Rak J W, St Croix B D, Kerbel R S
Division of Cancer Research, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Anticancer Drugs. 1995 Feb;6(1):3-18. doi: 10.1097/00001813-199502000-00001.
The growth of solid tumors to a clinically relevant size is dependent upon an adequate blood supply. This is achieved by the process of tumor stroma generation where the formation of new capillaries is a central event. Progressive recruitment of blood vessels to the tumor site and reciprocal support of tumor expansion by the resulting neovasculature are thought to result in a self-perpetuating loop helping to drive the growth of solid tumors. The development of new vasculature also allows an 'evacuation route' for metastatically-competent tumor cells, enabling them to depart from the primary site and colonize initially unaffected organs. Several molecular and cellular mechanisms have been identified by which tumor parenchyma may exert its angiogenic effect on host endothelial cells. As a result of this paracrine influence, tumor-associated endothelial cells acquire an 'immature' phenotype manifested by rapid proliferation, migration, release of proteases and expression of cytokines, endothelial-specific tyrosine kinases (e.g. flk-1, tek and others) as well as numerous other molecular alterations. Consequently a network of structurally and functionally aberrant blood vessels is formed within the tumor mass. There is also evidence that endothelial cells themselves, and likewise other stromal cells, may act reciprocally to alter the behavior of adjacent tumor cells in a paracrine or cell contact mediated fashion. For example, production of interleukin 6(IL-6) by endothelial cells may have a differential effect on human melanoma cells expressing different degrees of aggressiveness. In this manner endothelial derived cytokines could conceivably contribute to tumor progression by suppressing the growth of the less aggressive tumor cells and promoting dominance of their malignant counterparts in 'strategic' perivascular zones. Distinct biological features expressed by tumor-associated vasculature may serve as potential prognostic markers of disease progression as well as novel targets for therapeutic intervention.
实体瘤生长到临床相关大小依赖于充足的血液供应。这是通过肿瘤基质生成过程实现的，其中新毛细血管的形成是核心事件。血管向肿瘤部位的逐步募集以及由此产生的新血管对肿瘤扩展的相互支持被认为会形成一个自我延续的循环，有助于推动实体瘤的生长。新血管的形成还为具有转移能力的肿瘤细胞提供了一条“撤离途径”，使它们能够离开原发部位并在最初未受影响的器官中定植。已经确定了几种分子和细胞机制，肿瘤实质可通过这些机制对宿主内皮细胞发挥其血管生成作用。由于这种旁分泌影响，肿瘤相关内皮细胞获得一种“不成熟”表型，表现为快速增殖、迁移、蛋白酶释放、细胞因子表达、内皮特异性酪氨酸激酶（如flk-1、tek等）以及许多其他分子改变。因此，在肿瘤块内形成了一个结构和功能异常的血管网络。也有证据表明内皮细胞本身以及同样的其他基质细胞可能以旁分泌或细胞接触介导的方式相互作用，改变相邻肿瘤细胞的行为。例如，内皮细胞产生的白细胞介素6（IL-6）可能对表达不同侵袭程度的人黑色素瘤细胞有不同影响。通过这种方式，内皮细胞衍生的细胞因子可以通过抑制侵袭性较低的肿瘤细胞生长并促进其恶性对应物在“战略”血管周围区域的优势地位，从而可能促进肿瘤进展。肿瘤相关血管系统表达的独特生物学特征可能作为疾病进展的潜在预后标志物以及治疗干预的新靶点。
