Renal cell carcinoma(RCC)is a challenging urologic malignancy characterized by its aggressive nature,including invasion,metastasis,and treatment resistance.To explore multi-targeted therapies,we established an advance...Renal cell carcinoma(RCC)is a challenging urologic malignancy characterized by its aggressive nature,including invasion,metastasis,and treatment resistance.To explore multi-targeted therapies,we established an advanced clear cell renal cell carcinoma(cc RCC)model via orthotopic tumor transplantation in mice,and established another model simulating post-surgical recurrence by performing radical nephrectomy.We engineered a genetic circuit to reprogram the host liver as a bioreactor,enabling the production and delivery of in vivo self-assembled si RNAs(IVSA-si RNAs)for co-targeting VEGFR2 and m TOR.The efficacy and toxicity of this IVSA-si RNA system were evaluated and compared with the combination therapy of sunitinib and everolimus.In the established models,the combination therapy of sunitinib and everolimus showed efficacy but induced severe adverse effects.In contrast,IVSA-si RNAs potently silenced VEGFR2 and m TOR expression,achieving therapeutic effects in both advanced and radical nephrectomy cc RCC models without discernible toxicity.展开更多
Vascular endothelial growth factor(VEGF)and its receptors(VEGFRs)serve an essential role in tumor angiogenesis and have emerged as potential therapeutic targets in lung cancer.This review explores the significance of ...Vascular endothelial growth factor(VEGF)and its receptors(VEGFRs)serve an essential role in tumor angiogenesis and have emerged as potential therapeutic targets in lung cancer.This review explores the significance of serum VEGF levels as a predictive biomarker in non-small cell lung cancer(NSCLC).The VEGF family,consisting of VEGFA,VEGFB,VEGFC,VEGFD,and placenta growth factor(PlGF),engages with specific receptors,including tyrosine kinase receptors(VEGFR-1,VEGFR-2,and VEGFR-3)and neuropilin receptors(NRP-1 and NRP-2),to promote angiogenesis and lymphangiogenesis.VEGF-A,the primary component of the VEGF family,binds to VEGFR-2 to stimulate endothelial cell proliferation and migration,while VEGF-B,VEGF-C,and VEGF-D interact with VEGFR-1 and VEGFR-3 to regulate tumor angiogenesis,lymphangiogenesis,and metastasis.The VEGF/VEGFR signaling pathway activates various downstream effectors,including phospholipase Cγ1,mitogen-activated protein kinase(MAPK),and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt),which are essential for maintaining vascular homeostasis and promoting angiogenesis.In NSCLC,elevated serumVEGF levels have been observed,and the VEGF/VEGFR axis is frequently impaired,leading to irregular blood vessel formation and metastatic spread.Despite the development of anti-VEGF therapies,their impact on lung cancer outcomes has been limited.Further research is needed to optimize the effectiveness of these treatments and elucidate the potential of serum VEGF as a predictive biomarker in NSCLC.展开更多
Background:As a novel blocker of vascular endothelial growth factor receptor(VEGFR),fruquintinib has been approved for treating colorectal cancer(CRC).However,its dosage and therapeutic efficacy are limited by its wid...Background:As a novel blocker of vascular endothelial growth factor receptor(VEGFR),fruquintinib has been approved for treating colorectal cancer(CRC).However,its dosage and therapeutic efficacy are limited by its widespread adverse reactions.Venetoclax,recognized as the initial inhibitor of B-cell lymphoma protein 2(BCL2),has shown potential in boosting the effectiveness of immunotherapy against CRC.This study investigated the efficacy and mechanisms of fruquintinib combined with venetoclax in treating CRC.Methods and Materials:We developed a colon cancer mouse model with the CT26 colon cell line to demonstrate fruquintinib and venetoclax’s efficacy against tumors.Then we employed various techniques to evaluate different aspects of the experimental outcomes.Immunohistochemistry was used to detect cell proliferation and angiogenesis in tumor tissues.Western blot analysis was utilized to examine the occurrence of cell apoptosis,and flow cytometry to quantitate immune cells within the tumor tissues.Moreover,immunofluorescence was employed to measure cytokine levels.Results:The strongest inhibition on tumor growth was achieved by the combination of fruquintinib with venetoclax,as opposed to individual drug use.Venetoclax was found to amplify the impact of fruquintinib,leading to decreased cancer cell proliferation,increased cancer cell apoptosis,lowered angiogenesis,better vascular structure normalization,and improved immune cell infiltration.Conclusion:Our findings indicate that the addition of venetoclax enhances the impact of fruquintinib on vascular normalization and modulation of the tumor immune microenvironment.Our study presents the justification for utilizing the fruquintinib and venetoclax combination in treating CRC.Venetoclax holds promise in being assimilated into anticancer medications for CRC.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.32022015,31871295 and 82373158)the Training Program of the Major Research Plan of the National Natural Science Foundation of China(No.92268120)+1 种基金the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(No.SN-ZJU-SIAS-008)CAMS Innovation Fund for Medical Sciences(No.CIFMS-2021-I2M-5–015)。
文摘Renal cell carcinoma(RCC)is a challenging urologic malignancy characterized by its aggressive nature,including invasion,metastasis,and treatment resistance.To explore multi-targeted therapies,we established an advanced clear cell renal cell carcinoma(cc RCC)model via orthotopic tumor transplantation in mice,and established another model simulating post-surgical recurrence by performing radical nephrectomy.We engineered a genetic circuit to reprogram the host liver as a bioreactor,enabling the production and delivery of in vivo self-assembled si RNAs(IVSA-si RNAs)for co-targeting VEGFR2 and m TOR.The efficacy and toxicity of this IVSA-si RNA system were evaluated and compared with the combination therapy of sunitinib and everolimus.In the established models,the combination therapy of sunitinib and everolimus showed efficacy but induced severe adverse effects.In contrast,IVSA-si RNAs potently silenced VEGFR2 and m TOR expression,achieving therapeutic effects in both advanced and radical nephrectomy cc RCC models without discernible toxicity.
文摘Vascular endothelial growth factor(VEGF)and its receptors(VEGFRs)serve an essential role in tumor angiogenesis and have emerged as potential therapeutic targets in lung cancer.This review explores the significance of serum VEGF levels as a predictive biomarker in non-small cell lung cancer(NSCLC).The VEGF family,consisting of VEGFA,VEGFB,VEGFC,VEGFD,and placenta growth factor(PlGF),engages with specific receptors,including tyrosine kinase receptors(VEGFR-1,VEGFR-2,and VEGFR-3)and neuropilin receptors(NRP-1 and NRP-2),to promote angiogenesis and lymphangiogenesis.VEGF-A,the primary component of the VEGF family,binds to VEGFR-2 to stimulate endothelial cell proliferation and migration,while VEGF-B,VEGF-C,and VEGF-D interact with VEGFR-1 and VEGFR-3 to regulate tumor angiogenesis,lymphangiogenesis,and metastasis.The VEGF/VEGFR signaling pathway activates various downstream effectors,including phospholipase Cγ1,mitogen-activated protein kinase(MAPK),and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt),which are essential for maintaining vascular homeostasis and promoting angiogenesis.In NSCLC,elevated serumVEGF levels have been observed,and the VEGF/VEGFR axis is frequently impaired,leading to irregular blood vessel formation and metastatic spread.Despite the development of anti-VEGF therapies,their impact on lung cancer outcomes has been limited.Further research is needed to optimize the effectiveness of these treatments and elucidate the potential of serum VEGF as a predictive biomarker in NSCLC.
基金supported by the National Natural Science Foundation of China(82072675,82273197,82173933)Fundamental Research Funds for the Central Universities(020814380160).
文摘Background:As a novel blocker of vascular endothelial growth factor receptor(VEGFR),fruquintinib has been approved for treating colorectal cancer(CRC).However,its dosage and therapeutic efficacy are limited by its widespread adverse reactions.Venetoclax,recognized as the initial inhibitor of B-cell lymphoma protein 2(BCL2),has shown potential in boosting the effectiveness of immunotherapy against CRC.This study investigated the efficacy and mechanisms of fruquintinib combined with venetoclax in treating CRC.Methods and Materials:We developed a colon cancer mouse model with the CT26 colon cell line to demonstrate fruquintinib and venetoclax’s efficacy against tumors.Then we employed various techniques to evaluate different aspects of the experimental outcomes.Immunohistochemistry was used to detect cell proliferation and angiogenesis in tumor tissues.Western blot analysis was utilized to examine the occurrence of cell apoptosis,and flow cytometry to quantitate immune cells within the tumor tissues.Moreover,immunofluorescence was employed to measure cytokine levels.Results:The strongest inhibition on tumor growth was achieved by the combination of fruquintinib with venetoclax,as opposed to individual drug use.Venetoclax was found to amplify the impact of fruquintinib,leading to decreased cancer cell proliferation,increased cancer cell apoptosis,lowered angiogenesis,better vascular structure normalization,and improved immune cell infiltration.Conclusion:Our findings indicate that the addition of venetoclax enhances the impact of fruquintinib on vascular normalization and modulation of the tumor immune microenvironment.Our study presents the justification for utilizing the fruquintinib and venetoclax combination in treating CRC.Venetoclax holds promise in being assimilated into anticancer medications for CRC.
