Khanna Chand, Wan Xiaolin, Bose Seuli, Cassaday Ryan, Olomu Osarenoma, Mendoza Arnulfo, Yeung Choh, Gorlick Richard, Hewitt Stephen M, Helman Lee J
Pediatric Oncology Branch and Tissue Array Project Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Med. 2004 Feb;10(2):182-6. doi: 10.1038/nm982. Epub 2004 Jan 4.
Metastatic cancers, once established, are the primary cause of mortality associated with cancer. Previously, we used a genomic approach to identify metastasis-associated genes in cancer. From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane. In a mouse model of osteosarcoma, a highly metastatic pediatric cancer, we found ezrin to be necessary for metastasis. By imaging metastatic cells in the lungs of mice, we showed that ezrin expression provided an early survival advantage for cancer cells that reached the lung. AKT and MAPK phosphorylation and activity were reduced when ezrin protein was suppressed. Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT. To define the relevance of ezrin in the biology of metastasis, beyond the founding mouse model, we examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.
转移性癌症一旦形成，就是与癌症相关的主要死亡原因。此前，我们采用基因组学方法来鉴定癌症中与转移相关的基因。基于该基因组数据，我们选择埃兹蛋白进行进一步研究，因为它在将肌动蛋白细胞骨架与细胞膜进行物理和功能连接方面发挥作用。在骨肉瘤（一种高度转移性的儿童癌症）小鼠模型中，我们发现埃兹蛋白对转移至关重要。通过对小鼠肺部的转移细胞进行成像，我们表明埃兹蛋白的表达为到达肺部的癌细胞提供了早期生存优势。当埃兹蛋白被抑制时，AKT和MAPK的磷酸化及活性降低。埃兹蛋白介导的早期转移生存部分依赖于MAPK的激活，而非AKT。为了确定埃兹蛋白在转移生物学中的相关性，除了最初的小鼠模型外，我们还检测了自然发生骨肉瘤的犬类中埃兹蛋白的表达。犬类肿瘤中埃兹蛋白的高表达与转移的早期发生相关。与该数据一致，我们发现儿童骨肉瘤患者中埃兹蛋白的高表达与不良预后之间存在显著关联。
