Intratumor microvessel density as a prognostic factor in cancer.
Intratumor microvessel density as a prognostic factor in cancer.
复制标题
DOI：
--
复制
发表时间：
1995-07
期刊：
影响因子：
--
通讯作者：
N. Weidner
中科院分区：
文献类型：
--
作者：
N. Weidner
在这期杂志中，Hollingsworth等人提出证据表明，在新生血管最密集的区域，肿瘤内微血管密度的增加与晚期卵巢癌患者总生存率和无病生存率的降低有关。此外，使用Cox比例风险模型，他们显示肿瘤内微血管密度可能比分期、分级和肿瘤类型更好地预测无病生存，而分期是总生存的最佳预测因子。作者认为，分析晚期卵巢癌的肿瘤新生血管可能是一个有用的预后指标。显然，要使肿瘤生长，肿瘤细胞不仅要增殖，而且良性宿主组织，特别是新血管，也必须在肿瘤细胞周围形成。1971年，Folkman提出肿瘤的生长依赖于血管生成此外，他认为肿瘤细胞和血管组成了一个高度整合的生态系统，内皮细胞可以通过肿瘤细胞或相关炎症细胞的扩散信号从静止状态切换到快速生长状态，并且抗血管生成可能是一种有效的抗癌治疗方法。确实，现在有相当多的间接和直接证据表明，肿瘤生长依赖于血管生成，肿瘤细胞可以产生扩散性血管生成调节分子，血管生成拮抗剂可以减缓或阻止肿瘤生长。间接证据表明，体内和体外的肿瘤，如果不能进入血管，只有在被动扩散不能再提供足够的营养或废物进入邻近的培养基时才会生长在平衡状态下，这些无血管球体在体外的尺寸仅为4毫米，在体内可达2毫米除非球体血管化，否则不会发生额外的生长和转移。其他间接证据是，在乳腺癌中，肿瘤内内皮细胞的增殖速度比邻近良性基质中的内皮细胞快45倍，肿瘤进展的速度与肿瘤内微血管密度增加有关，微血管密度是肿瘤血管生成的形态学指标。19,20肿瘤生长依赖血管生成的直接证据已经在几项研究中提出，其中不同的特异性抑制血管生成（在体外对肿瘤细胞没有细胞抑制作用）的方法明显抑制了肿瘤在体内的生长。21-30例如，富马青霉素的合成类似物，一种费森曲霉天然分泌的抗生素，在体外抑制内皮细胞增殖和体内肿瘤诱导的血管生成24，这种血管抑制素（也称为agm - 1470或TNP-470）将抑制肿瘤生长，副作用很少。事实上，该药物以及其他血管生成抑制剂（如苔藓抑素、沙利度胺、血小板因子4、干扰素-a、羧胺三唑、金属蛋白酶抑制剂（BB94）和d -葡萄糖- d -半乳聚糖硫酸酯（DS4152））目前正处于临床试验的不同阶段，作为各种恶性实体瘤、白血病和婴儿血管瘤的化疗药物。2223此外，Kim等人已经证明，抑制血管内皮生长因子（VEGF）诱导的血管生成可以抑制体内肿瘤的生长。这些研究人员将人横纹肌肉瘤、多形性胶质母细胞瘤或平滑肌肉瘤细胞系注射到裸鼠体内，发现用VEGF特异性单克隆抗体治疗这些小鼠可以抑制肿瘤的生长，降低肿瘤血管密度，但对细胞的生长速度没有影响
In this issue, Hollingsworth et a1l present evidence that increasing intratumor microvessel density in the areas of most intense neovascularization is associated with decreasing overall and disease-free survival in patients with advanced stage ovarian cancer. Moreover, using a Cox proportional hazards model, they showed that intratumor microvessel density may be a better predictor of disease-free survival than stage, grade, and tumor type, whereas stage was the best predictor of overall survival. The authors conclude that analysis of tumor neovascularization in advanced stage ovarian cancer may be a useful prognostic marker. Clearly, for a tumor to grow, the tumor cells must not only proliferate, but benign host tissue, especially new blood vessels, must also form around the tumor cells. In 1971, Folkman proposed that tumor growth is dependent on angiogenesis.2 Furthermore, he suggested that tumor cells and blood vessels composed a highly integrated ecosystem, that endothelial cells could be switched from a resting state to one of rapid growth by a diffusible signal from tumor cells or associated inflammatory cells, and that antiangiogenesis could be an effective anticancer therapy. Indeed, now there is considerable indirect and direct evidence to show that tumor growth is angiogenesis dependent, that tumor cells can produce diffusible angiogenic regulatory molecules, and that angiogenesis antagonists can slow or prevent tumor growth. The indirect evidence is that tumors, both in vitro and in vivo, that lack access to blood vessels will grow only until passive diffusion can no longer provide adequate nutrients or allow waste products to exit into the adjacent medium.35 At equilibrium, these avascular spheroids reach sizes of only 4 mm in vitro6 and up to 2 mm in vivo.7 Additional growth and metastases do not occur unless the spheroids become vascularized.7 17 Other indirect evidence is that, in breast carcinoma, intratumor endothelial cells proliferate 45 times faster than endothelial cells in adjacent benign stroma,18 and the rate of tumor progression is associated with increased intratumor microvessel density, a morphological measure of tumor angiogenesis. 19,20 Direct evidence that tumor growth is angiogenesis dependent has been presented in several studies wherein different methods of specifically inhibiting angiogenesis (which are not cytostatic to tumor cells in vitro) clearly inhibited tumor growth in vivo.21-30 For example, a synthetic analogue of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius, inhibits endothelial proliferation in vitro and tumor-induced angiogenesis in vivo,24 and this angioinhibin (also known as AGM-1 470 or TNP-470) will suppress tumor growth with few side effects. Indeed, this drug, as well as other angiogenesis inhibitors (ie, bryostatin, thalidomide, platelet factor 4, interferon-a, carboxyaminotriazole, metalloproteinase inhibitor (BB94), and D-gluco-D-galactan sulfate (DS4152)), are now in various phases of clinical trials as chemotherapeutic agents for a variety of malignant solid tumors, leukemias, and infantile hemangiomas.2223 Also, Kim et a126 have shown that inhibition of vascular endothelial growth factor (VEGF)-induced angiogenesis suppresses tumor growth in vivo. These investigators injected human rhabdomyosarcoma, glioblastoma multiforme, or leiomyosarcoma cell lines into nude mice and found that treatment of these mice with a monoclonal antibody specific for VEGF inhibited the growth of the tumors and reduced tumor vessel density but had no effect on the growth rate of the