Collagen prolyl hydroxylases are essential for breast cancer metastasis.
Collagen prolyl hydroxylases are essential for breast cancer metastasis.
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DOI：
10.1158/0008-5472.can-12-3963
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发表时间：
2013-06-01
期刊：
影响因子：
11.2
通讯作者：
Semenza GL
中科院分区：
文献类型：
--
作者：
Gilkes DM;Chaturvedi P;Bajpai S;Wong CC;Wei H;Pitcairn S;Hubbi ME;Wirtz D;Semenza GL
转移是乳腺癌患者死亡的主要原因。了解细胞外基质在转移过程中的作用可能会导致癌症患者治疗方法的改进。肿瘤内缺氧存在于大多数乳腺癌中，并与转移风险和患者死亡率增加相关。在这里，我们证明，缺氧诱导因子1激活基因编码的胶原蛋白脯氨酰羟化酶的转录，这是至关重要的胶原蛋白沉积的乳腺癌细胞。我们发现胶原蛋白脯氨酰羟化酶的表达促进癌细胞沿胶原纤维沿着，从而增强对淋巴结和肺的侵袭和转移。最后，我们建立了人乳腺癌活检组织中胶原蛋白脯氨酰羟化酶mRNA表达的预后意义，并证明了3，4-二羟基苯甲酸乙酯，脯氨酰羟化酶抑制剂，在小鼠乳腺癌模型中减少肿瘤纤维化和转移。
Metastasis is the leading cause of death among patients with breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies for cancer patients. Intratumoral hypoxia is found in the majority of breast cancers and is associated with an increased risk of metastasis and patient mortality. Here we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that are critical for collagen deposition by breast cancer cells. We show that expression of collagen prolyl hydroxylases promotes cancer cell alignment along collagen fibers, resulting in enhanced invasion and metastasis to lymph nodes and lungs. Lastly, we establish the prognostic significance of collagen prolyl hydroxylase mRNA expression in human breast cancer biopsies, and demonstrate that ethyl 3,4-dihydroxybenzoate, a prolyl hydroxylase inhibitor, decreases tumor fibrosis and metastasis in a mouse model of breast cancer.