血管内皮生长因子抗体对肿瘤转移的抑制作用

目的探讨阻断血管内皮生长因子（ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒ,ＶＥＧＦ）是否可以抑制肿瘤的转移。方法应用ＩＶＴＡ２ＭＡ－８９１津白Ⅱ小鼠自发乳腺癌模型进行抗肿瘤转移的研究,此模型伴有高自发肺转移。结果Ｎｏｒｔｈｅｒｎ杂交及免疫组化证实,该乳腺癌原发灶及肺转移灶均可表达ＶＥＧＦ,且以后者为高。接种肿瘤后第９天,以ＶＥＧＦ抗体处理荷瘤小鼠,可明显抑制原发肿瘤的生长（４４．０％,Ｐ＜０．０５）,而对肺转移灶数目及转移灶大小的抑制率分别达７３．０％和８３．７％。结论ＶＥＧＦ抗体对肿瘤转移的抑制有潜在的应用价值。     

微血管定量和血管内皮生长因子表达在肠型胃癌中的意义

为研究血管形成和血管形成因子表达在肠型胃癌和弥漫型胃癌中的作用，应用抗因子Ⅷ相关抗原抗体、抗ＶＥＧＦ抗体及抗ｂＦＧＦ抗体的免疫组化ＬＳＡＢ法，分别对６３例肠型胃癌和４５例弥漫型胃癌中的微血管数量（ＭＶＣ）、ＶＥＧＦ和ｂＦＧＦ表达进行研究。ＭＶＣ和ＶＥＧＦ及ｂＦＧＦ表达在肠型胃癌明显高于弥漫型胃癌（Ｐ分别＜０．０５，０．００１和０．０１），同样，ＭＶＣ和ＶＥＧＦ表达在肝转移患者明显高于腹膜转移者（Ｐ分别＝０．００１和＜０．０１）；在肠型胃癌中，ＭＶＣ与ＶＥＧＦ表达明显相关（Ｐ＝０．０２），ＭＶＣ和ＶＥＧＦ表达随ＴＮＭ分期增加而增加，而与弥漫型胃癌无关。两型胃癌中的ｂＦＧＦ表达均与ＭＶＣ无关。本研究结果表明肠型胃癌的转移形式为血管依赖性，ＶＥＧＦ可能是诱导肠型胃癌血管形成的一个重要因子。     

原发性肝癌肿瘤血管密度及其表达的临床病理意义

目的研究肿瘤微血管密度（ＭＶＤ）和肿瘤血管生长因子（ＶＥＧＦ）的表达水平在原发性肝癌中的临床病理意义。方法对６３例手术切除的小肝癌（直径＜５ｃｍ）患者的临床病理资料进行了回顾性的研究。其中２年内转移复发组２９例,２年内无转移复发组３４例。每例取３张连续的切片分别进行ＨＥ染色、ＶＥＧＦ和生物素标记的荆豆凝集素Ｉ（Ｂｉｏ－ＵＥＡ－Ｉ）的免疫组化染色。根据Ｂｉｏ－ＵＥＡ－Ｉ染色的血管内皮细胞计数来测定ＭＶＤ。结果转移复发组和无转移复发组的ＭＶＤ分别为４９．６±２９．７、２２．７±２８．２（Ｐ＜０．０１）;转移复发组和无转移复发组的ＶＥＧＦ阳性率分别为８６．２％（２５／２９）、４７．１％（１６／３４）,两者差异有显著性（Ｐ＜０．０１）。两组在肿瘤分期、有无卫星灶、有无门脉癌栓３方面差异也具有显著性（Ｐ＜０．０５,Ｐ＜０．０５,Ｐ＜０．０１）。结论除肿瘤分期、卫星灶、门脉癌栓具有预后意义外,肝癌组织中ＭＶＤ和ＶＥＧＦ的表达也具有预后价值     

血管内皮生长因子抗体与实验性肿瘤的抑制作用

选择在肿瘤血管形成过程中较为重要的因子血管内皮生长因子（ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒ,ＶＥＧＦ）为靶,进行抗肿瘤形成的实验研究。方法应用亲和层析纯化的有中和活性的ＶＥＧＦ抗体进行实验性肿瘤的抑制研究。结论ＶＥＧＦ抗体对肿瘤具有潜在的应用价值。     

抗新生血管内皮细胞单克隆抗体BVE-1治疗实体瘤的实验研究

目的研究以肿瘤新生血管为靶,用抗血管内皮细胞单克隆抗体治疗实体肿瘤的可行性。方法裸小鼠移植人平滑肌肉瘤细胞,人肝癌细胞及人胰腺癌细胞,以抗血管内皮细胞的单克隆抗体ＢＶＥ１或１３１Ｉ标记抗体ＢＶＥ１腹腔给药,并与正常鼠ＩｇＧ及１３１ＩＩｇＧ治疗对比,观察肿瘤体积变化,死后及活杀鼠进行病理学检查,计算瘤内微血管密度。结果肝癌、胰腺癌、平滑肌肉瘤组经抗体ＢＶＥ１治疗后,抑瘤率分别为７０．５％、４８．７％和４９．８％,并抑制了平滑肌肉瘤转移和降低了死亡率。１３１Ｉ标记抗体ＢＶＥ１治疗组一次给药后抑瘤率达８６．６％～８２．２％,抑瘤生长率较单纯抗体组明显提高。病理检查证实,抗体ＢＶＥ１治疗组肿瘤区毛细血管管壁变性,管腔阻塞,周围肿瘤细胞大片坏死。瘤内微血管密度明显低于未治疗组及鼠ＩｇＧ组。结论抗增生血管内皮细胞抗体ＢＶＥ１具有杀伤及抑制肿瘤区血管内皮细胞生长作用,从而导致肿瘤区毛细血管阻塞,阻断血供,抑制了肿瘤生长和转移,降低了死亡率。以之为载体偶联核素可增强此作用。     

胃癌组织中血管内皮生长因子（VEGF）的表达及其病理意义

目的：探讨胃癌组织中血管内皮生长因子（ＶＥＧＦ）的表达与临床病理特点之间的关系。方法：应用ＳＰ免疫组化法检测１００例胃癌及５０例胃良性病变标本中ＶＥＧＦ的表达,并结合临床病理特点进行分析。结果：胃癌组织中ＶＥＧＦ阳性表达率７５％（７５／１００）,良性病变１４％（７／５０）（ｘ＾２＝５０．０３２３,Ｐ〈０．００１）,ＶＥＧＦ阳性表达率与瘤体的大小、分化程度无关（Ｐ〉０．０５）,与浆浸润、淋巴结转移ＴＮＭ分期有关（Ｐ〈０．００１）,结论：ＶＥＧＦ在肿瘤生长中刺激新生血管生成,与胃癌的恶性进程密切相关,是胃癌的生物学标记。     

骨肉瘤血管内皮生长因子表达与肿瘤血管生成及预后的关系

目的：研究血管内皮生长因子（ＶＥＧＦ）表达与骨肉瘤血管生成和预后的关系。方法：应用免疫组化和形态计量方法，检测８０例骨肉瘤ＶＥＧＦ表达和肿瘤微血管密度。结果：骨肉瘤ＶＥＧＦ表达（－）级者６例，（±）级者１０例，（＋）级者２２例，（＋＋）级者４２例。ＶＥＧＦ表达与肿瘤体积、Ｄａｈｌｉｎ’ｓ分型和Ｐｒｉｃｅ’ｓ分级无关，但与肿瘤微血管计数相关（Ｐ〈０．０５）。ＶＥＧＦ高表达组（＋＋）级多见于骨样组织幼     

大肠癌微血管密度和血管内皮生长因子表达的研究

目的 探讨大肠癌间质微血管密度（ＭＶＤ）和血管内皮生长因子（ＶＥＧＦ）表达与肿瘤浸润和转移和关系。方法 应用ＣＤ３４抗体和ＶＥＧＦ抗体,采用免疫组化Ｓ－Ｐ法对５６例手术切除的大肠癌患者进行血管标记和染色,并取１０例正常组织对照。结果 有淋巴结转移组大肠癌ＭＶＤ、ＶＥＧＦ表达强度与无淋巴结转移组、正常对照组组间比较,均有显著性差异（Ｐ〈０．０１）,且ＭＶＤ与ＶＥＧＦ表达两者呈相关（ｒ＝０．９２）。结     

胃腺癌的血管内皮细胞生长因子和KDR受体的表达及其临床意义

目的：研究胃腺癌的血管内皮细胞生长因子（ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ ｃｅｌｌ ｇｒｏｗｔｈ　ｆａｃｔｏｒ, ＶＥＧＦ）及其受体 ＫＤＲ（ＶＥＧＦＲ）的表达,并探讨其临床意义。方法：应用免疫组织化学染色法检测ＶＥＧＦ／ＶＥＧＦＲ的表达,并分析其与６１例胃腺癌临床病理特征之间的关系。结果：胃腺癌组织ＶＥＧＦ／ＶＥＧＦＲ的阳性表达率分别为５５．９％和３９．３％;其中粘液腺癌和管状腺癌表达率较高（Ｐ＜０．０５,Ｐ＜０．０１）,ＶＥＧＦ／ＶＥＧＦＲ表达率分别为７１．４Ｔ／４２．８％和６１．９％／５２．４％;ＶＥＧＦ／ＶＥＧＦＲ的阳性表达与ＴＮＭ分期有显著差异（Ｐ＜０．０５,Ｐ＜０．０１）,阳性率为Ⅵ＞Ⅲ＞Ⅱ＞Ⅰ期,Ⅳ、Ⅲ、Ⅱ、Ⅰ期的表达率分别为 ８０．０％／５０．０％,６８．２％／４５．５％,４０．０％／３０．０％和３６．８％／３１． ６％;胃腺癌并转移患者,ＶＥＧＦ／ＶＥＧＦＲ的阳性表达分别为７６．２％和４７．６％,远高于无转移的４５．０％和３５．０％（Ｐ＜０．０５,Ｐ＜０．０１）;术后生存期小于１年的ＶＥＧＦ的表达率为６６．７％,明显高于术后生存期１年以上的５２．２％。结论：ＶＥＧＦ是胃腺癌血管生成的正向调     

胃癌VEGF和nm23表达与血管生成的关系及其临床意义

目的 探讨血管内皮细胞生长因子（ＶＥＧＦ）和ｎｍ２３与血管生成及胃癌发展的关系。方法 采用免疫组织化学Ｓ－Ｐ法对４０例胃癌组织中的ＶＥＧＦ、ｎｍ２３蛋白表达和微血管密度（ＭＶＤ）进行检测,分析其与胃癌组织学类型、浸润深度、淋巴结转移和预后的关系。结果 ＶＥＧＦ阳性者（ＭＶＤ）值显著高于阴性者（Ｐ〈０．０１）,ＶＥＧＦ表达率和ＭＶＤ值与胃癌浸润深度、淋巴结转移呈正相关（Ｐ〈０．０５）,ｎｍ２３高表达     

Lung cancer risk in never-smokers: An overview of environmental and genetic factors

Lung cancer is the leading cause of cancer-related mortality globally, accounting for 1.8 million deaths in 2020. While the vast majority are caused by tobacco smoking, 15%−25% of all lung cancer cases occur in lifelong never-smokers. The International Agency for Research on Cancer (IARC) has classified multiple agents with sufficient evidence for lung carcinogenesis in humans, which include tobacco smoking, as well as several environmental exposures such as radon, second-hand tobacco smoke, outdoor air pollution, household combustion of coal and several occupational hazards. However, the IARC evaluation had not been stratified based on smoking status, and notably lung cancer in never-smokers (LCINS) has different epidemiological, clinicopathologic and molecular characteristics from lung cancer in ever-smokers. Among several risk factors proposed for the development of LCINS, environmental factors have the most available evidence for their association with LCINS and their roles cannot be overemphasized. Additionally, while initial genetic studies largely focused on lung cancer as a whole, recent studies have also identified genetic risk factors for LCINS. This article presents an overview of several environmental factors associated with LCINS, and some of the emerging evidence for genetic factors associated with LCINS. An increased understanding of the risk factors associated with LCINS not only helps to evaluate a never-smoker’s personal risk for lung cancer, but also has important public health implications for the prevention and early detection of the disease. Conclusive evidence on causal associations could inform longer-term policy reform in a range of areas including occupational health and safety, urban design, energy use and particle emissions, and the importance of considering the impacts of second-hand smoke in tobacco control policy.     

Crosstalk between TF/FVIIa and EGFR signaling in colorectal cancer cells

TF/FVIIa (Tissue Factor/Active Coagulation factor VII) and EGFR (Epidermal Growth Factor Receptor) signaling both promote malignant progression of colorectal cancer. However, the crosstalk of these two signaling pathways in human colorectal cancer cells remains unclear. Here we detected the changes of mRNA profile in human colorectal cancer cell SW620 exposed to FVIIa. Microarray showed that mRNA levels of EGFR ligands were significantly upregulated. Western blot analysis confirmed the upregulation of EGFR ligands and the phosphorylation of EGFR at tyrosine-845 in colorectal cancer cells exposed to FVIIa. However, knockdown of TF by RNAi could block the upregulation of EGFR ligands induced by FVIIa stimulation. On the other hand, the expression of components of TF/FVIIa signaling was significantly upregulated in LoVo cells stimulated by EGF. However, the crosstalk between the two signaling pathways could not be detected in HT-29 colon cancer cells bearing wild-type KRAS. Taken together, our study suggest that the crosstalk between TF/FVIIa and EGFR signaling pathways in colon cancer cells depends on KRAS mutation.     

The role of tumour necrosis factor-alpha (TNF-alpha) and platelet-activating factor (PAF) interaction on murine candidosis

Tumour necrosis factor-alpha (TNF-alpha) is related to some other factors in addition to being the essential cytokine of the sepsis which results from Candida infections. In our study, we investigated serum TNF-alpha levels, measured by enzyme-linked immunosorbent assay (ELISA), and platelet-activating factor (PAF)-like activity, measured by high-pressure liquid chromatography (HPLC) of the mice infected with Candida species. The PAF antagonist, ginkgolide BN 52021 was used to evaluate the possible interaction between TNF-alpha and PAF. The average TNF-alpha levels were found to be 396, 489, 699 and 803 pg ml(-1) on the 4th, 5th, 6th and 19th days of Candida albicans infection, respectively (P<0.05). There was no statistically significant difference between the serum TNF-alpha levels of the groups infected with other Candida species, such as C. kefyr, C. krusei and C. tropicalis (P>0.05). Serum TNF-alpha levels were found to be more significantly different in mice with C. albicans infection that were injected with PAF antagonists on the 6th day (23 pg ml(-1)). It was therefore thought that PAF antagonists have an inhibitory effect on TNF-alpha production. No significant difference was found between PAF levels in the three groups: healthy control mice, C. albicans-infected mice and C. albicans-infected mice given PAF antagonists (466 milli-absorbance unit (mAU), 475 mAU and 329 mAU, respectively). It was noticed that the positive interaction between PAF and TNF-alpha was not important after the first 4 days of the infection had passed.     

Reversal of Tumor Necrosis Factor Resistance in Tumor Cells by Adriamycin via Suppression of Intracellular Resistance Factors

Tumor necrosis factor (TNF) and various chemotherapeutic drugs show synergistic antitumor effects in vitro and in vivo , though the mechanism is not clear. Based on our previous finding that endogenous TNF (enTNF) acts as an intracellular resistance factor against exogenous TNF by scavenging oxygen free radicals (OFR) with induced manganous superoxide dismutase (MnSOD), we examined the suppression of these resistance factors by chemotherapeutic drugs and the resulting increase in TNF cytotoxicity. Pretreatment of HeLa cells, which produce an appreciable amount of enTNF and show apparent TNF resistance, with TNF followed by adriamycin (ADM) resulted in an additive effect, whereas pretreatment with ADM followed by TNF resulted in a synergistic effect. After treatment of HeLa cells with ADM, the expression of enTNF was remarkably suppressed and MnSOD activity was decreased by one-half. These results indicate that suppression of the intracellular resistance factors, i.e., enTNF and MnSOD, by ADM plays an important role in the mechanism of the synergistic antitumor effect of TNF in combination with ADM.     

前列腺癌与凝血和纤溶因子研究进展

前列腺癌病人中血液高凝状态常见，近年越来越多研究显示凝血和纤溶因子异常与前列腺癌进展间有密切联系，本文回顾近年国内外关于前列腺癌病人中各种凝血和纤溶途径成分异常的临床和基础研究，并就前列腺癌与凝血和纤溶因子研究进展进行综述.     

Combination therapy of imatinib mesylate and interferon-alpha demonstrates minimal activity and significant toxicity in metastatic renal cell carcinoma: results of a single- institution phase II trial

Background

Renal cell carcinoma (RCC) is characterized by increased expression of vascular endothelial growth factor and platelet-derived growth factor (PDGF)-β, both of which contribute to its angiogenic phenotype. Interferon-α (IFN-α) improves survival in patients with metastatic RCC, perhaps partly because of its antiangiogenic properties. Imatinib mesylate inhibits PDGF-mediated signal transduction and might thus have antiangiogenic activity as well.

Patients and Methods

Patients with metastatic RCC were treated with IFN-α (9 × 10⁶ IU subcutaneously 3 times weekly) and oral imatinib mesylate (600 mg daily starting on day 8). Therapy was continuous, and response was evaluated at 8-week intervals using the Response Evaluation Criteria in Solid Tumors. Baseline plasma PDGF-AA, PDGF-AB, and PDGF-BB levels were obtained.

Results

Between January 2003 and January 2005, 17 patients were treated. One patient (6%) had a partial response, 4 (24%) had stable disease, 7 (41%) had progressive disease, and 5 (29%) were unevaluable because of early withdrawal secondary to toxicity. Median time to progression (TTP) using the Kaplan-Meier method was 8 weeks, and median overall survival was 17.8 months. Six patients (35%) withdrew from therapy because of toxicity, and 9 patients (53%) experienced ≥ 1 grade 3/4 toxicity. Platelet-derived growth factor AA, AB, and BB plasma levels did not correlate with TTP or overall survival.

Conclusion

Based on a response rate of only 6%, a median TTP of 2 months, and significant toxicities, further study of IFN-α in combination with imatinib mesylate is not recommended in patients with metastatic RCC.     

Citation indexes do not reflect methodological quality in lung cancer randomised trials.

BACKGROUND: Citation factors are applied to assess scientific work despite the fact that they were developed commercially in order to compare competing journals. The aim of the present study was to determine whether there is a relationship between citation factors and a trial's methodological quality using published randomised trials in lung cancer clinical research. Material and methods All of the randomised trials included in nine systematic reviews performed by the European Lung Cancer Working Party (ELCWP) were assessed using two quality scales (Chalmers and ELCWP). RESULTS: One hundred and eighty-one articles were eligible. The median overall ELCWP and Chalmers quality scores were 61.8% and 49.0%, respectively, with a correlation coefficient (r(s)) of 0.74 (P <0.001). A weak association was observed between citation factors and quality scores with the respective correlation coefficients ranging from 0.18 to 0.40 (ELCWP scale) and from 0.21 to 0.38 (Chalmers scale). American authors published trials significantly more often in journals with high citation factors than European or non-American authors (P <0.0001), despite no better methodological quality. Positive trials, which were significantly more likely to be published in journals with higher citation factors, were of no better quality than negative ones. CONCLUSION: Journals with higher citation factors do not appear to publish clinical trials with higher levels of methodological quality, at least for trials in the field of lung cancer research.     

Prognostic versus predictive value of biomarkers in oncology

Numerous options are currently available for tumour typing. This has raised intense interest in the elucidation of prognostic and predictive markers. A prognostic biomarker provides information about the patients overall cancer outcome, regardless of therapy, whilst a predictive biomarker gives information about the effect of a therapeutic intervention. A predictive biomarker can be a target for therapy. Amongst the genes that have proven to be of relevance are well-known markers such as ER, PR and HER2/neu in breast cancer, BCR–ABL fusion protein in chronic myeloid leukaemia, c-KIT mutations in GIST tumours and EGFR1 mutations in NSCLC. Several reasons for the difficult elucidation of new markers will be addressed including the involvement of cellular pathways in tumour biology instead of single genes and interference in disease outcome as a result of anticancer therapies. Future perspectives for the development of prognostic and predictive markers will be given.     

Tumor suppressor function of a dominant negative retinoic acid receptor mutant

Mutations in receptors for the vitamin A metabolite retinoic acid (RAR) that repress retinoic acid (RA)-responsive gene expression have been identified and characterized. We previously reported an absence of target gene response to RA in all but one of a series of transformed human epithelial cell lines. To elucidate the mechanisms of this unresponsiveness, we created stable transfectants that expressed an RARα mutant (RARα403) previously shown to have dominant negative activity due to a C-terminal truncation. All clones exhibited repressed RA-responsive gene expression. These cells grew slowly and demonstrated greater growth inhibition by RA. Pretreatment of both control and experimental groups with RA enhanced epidermal growth factor–induced proliferation despite RA-dependent downregulation of epidermal growth factor receptor expression. In addition, clones expressing the mutant RARα were 60% less invasive in an in vitro assay. This reduced invasiveness correlated with decreased gelatinase activity in these cells. We showed for the first time that a dominant negative mutation in RARα can function as a tumor suppressor in transformed epithelial cells. Mol. Carcinog. 22:26–33, 1998. © 1998 Wiley-Liss, Inc.     

Spontaneous regression of lung metastasis in the absence of tumor necrosis factor receptor p55

In order to clarify the roles of tumor necrosis factor (TNF)-alpha in lung metastasis, we injected Renca cells intravenously into TNF receptor p55-deficient (TNF-Rp55 KO) and wild-type (WT) mice. Microscopic and macroscopic metastasis foci appeared in lungs at 7 and 14 days after the tumor injection, respectively. Moreover, metastasis foci expanded at similar rates in both WT and TNF-Rp55 KO mice until 21 days, and lungs were occupied with metastasis foci. However, later than 21 days after the injection, metastasis foci spontaneously regressed in TNF-Rp55 KO mice, whereas WT mice exhibited a progressive growth of metastasis foci. Moreover, metastasis foci remained reduced sizes in TNF-Rp55 KO mice even at 26 days, when all WT mice died with lungs filled with metastasis foci. Later than 21 days after the tumor injection, the number of apoptotic tumor cells was increased in TNF-Rp55 KO mice. In contrast, neovascularization was less evident in TNF-Rp55 KO than WT mice, with depressed hepatocyte growth factor (HGF) gene in TNF-Rp55 KO mice at 21 days after the tumor injection. Thus, TNF-Rp55-mediated signals can maintain tumor neovascularization at least partly by inducing HGF expression, and eventually support lung metastasis process.