Wideł Maciej S, Wideł Maria
Klinika Chirurgii Onkologicznej Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Oddział w Gliwicach.
Postepy Hig Med Dosw (Online). 2006;60:453-70.
The ability of neoplastic cells to dissemination from a primary tumor to lymphatic nodes and to adjacent and distant tissues and organs is an inseparable feature of malignant tumors and the main cause of failure in their treatment. Metastasis formation is a multistage process which includes proteolysis, the motility and migration of cells, proliferation, and neoangiogenesis. In the first step, the cells released from the primary tumor have to penetrate to the blood or lymphatic vessels (intravasation), the road which dissemination follows. Circulating cells can then migrate through the walls of vessels to surrounding tissues (extravasation) where they settle, proliferate, and induce angiogenesis, creating metastases. Indispensable in the process of intra- and extravasation is the activation of proteolytic enzymes capable of degrading the extracellular matrix (ECM) surrounding the endothelium or creating the basement membrane of epithelial tissue in different organs. In this stage, the activation of proteolytic enzymes, such as proteinases of the plasmin system, serine proteinases, and matrix metalloproteinases (MMPs), is necessary. Simultaneously, changes occur in the expression of many superficial glycoproteins and factors responsible for cell adhesion (integrins) and intercellular communication (cadherins). Neoangiogenesis is connected with the expression of many markers of this process, among them vascular endothelial growth factor (VEGF), endoglin (CD105), a transmembranous glycoprotein which is a component of the receptor for transforming growth factor beta (TGFbeta), as well as neuropilin (NRP), the co-receptor for VEGF. Conventionally, the prognosis of neoplastic disease and its treatment are based mainly on exact clinical and histopathological staging. This prognosis could, however, be improved by measuring the molecular and cellular markers which play key roles in tumor progression. Understanding the cellular processes responsible for tumor dissemination can be useful not only in the diagnosis and prognosis of treatment results, but also in developing targeted drugs, selectively directed towards those factors responsible for tumor invasiveness, as well as in creating new therapeutic strategies permitting the use of such drugs. In the present review the authors concentrate mainly on one tumor type, colorectal carcinoma, in which distant metastases, predominantly to the liver, are the main cause of failure, in spite of surgical curing of the primary tumor.
肿瘤细胞从原发性肿瘤扩散至淋巴结以及邻近和远处组织与器官的能力是恶性肿瘤不可分割的特征，也是其治疗失败的主要原因。转移的形成是一个多阶段过程，包括蛋白水解、细胞的运动性和迁移、增殖以及新生血管形成。第一步，从原发性肿瘤释放的细胞必须穿透进入血液或淋巴管（血管内渗），这是扩散的途径。循环细胞随后可穿过血管壁迁移至周围组织（血管外渗），在那里定居、增殖并诱导血管生成，形成转移灶。血管内渗和外渗过程中不可或缺的是能够降解内皮周围细胞外基质（ECM）或形成不同器官上皮组织基底膜的蛋白水解酶的激活。在这个阶段，纤溶酶系统的蛋白酶、丝氨酸蛋白酶和基质金属蛋白酶（MMPs）等蛋白水解酶的激活是必要的。同时，许多负责细胞黏附（整合素）和细胞间通讯（钙黏着蛋白）的表面糖蛋白和因子的表达也会发生变化。新生血管形成与该过程的许多标志物的表达相关，其中包括血管内皮生长因子（VEGF）、内皮糖蛋白（CD105），一种作为转化生长因子β（TGFβ）受体成分的跨膜糖蛋白，以及VEGF的共受体神经纤毛蛋白（NRP）。传统上，肿瘤疾病的预后及其治疗主要基于准确的临床和组织病理学分期。然而，通过测量在肿瘤进展中起关键作用的分子和细胞标志物，这种预后可能会得到改善。了解导致肿瘤扩散的细胞过程不仅有助于诊断和判断治疗结果的预后，还有助于开发靶向药物，选择性地针对那些导致肿瘤侵袭性的因素，以及制定允许使用此类药物的新治疗策略。在本综述中，作者主要聚焦于一种肿瘤类型，即结直肠癌，尽管原发性肿瘤已通过手术治愈，但远处转移（主要转移至肝脏）仍是治疗失败的主要原因。
