Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mol Cancer Res. 2013 May;11(5):456-66. doi: 10.1158/1541-7786.MCR-12-0629. Epub 2013 Feb 1.
Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix (ECM) in the metastatic process may lead to the development of improved therapies to treat patients with cancer. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. We found that in hypoxic breast cancer cells, hypoxia-inducible factor 1 (HIF-1) activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the ECM. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. We show that PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs.
转移是乳腺癌患者死亡的主要原因。了解细胞外基质（ECM）在转移过程中的作用可能会导致开发出改善的疗法来治疗癌症患者。大多数乳腺癌中存在的肿瘤内缺氧与转移和死亡风险增加有关。我们发现，在缺氧的乳腺癌细胞中，缺氧诱导因子 1（HIF-1）激活编码脯氨酰羟化酶的 PLOD1 和 PLOD2 基因的转录，脯氨酰羟化酶是胶原生物发生所必需的，胶原是 ECM 的主要成分。乳腺癌活检中高 PLOD2 表达与死亡率增加相关。我们表明 PLOD2 对于乳腺癌细胞中纤维状胶原的形成至关重要，增加肿瘤硬度，并需要转移到淋巴结和肺部。
