Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy.
Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy.
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发表时间：
1993
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通讯作者：
J. Denekamp
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作者：
J. Denekamp
大量证据表明，在许多现有形式的抗肿瘤治疗后，血管介导的损伤发生在小鼠肿瘤中（见Moore & West编辑的Gray会议论文集，1991年）。体外细胞的快速常规筛选或使用白血病或淋巴瘤将无法检测到这种作用模式，因此这种筛选将错过有效的药物。需要改变实验性癌症治疗方法，以确保这一重要的新途径得到充分研究。实体肿瘤需要研究，特定肿瘤细胞生物化学（如组织因子促凝活性）、内皮状态和宿主免疫能力的重要性可能都很重要。目前，移植的小鼠皮下肿瘤是否是合适的模型，以及它们是否能反映自发肿瘤的反应，甚至是移植到其他部位的反应，这是一个相当有争议的主题。如果免疫抑制的宿主缺乏该途径中细胞因子成分所需的细胞，则异种移植物可能不合适。对于“直接”肿瘤细胞或“间接”血管介导的方法，新药物的设计和筛选策略，现有药物的调度，特别是辅助治疗的排序可能完全不同。最终将血管操作与针对恶性细胞的直接细胞毒性结合起来可能是合适的，但这两种机制必须被视为不同的实体，并在试图协调它们之前分别考虑。因此，确定血管介导损伤的“特征”以及将其与直接细胞杀伤区分开来的方法是很重要的。这些可以在肿瘤反应中检测到，但也可以从现有和新疗法在正常组织中观察到的副作用中获得线索（图7）。血管介导的缺血治疗的吸引力在于它是全体性的，并且对任何具有新诱发血管网络（即直径约1mm）的肿瘤都有可能有效，但它对大肿瘤比小肿瘤更有效。因此，它既适用于大的原发肿瘤，也适用于弥散性的小转移瘤。对许多不同的抗癌药物的研究已经说明了反应的潜在复杂性，这些反应似乎可以通过血液供应的崩溃或闭塞导致肿瘤细胞死亡。他们还将注意力集中在不同药物的特征上，例如TNF， FAA， PDT，它们可能具有相似的途径。没有单一的新血管特征可以作为抗血管治疗的唯一途径。内皮细胞的快速增殖可能被证明是一个目标，但它也影响分化特征，使未成熟细胞功能异常。这些形成不良的血管的渗透性可能导致蛋白质外渗，导致间质压力增加，从而导致血管内和血管外压力失衡，从而导致薄壁血管塌陷。全身血压、心排血量、黏度或凝血的变化，尤其是局部灌注的再分布，在肿瘤和正常血管中都会产生不同的影响。显然，血管病理生理学和内皮细胞功能的复杂性及其在新生血管中的不平衡对于理解抗血管策略的作用机制是重要的。肿瘤学和许多其他医学和生物学领域之间的这一非常具有挑战性的界限有望改变人们对现有疗法的态度，并发现全新类型的抗癌药物。如果这一领域的进展继续像80年代末那样迅速，下一个十年应该转化为对患者的临床益处。我们现在必须确定是什么特征使一种肿瘤比另一种对热、PDT、细胞因子和FAA等因素更敏感，并学习如何从这些啮齿动物肿瘤推断到人类。
A body of evidence that vascular-mediated damage occurs in murine tumours after many existing forms of anti-tumour therapy is rapidly accumulating (see Gray Conference Proceedings edited by Moore & West, 1991). Rapid conventional screens of cells in vitro or using leukaemias of lymphomas will not detect this mode of action and such screens will therefore miss effective agents. A change in the approach to experimental cancer therapy is needed to ensure that this important new avenue is fully investigated. Solid tumours will need to be studied and the importance of specific tumour cell biochemistry (e.g. on tissue factor procoagulant activity), of endothelial status and the immunocompetence of the host are all likely to be important. It is a subject of considerable debate at present whether transplanted subcutaneous mouse tumours are adequate models and whether they will reflect the response of spontaneous tumours, or even of transplants into other sites. Xenografts are not likely to be appropriate if the immuno-suppressed hosts lack the cells needed for the cytokine component of the pathway. The strategy of design and screening of new agents, for scheduling of existing agents and particularly the sequencing of adjunctive therapies are likely to be completely different for the "direct" tumor cell or "indirect" vascular-mediated approaches. It may eventually be appropriate to combine vascular manipulation with direct cytotoxicity aimed at malignant cells but the two mechanisms must be recognized as distinct entities and considered separately before attempting to coordinate them. It is important therefore to identify the "hallmarks" of vascular mediated injury and the means by which this can be distinguished from direct cell kill. These may be detectable in the tumour response but clues can also be gained from the side effects that are seen in normal tissues both with existing and with novel therapies (Figure 7). The appeal of vascular-mediated ischaemic therapy is that it is systemic and will have the potential of being effective on any tumour with a newly evoked vascular network, i.e. of about 1 mm in diameter, but it will be even more effective on large tumours than on small. Thus it should affect both large primary tumours and disseminated small metastases. The studies with many different anti-cancer agents have illustrated the potential complexity of responses that can appear to cause tumour cell death by collapse or occlusion of the blood supply. They have also focused attention on features of disparate agents, e.g. TNF, FAA, PDT, which may share similar pathways. No single feature of neovasculature can be highlighted as the sole route by which such antivascular therapy should be targeted. Rapid proliferation of the endothelial cells may prove to be a target, but it also influences differentiation characteristics, so that the immature cells will function abnormally. The permeability of these poorly formed vessels may lead to extravasation of proteins leading to increase interstitial pressures and by this means to an imbalance between intravascular and extravascular pressures and hence to collapse of the thin-walled vessels. Changes in systemic blood pressure, cardiac output, viscosity or coagulation and especially a redistribution of regional perfusion would all have differential effects in tumours and normal vessels. Clearly both vascular patho-physiology and the complexity of endothelial cell function and its imbalance in neovasculature will be important in understanding the mechanism of action of antivascular strategies. This very challenging boundary between oncology and a number of other medical and biological fields promises to lead to altered attitudes to existing therapies and the discovery of completely new classes of anti-cancer agents. The next decade should translate into clinical benefit for patients if the progress in this field continues to be as rapid as it has been in the late eighties. We must now determine what characteristics make one tumour more sensitive than another to agents such as heat, PDT, cytokines and FAA, and learn how to extrapolate from those rodent tumours to the human.