This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase(SHP-2)on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2(Tie2)-expressin...This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase(SHP-2)on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2(Tie2)-expressing monocyte/macrophages(TEMs)and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)(Ang/Tie2-PI3K/Akt/mTOR)signaling pathway on the tumor microvascular remodeling in an immunosuppressive microenvironment.In vivo,SHP-2-deficient mice were used to construct colorectal cancer(CRC)liver metastasis models.SHP-2-deficient mice had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice,and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages’specific SHP-2-deficient mice(SHP-2MACKO)+planted tumor mice.Compared with the SHP-2 wild type mice(SHP-2WT)+planted tumor group,the SHP-2MAC-KO+planted tumor group experienced increased expression of p-Tie2,p-PI3K,p-Akt,p-mTOR,vascular endothelial growth factor(VEGF),cyclooxygenase-2(COX-2),matrix metalloproteinase 2(MMP2),and MMP9 in the liver tissue.TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cells and tumor cells as carriers.It was found that when Angpt1/2 was used for stimulation,the SHP-2MAC-KO+Angpt1/2 group displayed evident increases in the expression of the Ang/Tie2-PI3K/Akt/mTOR pathway.The number of cells passing through the lower chamber and the basement membrane and the number of blood vessels formed by cells compared with the SHP-2WT+Angpt1/2 group,while these indexes were subjected to no changes under the simultaneous stimulation of Angpt1/2+Neamine.To sum up,the conditional knockout of SHP-2 can activate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs,thereby strengthening tumor micro angiogenesis in the microenvironment and facilitating CRC liver metastasis.展开更多
目的探讨SHP-2蛋白在结直肠癌中的表达情况及其与病理特征的关系.方法采用免疫组织化学法和Western blot方法检测SHP-2蛋白在人结直肠癌组织中的表达情况,分析其与患者临床病理因素的关系.结果结直肠癌组织中S H P-2阳性表达率为25.6%(4...目的探讨SHP-2蛋白在结直肠癌中的表达情况及其与病理特征的关系.方法采用免疫组织化学法和Western blot方法检测SHP-2蛋白在人结直肠癌组织中的表达情况,分析其与患者临床病理因素的关系.结果结直肠癌组织中S H P-2阳性表达率为25.6%(43/168),与正常结直肠组织比较,差异有统计学意义(P<0.05).结直肠癌组织中SHP-2的蛋白水平为0.2396±0.0655,与配对正常结直肠组织比较(0.7665±0.1133),差异有统计学意义(P<0.0001).SHP-2蛋白的低表达与分化程度和淋巴结转移有关,与性别、年龄、浸润程度、远处转移、TNM分期无关.结论SHP-2可能在结直肠癌的发生发展过程中起抑制作用,并可能成为潜在的治疗靶点.展开更多
基金Natural Science Foundation Project of Hebei Province(H2022405033).
文摘This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase(SHP-2)on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2(Tie2)-expressing monocyte/macrophages(TEMs)and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)(Ang/Tie2-PI3K/Akt/mTOR)signaling pathway on the tumor microvascular remodeling in an immunosuppressive microenvironment.In vivo,SHP-2-deficient mice were used to construct colorectal cancer(CRC)liver metastasis models.SHP-2-deficient mice had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice,and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages’specific SHP-2-deficient mice(SHP-2MACKO)+planted tumor mice.Compared with the SHP-2 wild type mice(SHP-2WT)+planted tumor group,the SHP-2MAC-KO+planted tumor group experienced increased expression of p-Tie2,p-PI3K,p-Akt,p-mTOR,vascular endothelial growth factor(VEGF),cyclooxygenase-2(COX-2),matrix metalloproteinase 2(MMP2),and MMP9 in the liver tissue.TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cells and tumor cells as carriers.It was found that when Angpt1/2 was used for stimulation,the SHP-2MAC-KO+Angpt1/2 group displayed evident increases in the expression of the Ang/Tie2-PI3K/Akt/mTOR pathway.The number of cells passing through the lower chamber and the basement membrane and the number of blood vessels formed by cells compared with the SHP-2WT+Angpt1/2 group,while these indexes were subjected to no changes under the simultaneous stimulation of Angpt1/2+Neamine.To sum up,the conditional knockout of SHP-2 can activate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs,thereby strengthening tumor micro angiogenesis in the microenvironment and facilitating CRC liver metastasis.
文摘目的探讨SHP-2蛋白在结直肠癌中的表达情况及其与病理特征的关系.方法采用免疫组织化学法和Western blot方法检测SHP-2蛋白在人结直肠癌组织中的表达情况,分析其与患者临床病理因素的关系.结果结直肠癌组织中S H P-2阳性表达率为25.6%(43/168),与正常结直肠组织比较,差异有统计学意义(P<0.05).结直肠癌组织中SHP-2的蛋白水平为0.2396±0.0655,与配对正常结直肠组织比较(0.7665±0.1133),差异有统计学意义(P<0.0001).SHP-2蛋白的低表达与分化程度和淋巴结转移有关,与性别、年龄、浸润程度、远处转移、TNM分期无关.结论SHP-2可能在结直肠癌的发生发展过程中起抑制作用,并可能成为潜在的治疗靶点.
