The VEGFR2, COX‐2 and MMP‐2 polymorphisms are associated with clinical outcome of patients with inoperable non‐small cell lung cancer

Certain common inherited variations in genes involved in tumor angiogenesis, progression and metastasis may contribute to cancer therapy outcome and prognosis by altering the gene expression and protein activity. In this report, we examined the effect of functional polymorphisms in MMP‐1, MMP‐2, MMP‐3, VEGF, VEGFR2, FGFR4 and COX‐2 genes on overall (OS) and progression‐free survival (PFS) of 350 Caucasian patients with inoperable non‐small cell lung cancer (NSCLC). The results of multivariate analysis indicated that VEGFR2 ‐906C and COX‐2 ‐1195G alleles were strongly associated with poor OS and PFS (p = 0.002 and 0.015, respectively, for OS; p = 0.009 and 0.015, respectively, for PFS), while MMP‐2 ‐1306 T allele carriers had significantly reduced PFS (p = 0.010). Moreover, an increased risk of death and progression was significantly associated with the number of adverse alleles for VEGFR2/COX‐2 (p = 0.0005 for OS and 0.0006 for PFS in >1 adverse allele carriers) and VEGFR2/COX‐2/MMP‐2 combinations (p = 0.0003 for OS and 0.0001 for PFS in patients with >2 adverse alleles). Finally, VEGFR2 TC/CC, COX‐2 AG/GG and MMP‐2 CT/TT genotypes as well as “at risk” allele combinations were identified as independent predictors of unfavorable OS and PFS in the group. In conclusion, the data suggest that selected VEGFR2, COX‐2 and MMP‐2 polymorphisms may be potential prognostic markers in unresectable NSCLC treated with radiotherapy with or without chemotherapy, although further validation studies are warranted to confirm our observations.     

小鼠卵巢玻璃化冻存中FSH干预对移植卵巢VEGF和VEGFR-2表达的影响

目的 通过在玻璃化冻存液中给予重组人促卵泡刺激素（rhFSH）,观察冻存卵巢异体异位移植后VEGF和VEGFR-2表达的变化,探索卵巢玻璃化冻存中的FSH干预对移植卵巢血流重建相关因子的影响.方法 对4周龄C57BL/6J小鼠卵巢进行异体肾被膜下移植,实验分为新鲜移植组（FCG）、单纯玻璃化冻存移植组（VCG）和0.3IU·mL^-1 FSH干预玻璃化冻存移植组（VG-FSH）.通过监测受体小鼠动情周期的变化、卵巢组织切片中正常卵泡百分比、移植后2、7、14、28d卵巢VEGF及其受体VEGFR-2的表达,判断FSH干预效果.结果 FSH干预冻存组的正常卵泡数、VEGF及VEGFR-2的表达均高于单纯玻璃化冻存组（P＜0.05）,且均低于新鲜移植组;FSH干预冻存组动情周期恢复所需时间明显低于冻存组（P＜0.05）,而明显长于新鲜移植组（P＜0.05）.结论 玻璃化冻存全程添加FSH干预,有利于冻存卵巢移植后的卵泡存活及功能恢复,可能与上调促血管生成的VEGF、VEGFR-2蛋白的表达有关.     

Influence of Repetitive Contrast Agent Injections on Functional and Molecular Ultrasound Measurements

Quantitative contrast-enhanced ultrasound plays an important role in tumor characterization and treatment assessment. Besides established functional ultrasound techniques, ultrasound molecular imaging using microbubbles targeted to disease-associated markers is increasingly being applied in pre-clinical studies. Often, repeated injections of non-targeted or targeted microbubbles during the same imaging session are administered. However, the influence of repeated injections on the accuracy of the quantitative data is unclear. Therefore, in tumor-bearing mice, we investigated the influence of multiple injections of non-targeted microbubbles (SonoVue) on time to peak and peak enhancement in liver and tumor tissue and of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agents (MicroMarker) on specific tumor accumulation. We found significantly decreasing values for time to peak and a tendency for increased values for peak enhancement after multiple injections. Repeated injections of VEGFR2-targeted microbubbles led to significantly increased tumor accumulation, which may result from the exposure of additional binding sites at endothelial surfaces caused by mechanical forces from destroyed microbubbles.     

The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma

Vascular endothelial growth factor receptor 1 (VEGFR-1) is present on endothelial cells and subsets of human tumor cells, raising the hypothesis that angiogenic factors may promote tumor growth both by inducing angiogenesis and directly signaling through activation of VEGFR-1 on tumor cells. Here, we report that VEGFR-1 is expressed on a panel of 16 human breast tumor cell lines, and the vasculature and the tumor cell compartment of a subset of breast carcinoma lesions, and that selective signaling through VEGFR-1 on breast cancer cells supports tumor growth through downstream activation of the p44/42 mitogen-activated protein kinase (MAPK) or Akt pathways. Ligand-stimulated proliferation of breast tumor cells was inhibited by specific blockade with an anti-VEGFR-1 neutralizing monoclonal antibody. Treatment with anti-VEGFR-1 mAb significantly suppressed the growth of DU4475, MCF-7, BT-474 and MDA-MB-231 breast xenografts in athymic mice. Histological examination of anti-VEGFR-1 mAb treated tumor xenografts showed a significant reduction of activation of the p44/42 MAPK or Akt pathways in tumor cells resulting in an increase in tumor cell apoptosis. Importantly, cotreatment with mAbs targeting human VEGFR-1 on tumor cells and murine VEGFR-1 on vasculature led to more potent growth inhibition of breast tumor xenografts. The results suggest that VEGF receptors may not only modulate angiogenesis, but also directly influence the growth of VEGF receptor expressing tumors.     

Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor-2 (VEGFR2) blockade

The formation of new blood vessels (angiogenesis) represents a critical factor in the malignant growth of solid tumors and metastases. Vascular endothelial cell growth factor (VEGF) and its receptor VEGFR2 represent central molecular targets for antiangiogenic intervention, because of their integral involvement in endothelial cell proliferation and migration. In the current study, we investigated in vitro and in vivo effects of receptor blockade on various aspects of the angiogenic process using monoclonal antibodies against VEGFR2 (cp1C11, which is human specific, and DC101, which is mouse specific). Molecular blockade of VEGFR2 inhibited several critical steps involved in angiogenesis. VEGFR2 blockade in endothelial cells attenuated cellular proliferation, reduced cellular migration, and disrupted cellular differentiation and resultant formation of capillary-like networks. Further, VEGFR2 blockade significantly reduced the growth response of human squamous cell carcinoma xenografts in athymic mice. The growth-inhibitory effect of VEGFR2 blockade in tumor xenografts seems to reflect antiangiogenic influence as demonstrated by vascular growth inhibition in an in vivo angiogenesis assay incorporating tumor-bearing Matrigel plugs. Further, administration of VEGFR2-blocking antibodies in endothelial cell cultures, and in mouse xenograft models, increased their response to ionizing radiation, indicating an interactive cytotoxic effect of VEGFR2 blockade with radiation. These data suggest that molecular inhibition of VEGFR2 alone, and in combination with radiation, can enhance tumor response through molecular targeting of tumor vasculature.     

大肠腺癌中Sema4D和VEGFR2的表达及意义

目的探讨Sema4D和血管内皮生长因子受体2(VEGFR2)在大肠腺癌组织中的表达及其临床意义。方法运用组织芯片和免疫组化SP法检测115例大肠腺癌组织、19例大肠腺瘤组织和12例正常大肠黏膜组织中Sema4D与VEGFR2的表达,并分析其与临床病理特征的关系。结果 Sema4D在正常大肠黏膜表达阳性率8.33%,在腺瘤和腺癌中阳性表达率为15.79%和39.13%,差异有统计学意义且与淋巴结转移、Dukes临床分期明显相关(P<0.05)。VEGFR2在正常大肠黏膜中阳性率16.67%,在腺瘤和腺癌中表达率为21.05%和51.3%,差异有统计学意义其表达与淋巴结转移、浸润程度、Dukes临床分期明显相关(P<0.05)。结论大肠腺癌中Sema4D与VEGFR2的表达可能在大肠腺癌的发生、发展中发挥重要作用。     

Biology of vascular endothelial growth factor and its receptors in head and neck cancer: beyond angiogenesis

Angiogenesis is a necessary process for tumor progression and is driven through molecular interactions between cancer cells and neighboring vascular endothelial cells. The primary mediators of angiogenesis are the vascular endothelial growth factors and their respective receptors on endothelial cells. There are several U.S. Food and Drug Administration-approved anti-angiogenic agents in clinical use. In head and neck cancer there are clinical trials assessing the efficacy of anti-angiogenic agents in combination with chemoradiation therapy. Although the aforementioned growth factors and receptors have been traditionally viewed as anti-angiogenic targets, there are concomitant efforts to understand the role these molecules play within the tumor cells. In this review, we first discuss the biology of angiogenic proteins and the targeting of angiogenic molecules for cancer treatment. We summarize the current clinical trials of anti-angiogenic therapies in head and neck squamous cell carcinoma. Finally, the additional role these molecules play in tumor progression independent of angiogenesis is discussed.     

Cellular basis of cancer metastasis: A review of fundamentals and new advances

This review provides an introduction to fundamentals and new advances in cancer metastasis for general readers. The first segment includes topics such as cell adhesion, cell migration, proteases, inflammation, coagulation and site selection in metastasis. Then follows a discussion of an interesting report by Kaplan et al. [VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005;438:820-7] that provides evidence for a role of VEGFR1+bone marrow cells in preparing pre-metastatic niches in specific organs that host the arrival and growth of metastatic cancer cells. The therapeutic implications of this study are explored.