Effect of kanglaite injection combined with chemotherapy on tumor factors, angiogenesis and immunoglobulin in patients with lung adenocarcinoma

Objective:To explore the effect of Kanglaite injection combined with chemotherapy on the levels of tumor factors, angiogenesis and immunoglobulin in patients with lung adenocarcinoma.Method: A total of 88 patients with lung adenocarcinoma in our hospital and the Fifth Peoples Hospital of Wuxi from February 2014 to December 2017 were divided randomly into observation group and control group according to the visiting time, 44 cases for each group. The observation group was treated with chemotherapy combined with Kanglaite injection, and the control group was treated with chemotherapy only.Both groups were treated for 6 weeks and then the levels of CEA, CA125, CA199, VEGFA, VEGFB, VEGFC, and IgA, IgM, IgG after treatment in both groups were compared.Result: Before treatment, there were no significant differences in the levels of CEA, CA125 and CA199 between two groups. The level of CEA in the observation group (29.88±7.07) μg/L was lower than that in the control group,and the difference was statistically significant. The levels of CA125 and CA199 after treatment were lower than those before treatment, but with no significant difference. Between the two groups, there was no significant difference of the levels of VEGFA,VEGFB and VEGFC before treatment, the level of VEGFA after treatment in the observation group (80.49±12.29) ng/mL was lower than that in the control group and the difference was statistically significant, and the levels of VEGFB and VEGFC after treatment were also lower than those before treatment, but with no significant difference. The levels of IgA, IgM and IgG before treatment in two groups had no significant difference, The level of IgM after treatment in the observation group (1.52±0.30) g/L was lower than that in the control group, with a statistical difference. The levels of IgA and IgG after treatment were lower than those before treatment, but with no significant difference;No serious adverse reaction was observed after treatment in both groups.Conclusion: Kanglaite injection combined with chemotherapy has a good clinical effect in lung adenocarcinoma, which can effectively inhibit the high expression of tumor markers, reduce angiogenesis, enhance body immunity, and can be recommended for clinical application.

Correlation research of Runt-related transcription factor 2 with proliferation genes, tumor suppressor genes and angiogenesis molecules in colon cancer lesions

Objective: To investigate the correlation of Runt-related transcription factor 2 (RunX2) with proliferation genes, tumor suppressor genes and angiogenesis molecules in colon cancer lesions. Methods: A total of 90 patients with primary colon cancer were enrolled in colon cancer group, 68 patients with benign colon polyps were enrolled in colon polyps group, the differences in the expression levels of RunX2, proliferation genes, tumor suppressor genes and angiogenesis molecules in the two groups of lesions were compared, and Pearson test was further used to evaluate the correlation of RunX2 expression level with proliferation gene, tumor suppressor gene and angiogenesis molecule expression levels in colon cancer tissues. Results: RunX2 mRNA expression level in the lesions of colon cancer group was higher than that of colon polyps group. Proliferation genes GTPBP4, HOXB7, ZNF331, ADAM17 and HSP60 mRNA expression levels in the lesions of colon cancer group were higher than those of colon polyps group;tumor suppressor genes ATF3, FOXN3, OTUD1 and NDRG2 mRNA expression levels were lower than those of colon polyps group;angiogenesis molecules Musashi 1, NF-κB, RegⅣ and STAT3 mRNA expression levels were higher than those of colon polyps group. RunX2 mRNA expression level in the colon cancer lesions was directly correlated with the expression levels of the above proliferation genes, tumor suppressor genes and angiogenesis molecules. Conclusion: RunX2 expression is abnormally high in colon cancer lesions, the specific expression level is positively correlated with cancer cell proliferation activity and angiogenesis activity, and it is an important molecular target that can lead to the occurrence and development of colon cancer.

Effects of Xiaocangping tablets combined with 5-fluorouracil and cisplatin on immunity, tumor markers, angiogenesis and related factors in patients with advanced esophageal cancer

Objective:To explore the effects of Xiaocangping tablets combined with 5-fluorouracil and cisplatin on immunity, tumor markers, angiogenesis and related factors in patients with advanced esophageal cancer.Methods:86 patients with advanced esophageal cancer admitted to our hospital from March 2014 to February 2017 were randomly divided into control group (43 cases) and observation group (43 cases). All the subjects were treated with 5-fluorouracil plus cisplatin, and the observation group was treated with Xiaocangping tablets on this basis. The changes of immune function, tumor markers, angiogenesis and related factors in the two groups were compared and analyzed.Results:After treatment, the levels of CD4+, CD4+/CD8 + in both groups were significantly higher than those before treatment (P<0.05), while the levels of CD8+ were significantly lower than those before treatment (P<0.05), the levels of CD4+ and CD4+/CD8+ in the observation group were significantly higher than those in the control group (P<0.05), while the levels of CD8+ in the observation group was significantly lower than that in the control group (P<0.05);the levels of CA125, CEA and CA19-9 in the two groups were significantly lower than those before treatment (P<0.05), and the levels of CA125, CEA and CA19-9 in the observation group were significantly lower than those in the control group (P<0.05);the levels of VEGF, TGF-β1, MMP-9, NGAL in the two groups were significantly lower than those before treatment (P<0.05), and the levels of VEGF, TGF-β1, MMP-9, NGAL in the observation group were significantly lower than the control group (P<0.05).Conclusions:Chemotherapy combined with fluorouracil + cisplatin chemotherapy for advanced esophageal cancer can effectively improve the immune function of patients, reduce the level of tumor markers, inhibit the proliferation of tumor blood vessels, and have significant anti-cancer effects, which is of positive significance for controlling the development of patients' conditions.

Inhibitory effect of arsenic trioxide on angiogenesis and expression of vascular endothelial growth factor in gastric cancer

AIM: To investigate the inhibitory effect of As2O3 on angiogenesis of tumor and expression of vascular endothelial growth factor (VEGF) in tumor cells in vivo and in vitro. METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were randomly divided into three groups. As2O3 was injected into the arsenic-treated groups (2.5 mg/kg and 5 mg/kg) and the same volume of saline solution was injected into the control group. Microvessel density (MVD) and expression of VEGF were detected with immunofluorescence laser confocal technology. Further expression of VEGF protein and VEGF mRNA was measured with Western bloting and fluorescence quantitative RT- PCR in SGC-7901 cells treated with As2O3. RESULTS: In nude mice, after treatment with 5 mg/kg and 2.5 mg/kg As2O3 respectively, about 50% and 30% tumor growth inhibition were observed correspondingly (P < 0.05, P < 0.05). Decrease in MVD appeared in As2O3-treated tumors compared with control group (P < 0.001, P < 0.001). MVD in tumors was significantly lower in 5 mg/kg group than in 2.5 mg/kg group (P < 0.01). The fluorescence intensity levels of VEGF in tumor cells were significantly lowered in the arsenic-treated groups (P < 0.01, P < 0.01). The fluorescence intensity level of VEGF in 5 mg/kg group was lower than that in 2.5 mg/ kg group (P < 0.01). In vitro, the expression of VEGF protein decreased in dose- and time-dependent manner after the treatment with As2O3, but in VEGF mRNA no significant difference was found between the control group and the treated groups. CONCLUSION: As2O3 can inhibit solid tumor growth by inhibiting the formation of new blood vessels. One of the mechanisms is that As2O3 can inhibit VEGF protein expression.

Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1-regulated proliferation of gastric cancer stem-like cells

AIM: To determine the underlying mechanisms of action and influence of Xiaotan Sanjie (XTSJ) decoction on gastric cancer stem-like cells (GCSCs).

Tumor angiogenesis and its clinical significance in pediatric malignant liver tumor

AIM: To investigate the expression of vascular endothelial growth factor (VEGF) and microvascular density (MVD) count in pediatric malignant liver tumor and their clinical significances. METHODS: Fourteen children with malignant liver tumors including seven hepatocellular carcinomas (HCCs), five hepatoblastomas, one malignant mesenchymoma and one rhabdomyosarcoma were studied. Twelve adult HCC samples served as control group. All samples were examined with streptavidin-biotin peroxidase (SP) immunohistochemical staining for VEGF expression and MVD count. RESULTS: VEGF positive expression in all pediatric malignant liver tumors was significantly higher than that in adult HCC (0.4971±0.14 vs0.4027±0.03, P<0.05). VEGF expression in pediatric HCC group was also markedly higher than that in adult HCC group (0.5665±0.10 vs0.4027±0.03, P<0.01) and pediatric non-HCC group (0.5665±0.10 vs 0.4276±0.15, P<0.05). The mean value of MVD in pediatric malignant liver tumors was significantly higher than that in adult HCC (33.66±12.24 vs 26.52±4.38, P<0.05). Furthermore, MVD in pediatric HCC group was significantly higher compared to that in adult HCC group (36.94±9.28 vs 26.52±4.38, P<0.05), but there was no significant difference compared to the pediatric non-HCC group (36.94±9.28 vs 30.37±14.61, P>0.05). All 7 children in HCC group died within 2 years, whereas the prognosis in pediatric non-HCC group was better, in which two patients survived more than 5 years. CONCLUSION: Children with malignant liver tumors, especially with HCC, may have extensive angiogenesis that induces a rapid tumor growth and leads to a poor prognosis.

Effect of non-anticoagulant N-desulfated heparin on expression of vascular endothelial growth factor, angiogenesis and metastasis of orthotopic implantation of human gastric carcinoma

AIM： To investigate the effect of N-desulfated heparin on tumor metastasis and angiogenesis, and expression of vascular endothelial growth factor （VEGF） of orthotopic implantation of human gastric carcinoma in male severe combined immune deficiency （SCID） mice. METHODS： Human gastric cancer SGC-7901 cells were orthotopically implanted into the stomach of SC/D mice. The mice were randomly divided into normal saline group and N-desulfated heparin group. One week after operation, the mice in N-desulfated heparin group reo ceived i.v. injections of N-desulfated heparin （Shanghai Institute of Cell Biology, Chinese Academy of Sciences, 10 mg/kg.d） twice weekly for 3 wk. The mice in normal saline group received i.v. injections of normal saline （100 μL） twice weekly for 3 wk. The mice were sacrificed six weeks after implantation. Tumor metastasis was evaluo ated histologically for metastasis under microscope. Intratumoral microvessel density （MVD） and VEGF expression were evaluated immuohistochemically. VEGF mRNA expression in gastric tissue of SC/D mice was detected by real time PCR. RESULTS： The tumor metastasis rate was 80% in normal saline group and 20% in N-desulfated heparin group （P 〈 0.05）. MVD was 8.0 ± 3.1 in normal saline group and 4.3 ± 1.8 in N-desulfated heparin group （P 〈 0.05）. VEGF positive immunostaining was found in cytoplasm of cancer cells. The rate of VEGF positive expression was higher in normal saline group than in N-desulfated hepa- rin treated group （90% vs 20%, P 〈 0.05）. VEGF mRNA expression was significantly inhibited by N-desulfated heparin and was higher in normal saline group than in N-desulfated heparin group （Ct value 19.51 ± 1.01 vs 22.55± 1.36, P 〈 0.05）. N-desulfated heparin significantly inhibited the expression of VEGF mRNA in cancer cells. No bleeding occurred in N-desulfated heparin group. CONCLUSION： N-desulfated heparin can inhibit metastasis of gastric cancer by suppressing tumor VEGF expression and tumor angiogenesis, but has no obvious anticoagulant activity.

Angiogenic markers endoglin and vascular endothelial growth factor in gastroenteropancreatic neuroendocrine tumors

AIM:To investigate the expression and potential prognostic role of vascular endothelial growth factor(VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors(GEP-NETs) . METHODS:Microvessel density(MVD) in GEP-NETs was evaluated using endoglin and CD31 immunohistochemistry.In addition,tissue levels of endoglin and VEGF were determined in homogenates by ELISA. RESULTS:Endoglin was highly expressed on tumor endothelial cells.CD31 MVD in GEP-NETs was significantly higher compared to endoglin MVD(P<0.01) .Two-tofour-fold higher tissue levels of endoglin and VEGF were seen in tumors compared to associated normal tissue. This increased endoglin tissue expression in tumors was significantly related to tumor size(P<0.01) ,presence of metastases(P=0.04) ,and a more advanced tumor stage(P=0.02) ,whereas expression of VEGF was not. CONCLUSION:We suggest that endoglin is a potential marker to indicate and predict metastases,which might be useful in the post-resection therapeutic approach of patients with GEP-NETs.

Angiogenesis in hepatocellular carcinoma:mechanisms and anti-angiogenic therapies

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.

Exploration on Effect and Mechanism of Suiqing Pill (髓清丸) on Tumor Angiogenesis in Nude Mouse B16 Melanoma Model

Objective: To study the effect of Suiqing Pill (SQP, 髓清丸),a TCM compound drug that can activate blood circulation and get rid of blood stasis, on angiogenesis in tumor and its possible mechanism. Method: BALB/c nude mice were inoculated with melanoma cell line B16 at right armpit subcutaneously to establish cancer spontaneous metastasis model. Levels of microvessel density (MVD), vascular endothelial growth factor (VEGF) and protein expression of matrix metalloproteinase-2 (MMP-2) in tumor tissues were observed and compared. Results: Strong expression of anti-Factor Ⅷ (FⅧ) related antigen and plentiful tumor angiogenesis were seen in model control animals, while in the high-dose and low-dose SQP treated model mice, MVD was inhibited by 33. 5% and 22. 6% respectively ( P<0. 01, P<0. 05). The strong positive protein expression of VEGF and MMP-2 in model control also reduced in the SQP treated groups. Conclusion: SQP could inhibit tumor angiogenesis, protein expression of VEGF and MMP-2 in nude mice B16 melanoma models.

Angiogenesis Factors Associated with New Breast Cancer Cell Line AMJ13 Cultured <i>in Vitro</i>

Background: AMJ13 is a new breast cancer cell line that has been established from a 70-year-old Iraqi woman with a histological diagnosis of infiltrating ductal carcinoma. It is the first for an Iraqi population. In breast cancer, angiogenesis provides the tumor tissue, which is rapidly proliferated with oxygen and nutrients, removes wastes and increases the opportunity of cancer cells to invade other organs. Methods: The AMJ13 breast cancer cell line was represented at three different passages and incubated for interval times. Microarray panel of 43 different angiogenesis markers was used to scan the supernatant for the factors. ELISA was used to quantify some of the important angiogenesis factors released in the culture medium and to confirm absence of those who was not detected by the antibody array. RT-PCR was used to confirm the gene expression (mRNA) of studied factors. Results: Microarray analysis showed that TIMP1 and two secreted at highest levels compared to the rest of the factors with low presence of endostatin. Other non-detectable factors by microarray examined by ELISA assay that showed highest expression level of VEGF-A were obtained at earliest passage, while the highest levels of FGF-b were obtained at late passage. The VEGF-D secretion was shown low concentrations at all studied passages. There is no detectable level of EGF protein in different passages and times interval tested. There are no significant differences in secretion of sICAM between different passages and incubation periods. Conclusion is that AMJ13 cell line depends on VEGF-A as main angiogenesis factor to induce micro-vessels supported by low levels of VEGF-D for lymphatic vessels formation. AMJ13 cell line depends on FGF as growth factors as in late passages it was shifted to depend mainly on FGF completely. All of this process may be regulated by TGF-β. TIMP-1 has proangiogentic effect and has feedback talk with TIMP-2. Understanding the angiogenesis process for breast cancer can give us better targets for therapy and more effective treatments.

Effect of grape proanthocyanidins on tumor growth and angiogenesis in H22 liver cancer xenograft model

Objective: The aim of this study was to investigate the effect of grape proanthocyanidins(GPC) on the growth and angiogenesis of hepatocellular carcinoma H22 cells xenograft in mice. Methods: The xenograft model was established using injected subcutaneously H22 cells into the right axilla of the mice. Each group was treated with different doses of GPC and Endostar. All these treatments were maintained for 10 days, and mice were sacrificed. The xenograft tumors in mice were measured. The proliferation activity level of H22 cells was determined by MTT assay, and the levels of vascular endothelial growth factor(VEGF) protein were examined by immunohistochemistry. Results: When treated with 50, 100 and 200 mg/kg of GPC and Endostar, the tumor inhibition rates were 13.17%, 23.37%, 36.15% and 14.71%, respectively. The tumor weight of xenograft was significantly lighter in high GPC group than the control group(P < 0.05). The ODs in GPC groups were 0.835, 0.666 and 0.519, respectively. The absorbances in middle and high GPC groups were statistically significant, compared with control group(P < 0.01). Immunohistochemical technique showed the expression of VEGF of the GPC groups was downregulated significantly compared with the control group(P < 0.01). Conclusion: GPC can inhibit the growth of hepatocellular carcinoma H22 cell xenograft in mice. The inhibition of angiogenesis by the down-regulation of VEGF expression may play a key role in the anti-neoplastic effect of GPC.

Inhibitory Actions of Tetrandrine on Tumor Necrosis Factor α-Induced NF-κB Activation in Neovascularization of Cultured Choroidal Explants

Tetrandrine (1 μM), a bis-benzylisoquinoline alkaloid isolated from Stephania tetrandra S Moore, signifi-cantly decreased tumor necrosis factor alpha (TNFα;10 ng/ml)-induced increase in the number of micro vessels that budded from cultured rat choroidal explants. Tetrandrine also decreased the TNFα-induced in-crease in the number of cells composing the microvessels. Ammonium pyrrolidine dithiocarbamate (APDC;0.1-0.3 μM), an inhibitor of nuclear factor-κB (NF-κB), decreased the TNFα-induced increase in the number of microvessels in a concentration-dependent manner. TNFα increased the phosphorylation and degradation of inhibitor of NF-κB (IκBα), as well as increasing the DNA-binding activity of NF-κB in choroidal explants. TNF? induced an increase of vascular endothelial growth factor (VEGF)-A mRNA, but not VEGF-C mRNA or VEGF-D mRNA. TNFα-induced angiogenic action was inhibited by treatment of VEGF-A antibody in cultured choroidal capillaries. Tetrandrine inhibited the TNFα-induced increases of phosphorylation and degradation of IκBα, and reduced the TNFα-induced increase of DNA-binding activity of NF-κB in chor-oidal explants. In conclusion, tetrandrine inhibits TNFα-induced activation of NF-κB in the choroidal capil-laries via inhibition of TNFα-induced phosphorylation of IκBα.

白屈菜碱对小鼠肺癌细胞皮下移植瘤生长和血管生成的抑制作用及其机制

目的:探讨白屈菜碱对肺癌移植瘤小鼠肿瘤生长和血管生成的影响,并阐明其作用机制。方法:选取32只健康C57BL/6小鼠,制备Lewis肺癌移植瘤小鼠模型。将小鼠随机分为模型组(0.9%氯化钠)、低剂量白屈菜碱组(25 mg·kg^(-1)白屈菜碱)、高剂量白屈菜碱组(50 mg·kg^(-1)白屈菜碱)和阳性对照组(60 mg·kg^(-1)环磷酰胺),每组8只。称量各组小鼠移植瘤质量并计算抑瘤率,计算各组小鼠胸腺指数和脾脏指数,采用酶联免疫吸附测定(ELISA)法检测各组小鼠血清中白细胞介素2(IL-2)、γ干扰素(INF-γ)和肿瘤坏死因子α(TNF-α)水平,免疫组织化学法检测各组小鼠肿瘤组织中血管内皮生长因子(VEGF)蛋白表达情况并计算微血管密度(MVD)及VEGF蛋白表达评分,Westernblotting法检测各组小鼠肿瘤组织中核因子κB(NF-κB)和缺氧诱导因子1α(HIF-1α)蛋白表达水平。结果:与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠移植瘤质量均降低(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠移植瘤质量均降低(P<0.05),抑瘤率均升高(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠移植瘤质量均降低(P<0.05),抑瘤率升高(P<0.05)。与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠脾脏指数和胸腺指数均升高(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠脾脏指数及胸腺指数均升高(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠脾脏指数和胸腺指数均升高(P<0.05)。ELISA法,与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠血清中IL-2、INF-γ和TNF-α水平均升高(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠血清中IL-2、INF-γ和TNF-α水平均升高(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠血清中IL-2、INF-γ和TNF-α水平均升高(P<0.05)。与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠肿瘤组织MVD降低(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织MVD降低(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠肿瘤组织中MVD降低(P<0.05)。与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠肿瘤组织中VEGF蛋白表达量减少;与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织中VEGF蛋白表达量减少;与高剂量白屈菜碱组比较,阳性对照组小鼠肿瘤组织中VEGF蛋白表达量减少;模型组、低剂量白屈菜碱组、高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织VEGF蛋白表达评分比较差异有统计学意义(P<0.05)。Western blotting法,与模型组比较,低和高剂量白屈菜碱组及阳性对照组小鼠肿瘤组织中NF-κB和HIF-1α蛋白表达水平降低(P<0.05);与低剂量白屈菜碱组比较,高剂量白屈菜碱组和阳性对照组小鼠肿瘤组织中NF-κB和HIF-1α蛋白表达水平降低(P<0.05);与高剂量白屈菜碱组比较,阳性对照组小鼠肿瘤组织中NF-κB和HIF-1α蛋白表达水平降低(P<0.05)。结论:白屈菜碱能够抑制Lewis肺癌移植瘤小鼠肿瘤组织生长、保护免疫器官和抑制肿瘤血管生成,可能通过靶向NF-κB/HIF-1α信号通路和下调NF-κB及HIF-1α蛋白表达水平发挥治疗作用。

基于阴阳平衡理论研究血管新生中的双向调控机制

血管新生是由已有的脉管系统发育出新的脉管的过程。血管新生与缺血性疾病、血管异常增生疾病密切相关,是当前研究的热点。血管新生是一个双向调节的过程,一方面血管新生依赖于促血管生成因子和抑制血管生成因子2种因子正负调控的精确平衡。另一方面,血管新生对缺血性疾病和血管异常增生疾病也起到正反两方面调控作用。阴阳学说是中医学基本理论之一,贯穿中医辨证施治的始终。血管新生的双向调控正如阴阳双方既对立又统一的关系以维持血管新生的平衡。肿瘤坏死因子-α(TNF-α)、Notch信号通路、促红细胞生成素肝细胞激酶受体B4/促红细胞生成素肝细胞激酶受体配体B2(Eph B4/Ephrin B2)信号通路、转化生长因子-β(TGF-β)/Sma和Mad相关(Smad)信号通路等双向调控血管新生以维持血管新生的平衡,与阴阳平衡理论高度契合。

安罗替尼在非小细胞肺癌铂类为基础的联合化疗方案中的应用

目的:探讨安罗替尼在非小细胞肺癌(NSCLC)以铂类为基础联合化疗方案中的应用效果。方法:选取2021年6月至2022年12月于永城市人民医院就诊并治疗的NSCLC患者104例,随机分为研究组和对照组,每组各52例,对照组采用培美曲塞联合顺铂方案,研究组采用安罗替尼、培美曲塞联合顺铂方案。观察并比较治疗两个疗程后两组患者的临床疗效、血清肿瘤标志物水平、血管生成调节因子水平以及不良反应和患者生存质量情况。结果:同组相比,两组患者治疗后血清CEA、SCCA、CYFRA21-1、VEGF、MMP9平均值均低于治疗前,ES及FACT-L评分、KPS评分平均值均高于治疗前(P<0.05)。组间比较,治疗后,研究组患者客观缓解率(ORR)、疾病控制率(DCR)、ES平均水平、FACT-L评分、KPS评分平均值均高于对照组(P<0.05),血清CEA、SCCA、CYFRA21-1、VEGF、MMP9平均水平均低于对照组(P<0.05)。研究组与对照组患者出现乏力、出血、胃肠道反应、高血压、手足皮肤反应、白细胞与淋巴细胞计数减少、肝肾功能损害等不良反应的频率比较差异无统计学意义(P>0.05)。结论:安罗替尼联合培美曲塞、顺铂化疗方案能促进NSCLC的控制与缓解,改善血管生成调节因子水平,降低体内肿瘤标志物水平,提高患者生存质量,并且具有较好的应用安全性。

Prognostic angiogenic markers(endoglin, VEGF, CD31) and tumor cell proliferation(Ki67) for gastrointestinal stromal tumors

AIM: To evaluate the correlation between the immunoexpression of angiogenic markers [CD31, CD105 and vascular endothelial growth factor(VEGF)], proliferative index(Ki67), and prognosis of patients with gastrointestinal stromal tumors(GIST).METHODS: This is a retrospective study of 54 GIST cases. Medical records were searched to obtain the GIST patients' demographic and clinical data, and paraffin-embedded blocks of tumor samples were retrieved from the hospital archives to conduct a new immunohistochemical evaluation. The tumor samples of GIST patients were subject to immunohistochemical evaluation for endoglin(CD105), CD31, VEGF, and Ki67 expression. The CD105 and CD31 intratumoral microvascular density(IMVD) was measured using automated analysis. We determined the correlation between the immunoexpression of CD105, CD31, VEGF,Ki67 and prognosis. In addition, we conducted a cutoff analysis using the receiver-operating characteristic curve. VEGF positivity was classified as either null/weak or strong. Ki67 was evaluated using a cutoff of 5%positive cells. The prognosis was classified as good(patient alive without recurrence) or poor(patient with recurrence/death).RESULTS: The distribution of tumor sites among the54 analyzed samples was as follows: 27(50%) in the stomach, 20(37.1%) in the small intestine, 6(11.1%)in the colon, and 1(1.8%) in the esophagus. The size of the tumors ranged from 2 to 33 cm(median: 8cm); in 12 cases(22.2%), the tumor was below 5 cm at the largest diameter, but in 42 cases(77.7%), the tumor was larger than 5 cm. The means of CD105 and CD31 were significantly higher in the group with poor prognosis(P < 0.001). The cut-off values of CD105(>1.2%) and CD31(> 2.5%) in the receiver-operating characteristic curve were related to a poorer prognosis.Cases with a better prognosis showed significantly null/weak staining for VEGF(P < 0.001). Ki-67 expression of≥ 5% was strongly correlated with a worse prognosis(P< 0.001). In the multivariate analysis, CD105 was the variable that most strongly correlated with prognosis.CONCLUSION: The IMVD cutoff values for the angiogenic markers CD105 and CD31, may be prognostic factors for GIST, in addition to VEGF and Ki67.

Effects of endostatin on expression of vascular endothelial growth factor and its receptors and neovascularization in colonic carcinoma implanted in nude mice

AIM:To investigate the antiangiogenic effects of endostatin on colonic carcinoma cell line implanted in nude mice and its mechanism. METHODS:Nude mice underwent subcutaneous injection with LS-174t colonic carcinoma cell line to generate carcinoma and were randomly separated into two groups.Mice received injection of vehicle or endostatin every day for two weeks. After the tumor was harvested,the tumor volumes were determined,and the expressions of CD34,VEGF and FIk-1 were examined by immunohistochemical method. RESULTS:Tumor volume was significantly inhibited in the endostatin group(84.17%)and tumor weight was significantly inhibited in the endostatin group(0.197±0.049) compared to the control group(1.198±0.105)(F=22.56, P=0.001),microvessel density(MVD)was significantly decreased in the treated group(31.857±3.515)compared to the control group(100.143±4.290)(F=151.62,P<0.001). Furthermore,the expression of FIk-1 was significantly inhibited in the treated group(34.29%) ompared to the control group(8.57%)(X^2=13.745,P=0.001).However no significant decrease was observed in the expression of vascular endothelial growth factor(VEGF)between these two groups(X^2=0.119,P=0.730). CONCLUSION:Endostatin can inhibit tumor growth and angiogenesis by blocking Vegf/FIk-1 pathway.This experiment provides the theory basis for developing a new anti-carcinoma drug through studying the properties of anti-angiogenesis inhibitors.

Expression of vascular endothelial growth factor and its role in oncogenesis of human gastric carcinoma

AIM: To establish the role of vascular endothelial growth factor (VEGF) in the oncogenesis of human gastric carcinoma more directly. METHODS: The expression of VEGF and its receptor kinase-domain insert containing receptor (KDR) in human gastric cancer tissue were observed by immunohistochemical staining. VEGF levels were manipulated in human gastric cancer cell using eukaryotic expression constructs designed to express the complete VEGF(165) complimentary DNA in either the sense or antisense orientation. The biological changes of the cells were observed in which VEGF was up-regulated or down-regulated. RESULTS: VEGF-positive rate was 50%, and VEGF was mainly localized in the cytoplasm and membrane of the tumor cells, while KDR was mainly located in the membrane of vascular endothelial cells in gastric cancer tissues and peri-cancerous tissue. In 2 cases of 50 specimens, the gastric cancer cells expressed KDR, localized in both the cytoplasm and membrane. Introduction of VEGF(165) antisense into human gastric cancer cells (SGC-7901, immunofluorescence intensity, 31.6%)) resulted in a significant reduction in VEGF-specific messenger RNA and total and cell surface VEGF protein (immunofluorescence intensity, 8.9%) (P【0.05). Conversely, stable integration of VEGF(165) in the sense orientation resulted in an increase in cellular and cell surface VEGF (immunofluorescence intensity, 75.4%) (P【0.05). Lowered VEGF levels were associated with a marked decrease in the growth of nude mouse xenografted tumor (at 33 days postimplantation, tumor volume: 345.40 +/- 136.31 mm3)(P【0.05 vs control SGC-7901 group: 1534.40 +/- 362.88 mm3), whereas up-regulation of VEGF resulted in increased xenografted tumor size (at 33 days postimplantation, tumor volume: 2350.50 +/- 637.70 mm3) (P【0.05 vs control SGC-7901 group). CONCLUSION: This study provides direct evidence that VEGF plays an important role in the oncogenesis of human gastric cancer.

Tea polyphenols inhibit the growth and angiogenesis of breast cancer xenografts in a mouse model

Objective:To investigate the anti-angiogenic effect of tea polyphenols(TPS)on breast cancer and normal tissues in a mouse model.Methods:Breast cancer was successfully implanted into 48 BALB/c mice,which were then randomly divided into a TP oral gavage group,a TP local injection group,a ginsenoside Rg3 group,and a model control group according to a random number table.The tumor inhibitory rates of each group were calculated,while microvessel density(MVD)and the expression of vascular endothelial growth factor(VEGF),basic fibroblast growth factor(bFGF),and tissue inhibitor of metalloproteinase(TIMP-2)were detected by immunohistochemistry.Results:TPs could inhibit the growth of breast cancer xenografts in the mouse model.The tumor inhibition rates of the TP oral gavage and TP local injection groups were 37.43%and 40.94%,respectively.Compared with the model control group,MVD and VEGF and bFGF expression was downregulated(all P<.05),whereas TIMP-2 expression was elevated in the TP oral gavage and TP local injection groups(P=.015 and P=.032).TPs showed no significant effect on MVD and VEGF and TIMP-2 expression in the heart,brain,and kidney of the mouse model.Conclusion:TPs can restrict the growth of breast cancer by specifically inhibiting the angiogenesis of breast tumor tissue while having little effect on the normal tissue of important organs including the heart,brain,and kidney.