770272,and 81970425)+1 种基金the Beijing Natural Science Foundation(Grant No.7212044)the Beijing Hospital Authority Youth Program(Grant No.QML20190306)。
文摘Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.
基金National Nature Science Foundation of China(81773989and 81530098)
文摘OBJECTIVE To identify the bioactive anti-angiogenic constitutes targeting tumor endothelial cells(TECs)in Shenmai Injection(SMI).METHEODS For pharmacokinetic(PK)studies,Balb/c mice harboring human colorectal cancer(LoVo)xenografts were treated with SMI 10 mL·kg^-1 daily for 1 or 8 d.Multidimensional PK profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.For PD studies,the tumor-bearing mice Intravital multi-photon imaging and CD31 immunofluorescence staining were used to evaluate the number of microves⁃sels and braches.Double staining of CD31 and α-SMA was performed to evaluate pericytes coverage ratios around vessels.ELISA was performed to determine the concentrations of VEGF and FGF in tumor tissues.For synergistic anti-tumor study,the tumor-bearing mice were treated with SMI 10 mL·kg^-1 daily,Rd 5 mg·kg^-1 daily with or without 5-FU 15 mg·kg^-1 every 3 d for 20 d.HPLC-MS/MS was used to determine the concentrations of 5-FU in plasma and tumor tissues.RESULTS SMI decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and improved vascular pericytes coverage(P<0.05).PK studies showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both,plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In fact,the proportion of Rd in the detectable components of SMI gradually increased in the following order:SMI formula(2.8%),plasma(16.0%),tumor tissues(34.3%),and TECs(40.3%).In vivo bioactivity results showed that Rd 5 mg·kg^-1 daily significantly decreased the number of microvessels(P<0.05)and vessel branches(P<0.05)and increased pericytes coverage(P<0.05)while Rd 0.5 mg·kg^-1 daily,Rb1 and Rg1 had no significant effect on them.Rd 5 mg·kg^-1 suppressed the expression of VEGF and FGF simultaneously.Rd 5 mg·kg^-1 enhanced the antitumor effect of 5-FU via increasing the distribution of 5-FU in tumor tissues(P<0.05)in xenograft mice.CONCLUSION Ginsenoside Rd may be the major bioactive anti-angiogenic constituent targeting TECs after SMI treatment.
文摘Colorectal cancer(CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various antiangiogenic agents in patients with metastatic CRC(m CRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in m CRC patients. Despite the discovery of several promising anti-angiogenic agents, m CRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.
基金supported by the China National Nature Science Foundation(81573496,81773989,81530098 and 81573494)National Research Council of Science and Technology Major Project of China(2017ZX09201004-019 and 2019ZX09721001006-005)+6 种基金International Science and Technology Center Program of China(2017YFE0109600)Foundation for Innovative Research Groups of the National Natural Science Foundation of China(No.81421005)Jiangsu Province Nature Science Foundation(No.BK20160076,China)Jiangsu Province“333”project,ChinaSix talent peaks project in Jiangsu Province(YY-060),ChinaNational Basic Research Program of China(973 Program,No.2017YFA0205400)“Double First-Class”University project(CPU2018GF01,China)
文摘Shenmai injection(SMI)is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer.Previously,we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors.However,the underlying mechanisms and bioactive constituents remained unknown.In the present work,the regulatory effects of SMI on tumor vasculature were determined,and the potential anti-angiogenic components targeting tumor endothelial cells(TECs)were identified.Multidimensional pharmacokinetic profiles of ginsenosides in plasma,subcutaneous tumors,and TECs were investigated.The results showed that the concentrations of protopanaxadiol-type(PPD)ginsenosides(Rb1,Rb2/Rb3,Rc,and Rd)in both plasma and tumors,were higher than those of protopanaxatriol-type(Rg1 and Re)and oleanane-type(Ro)ginsenosides.Among PPD-type ginsenosides,Rd exhibited the greatest concentrations in tumors and TECs after repeated injection.In vivo bioactivity results showed that Rd suppressed neovascularization in tumors,normalized the structure of tumor vessels,and improved the anti-tumor effect of 5-fluorouracil(5 FU)in xenograft mice.Furthermore,Rd inhibited the migration and tube formation capacity of endothelial cells in vitro.In conclusion,Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.
基金supported by the National Natural Science Foundation of China(No.81502950)the Fundamental Research Funds for the Central Universities(2015ZD010)the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Angiogenesis is a crucial process in the development of inflammatory diseases,including cancer,psoriasis and rheumatoid arthritis.Recently,several alkaloids from Picrasma quassioides had been screened for angiogenic activity in the zebrafish model,and the results indicated that 1-methoxycarbony-β-carboline(MCC) could effectively inhibit blood vessel formation.In this study,we further confirmed that MCC can inhibit,in a concentration-dependent manner,the viability,migration,invasion,and tube formation of human umbilical vein endothelial cells(HUVECs) in vitro,as well as the regenerative vascular outgrowth of zebrafish caudal fin in vivo.In the zebrafish xenograft assay,MCC inhibited the growth of tumor masses and the metastatic transplanted DU145 tumor cells.The proteome profile array of the MCC-treated HUVECs showed that MCC could down-regulate several angiogenesis-related self-secreted proteins,including ANG,EGF,b FGF,GRO,IGF-1,PLG and MMP-1.In addition,the expression of two key membrane receptor proteins in angiogenesis,TIE-2 and u PAR,were also down-regulated after MCC treatment.Taken together,these results shed light on the potential therapeutic application of MCC as a potent natural angiogenesis inhibitor via multiple molecular targets.
文摘Cancer is a group of diseases with significant morbidity and mortality.In cancer cells,where energy requirements are exceptionally high,angiogenesis,which is the sprouting of new blood vessels from pre-existing ones,is an important process for tumour survival and progression.Hence,extensive research in recent years focuses on the discovery of new anticancer drugs that target angiogenesis.Several methodologies have been developed preclinically,including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones.The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years.Many new anticancer drugs targeting angiogenesis are identified in the literature.The results of the in vitro and in vivo evaluation of these drugs show that,apart from inhibiting angiogenesis,they also affect cancer cell proliferation and tumour growth.Recent clinical studies show that these drugs increase the overall or disease-free survival of patients,even those with persistent,chemotherapy-resistant and metastatic types of cancer,although treatment-related side effects are not uncommon.Drugs that target the process of angiogenesis are likely to be the future of anticancer therapy,especially in cases where more traditional treatments do not produce the desired results and where combination regimens of anti-angiogenic agents with standard chemotherapeutics increase patient survival.
基金financially supported by the National Natural Science Foundation of China(U1132604 and 81302670)
文摘Deoxyactein(DA)is a triterpenoid isolated from the root of Cimicifuga foetida which is a source of traditional Chinese herb'shengma'and is traditionally used as an antipyretic and analgesic agent.Previous studies showed that DA exhibited anti-proliferative effect in human breast cancer cells.Hence,the objectives of this study were to
文摘Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenomenon of resistance was based on the fact that was targeting normal vessels rather than tumour cells prone to mutation and subject to drug induced selection.However,reality turned out to be more complex and since 1997,several mechanisms of resistance have been described to the point that the study of resistance to these drugs is now a very large field.Far from being exhaustive,this paper presents the main mechanisms discovered trough some examples.
文摘Angiogenesis affects both wound healing and malignant cell growth through nutrients and oxygen.Vascular endothelial growth factor(VEGF) is the most important element involved in this complex process.Inhibition of VEGF influences angiogenesis and may restrict tumor growth and metastatic ability.Modern antiangiogenic therapy is based on this theory.Bevacizumab is a recombinant humanized monoclonal antibody(immunoglobulin G1) which binds with VEGF-A forming a large molecule.It can not be bound with VEGF tyrosine kinase receptors preventing VEGF-A incorporation;thus its activity is inhibited inducing blockage of VEGFmediated angiogenesis.Bevacizumab,in combination with chemotherapy or other novel targeted therapeutic agents,is currently used more frequently in clinical practice,mainly for managing advanced colorectal cancer.It is also used for managing other malignancies,such as breast cancer,pancreatic cancer,prostate cancer,non small-cell lung cancer,metastatic renal carcinoma and ovarian tumors.Although it is generally considered a safe treatment,there are reports of some rare side effects which should be taken into account.Recent experiments in rats and mice show promising results with a wider therapeutic range.
文摘Various imaging modalities are available for the diagnosis, staging and response evaluation of patients with renal cell carcinoma(RCC). While contrast enhanced computed tomography(CT) is used as the standard of imaging for size, morphological evaluation and response assessment in RCC, a new functional imaging technique like perfusion CT(p CT), goes down to the molecular level and provides new perspectives in imaging of RCC. p CT depicts regional tumor perfusion and vascular permeability which are indirect parameters of tumor angiogenesis and thereby provides vital information regarding tumor microenvironment. Also response evaluation using p CT may predate the size criteria used in Response Evaluation Criteria in Solid Tumors, as changes in the perfusion occurs earlier following tissue kinase inhibitors before any actual change in size. This may potentially help in predicting prognosis, better selection of therapy and more accurate and better response evaluation in patients with RCC. This article describes the techniques and role of p CT in staging and response assessment in patients with RCCs.
基金supported by the Ministry of Oceans and Fisheries,Korea(the project title:Development of marine material based near infrared fluorophore complex and diagnostic imaging instruments)by a Grant(1910070)from the National Cancer Center
文摘In this study, a fucoidan-based theranostic nanogel(CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve acti-vatable near-infrared fluorescence imaging of tumor sites and an enhanced photodynamic therapy(PDT) to induce the com-plete death of cancer cells. A CFN-gel has nanomolar a nity for P-selectin, which is overexpressed on the surface of tumor neovascular endothelial cells as well as many other cancer cells. Therefore, a CFN-gel can enhance tumor accumulation through P-selectin targeting and the enhanced permeation and retention e ect. Moreover, a CFN-gel is non-fluorescent and non-phototoxic upon its systemic administration due to the aggregation-induced self-quenching in its fluorescence and singlet oxygen generation. After internalization into cancer cells and tumor neovascular endothelial cells, its photoactivity is recovered in response to the intracellular redox potential, thereby enabling selective near-infrared fluorescence imaging and an enhanced PDT of tumors. Since a CFN-gel also shows nanomolar a nity for the vascular endothelial growth factor, it also provides a significant anti-tumor e ect in the absence of light treatment in vivo. Our study indicates that a fucoidan-based theranostic nanogel is a new theranostic material for imaging and treating cancer with high e cacy and specificity.
文摘Hepatocellular carcinoma(HCC)is the most common primary liver cancer.For advanced HCC,sorafenib was considered the standard of care for more than ten years.Recently the atezolizumab and bevacizumab combination has become standard of care for these patients without contraindications to either immune checkpoint inhibitors or antiangiogenic therapy.We now review the practical aspects of the atezolizumab and bevacizumab combination,including current evidence,indications,contraindications,management of adverse events,sequencing of this combination,areas of current knowledge gaps and future areas of active clinical research of this combination for busy clinicians in clinical practice.
文摘Angiogenesis, the growth of new vessels from pre-existing ones, is an important feature of tumor growth that has been exploited as a therapeutic target in oncology. Given its key role in facilitating blood vessel sprouting, VEGF has been a major focus of anti-angiogenic strategies, but the observation of resistance in some clinical trials utilizing such agents has led to a search for new or complementary targets in angiogenesis process. The Angiopoietin/Tie2 pathway and in particular the Angiopoietin-2 (Ang-2) ligand which is critically involved in the destabilization of normal vasculature, has been identified as one such target. The current study investigated the potential benefits of combining an Ang-2 targeted therapy with small molecule VEGF targeted agents (Sunitinib, Cediranib) in a human renal cell carcinoma model. The results showed that while both Ang-2 and VEGF interference on their own impaired tumor growth and new blood vessel formation, the combination of agents that targeted both pathways resulted in significantly superior anti-tumor and anti-angiogenic effects.
文摘In recent years,seeking effective anti-angiogenic components and therapeutic methods from traditional Chinese Medicine(TCM)has been a hot spot in the treatment of malignant tumors.In particular,the active ingredients found in Chinese herbal extracts have shown strong inhibition of tumor neovascularization.
文摘BACKGROUND Pseudomyxoma peritonei(PMP)is a rare benign,but progressive,disease according to myxoma histopathology.Surgical resection is the preferred and most effective treatment,but the outcomes are often unsatisfactory.CASE SUMMARY A 63-year-old Chinese woman with PMP received apatinib at a daily dose of 0.5 mg for 15 d per cycle and at a daily dose of 0.4 mg to date for recurrent abdominal distension after surgical treatment and hyperthermic intraperitoneal chemotherapy.During the follow-up period,apatinib was the maintenance treatment with a progression-free period of 10 mo and the toxicity of apatinib was controllable and tolerable.Unfortunately,recurrence occurred 10 mo after administration.After two operations,the patient gave up treatment at the 18th mo and eventually died of intestinal obstruction and multiple organ failure.CONCLUSION Apatinib may be an option for recurrent PMP after surgical treatment,but this conclusion remains to be confirmed.
基金supported by Institutode Salud Carlos Ⅲ(Grant PI17/00949)Fondo Europeode Desarrollo Regional(FEDER)“Una manera de hacer Europa” from the European Union+1 种基金Centrode Investigación Biomédicaen Redsobre Enfermedades Neurodegenerativas(CIBERNED-612)Fundación FEDER(Federación Espa?olade Enfermedades Raras),Consolidated Groupsfrom Gobiernode Aragón
文摘Among collagen members in the collagen superfamily,type XIX collagen has raised increasing interest in relation to its structural and biological roles.Type XIX collagen is a Fibril-Associated Collagen with Interrupted Triple helices member,one main subclass of collagens in this superfamily.This collagen contains a triple helix composed of three polypeptide segments aligned in parallel and it is associated with the basement membrane zone in different tissues.The molecular structure of type XIX collagen consists of five collagenous domains,COL1 to COL5,interrupted by six non-collagenous domains,NCI to NC6.The most relevant domain by which this collagen exerts its biological roles is NCI domain that can be cleavage enzymatically to release matricryptins,exerting anti-tumor and anti-angiogenic effect in murine and human models of cancer.Under physiological conditions,type XIX collagen expression decreases after birth in different tissues although it is necessary to keep its basal levels,mainly in skeletal muscle and hippocampal and telencephalic interneurons in brain.Notwithstanding,in amyotrophic lateral sclerosis,altered transcript expression levels show a novel biological effect of this collagen beyond its structural role in basement membranes and its anti-tumor and anti-angiogenic properties.Type XIX collagen can exert a compensatory effect to ameliorate the disease progression under neurodegenerative conditions specific to amyotrophic lateral sclerosis in transgenic SOD1 G93 A mice and amyotrophic lateral sclerosis patients.This novel biological role highlights its nature as prognostic biomarker of disease progression in and as promising therapeutic target,paving the way to a more precise prognosis of amyotrophic lateral sclerosis.
基金This work was supported by the Leading Investigator Program of Shanghai municipal government(17XD1401100)the National Key Basic Research Program(973 Program,2015CB554005)the National Natural Science Foundation of China(81372655,81472224 and 81672326)to HCS.
文摘Liver cancer,mostly hepatocellular carcinoma(HCC),is the second leading cause of cancer mortality globally.Most patients were diagnosed at an advanced stage,and systemic therapy is the standard of care.All the approved systemic therapies for HCC are molecular targeted therapies with anti-angiogenic effects targeting the vascular endothelial growth factor signaling pathway.Sorafenib and lenvatinib are the first-line treatment,and regorafenib,ramucirumab,and cabozantinib are second-line treatment options.Although anti-PD-1 antibodies,including nivolumab and pembrolizumab,demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials,both failed in phase III studies.Anti-angiogenic treatment remains the backbone of systemic therapy for HCC.In this review,we summarized the approved anti-angiogenic medicines and discussed the potential strategies to improve the efficacy of anti-angiogenic therapy,including combination therapy with other treatments,and discussed the approaches to overcome the drawbacks of anti-angiogenic therapies.
基金from State Project for Essential Drug Research and Development of the People’s Republic of China(No.2018ZX09303014)the Health and Family Planning Commission of Sichuan Province(No.18PJ194).
文摘Sarcomatoid carcinoma is a rare tumor that is composed of a mixture of malignant epithelial cells and mesenchymal cells.Many studies have reported that sarcomatoid carci-noma occurs in multiple organs including the liver.Sarco-matoid intrahepatic cholangiocarcinoma(S-iCCA)is an ex-tremely rare tumor that primarily occurs in the liver.This case occurred in a middle-aged man who was admitted to our hospital with abdominal pain.Enhanced computed to-mography of the abdomen showed a low-density mass in the upper right posterior lobe of the liver with enhancement in the periphery.Histological and immunohistochemical examination indicated that the tumor was malignant,with both cancer and sarcoma components,and was positive for cytokeratin and vimentin.The patient was diagnosed with S-iCCA.Metastases appeared in the liver and lung 4 months after surgery.Two cycles of chemotherapy were adminis-tered.Because of enlargement of the tumor,anti-angiogen-ic agents combined with immunotherapy were subsequently given to achieve disease control.To the best of our knowl-edge,this is the first reported case of a programmed cell death-1 inhibitor used in a S-iCCA patient.The purpose of this case report and literature review is to enhance clinician understanding of S-iCCA and to explore safe and effective treatment methods.
