Gort Eelke H, Groot Arjan J, van der Wall Elsken, van Diest Paul J, Vooijs Marc A
Department of Pathology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Curr Mol Med. 2008 Feb;8(1):60-7. doi: 10.2174/156652408783565568.
Metastases formation is a major factor in disease progression and accounts for the majority of cancer deaths. The molecular mechanisms controlling invasion, dissemination to blood or lymphatic systems and spread of tumor cells to distant organs are still poorly understood. Recent observations indicate that the meta-static phenotype may already be present during the angiogenic switch of tumors. Intratumoral hypoxia correlates with poor prognosis and enhanced metastases formation. The Hypoxia Inducible Factors (HIFs) are key molecules in the hypoxic response and play critical roles during tumor cell expansion by regulating energy metabolism and the induction of angiogenesis. Increasing evidence implicates HIF function in metastatic cell characteristics, like epithelial to mesenchymal transition, cell detachment, invasion and tumor cell seeding. Here, we review the link between tumor cell hypoxia and the acquisition of metastatic behavior. We hypothesize that polyclonal tumor selection by hypoxia enhances metastatic capacity by transcriptional control of key regulators of metastasis. This polyclonal hypoxic gene profile potentially develops into a metastatic profile, driving metastasis formation. The hypoxic gene profile in primary tumors may therefore provide a prognostic indicator in clinical decision-making.
转移灶的形成是疾病进展的主要因素，也是大多数癌症死亡的原因。目前，对于控制肿瘤细胞侵袭、扩散至血液或淋巴系统以及转移至远处器官的分子机制仍知之甚少。最近的观察结果表明，转移表型可能在肿瘤血管生成转换过程中就已出现。肿瘤内缺氧与预后不良及转移灶形成增加相关。缺氧诱导因子（HIFs）是缺氧反应中的关键分子，通过调节能量代谢和诱导血管生成，在肿瘤细胞增殖过程中发挥关键作用。越来越多的证据表明，HIF功能与转移细胞特性有关，如上皮-间质转化、细胞脱离、侵袭和肿瘤细胞播种。在此，我们综述肿瘤细胞缺氧与转移行为获得之间的联系。我们推测，缺氧对肿瘤细胞的多克隆选择通过对转移关键调节因子的转录控制增强了转移能力。这种多克隆缺氧基因谱可能发展为转移谱，驱动转移灶形成。因此，原发性肿瘤中的缺氧基因谱可能为临床决策提供预后指标。
