The prometastatic microenvironment of the liver.
The prometastatic microenvironment of the liver.
复制标题
肝脏的前态微环境。
DOI：
10.1007/s12307-008-0011-6
复制
发表时间：
2008-12
影响因子：
--
通讯作者：
Vidal-Vanaclocha, Fernando
中科院分区：
文献类型：
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作者：
Vidal-Vanaclocha, Fernando
肝脏是主要的转移敏感部位，并且大多数患有肝转移的患者在缺乏有效治疗的情况下死于该疾病。癌细胞的肝内循环和微血管停滞触发局部炎症反应，导致癌细胞凋亡和通过氧化应激介质（主要是一氧化氮和过氧化氢）和肝自然杀伤细胞的细胞毒性。然而，某些抵抗或甚至使这些抗肿瘤防御机制失活的癌细胞仍然可以通过促炎性丝氨酸介导的机制粘附于肝微血管的内皮细胞。在它们的临时居住期间，这些癌细胞中的一些忽略生长抑制因子，而对从肿瘤活化的肝细胞和窦状隙细胞释放的增殖刺激因子作出反应。这导致在肝小叶的门静脉周围区域产生无血管微转移。来自汇管区的肝细胞和肌成纤维细胞和活化的肝星状细胞随后被招募到这些无血管微转移瘤中。这些创造了一个私人的微环境，通过特异性释放促血管生成因子和癌细胞侵袭和增殖刺激因子来支持它们的发展。此外，来自肿瘤活化的肝细胞和肌成纤维细胞的可溶性因子也有助于转移性癌细胞基因的调节。因此，肝脏为循环癌细胞提供了支持转移发展的促转移微环境。抵抗抗肿瘤肝防御和利用肝细胞衍生因子的能力是肝转移癌细胞的关键表型特性。微环境对肝转移调节的认识为亚临床和晚期阶段的转移抑制提供了多种机会。此外，与转移相关的基因图谱揭示了原发性肿瘤中存在肝转移的可能性，新的生物标志物对肝转移的微环境可能有助于癌症患者肝转移风险的个体评估。
The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients.