Jasmer Kimberly J, Shanbhag Vinit C, Forti Kevin Muñoz, Woods Lucas T, Gudekar Nikita S, Weisman Gary A, Petris Michael J
Christopher S. Bond Life Sciences Center 540F, University of Missouri, 1201 E Rollins, Columbia, MO, 65211, USA.
Department of Biochemistry, University of Missouri, Columbia, MO, USA.
Clin Exp Metastasis. 2024 Dec 23;42(1):7. doi: 10.1007/s10585-024-10325-y.
Copper promotes tumor growth and metastasis through a variety of mechanisms, most notably as a cofactor within the lysyl oxidase (LOX) family of secreted cuproenzymes. Members of this family, which include LOX and LOX-like enzymes LOXL1-4, catalyze the copper-dependent crosslinking of collagens and elastin within the extracellular matrix (ECM). Elevated LOX expression is associated with higher incidence and worse prognosis in multiple cancers, including colorectal, breast, pancreatic, and head and neck. In this study, we demonstrated that elevated LOX expression correlates with decreased overall survival and shorter median time to first progression in patients with lung cancer. Previous studies have demonstrated that LOX secreted from tumors is critical for pre-metastatic niche formation by promoting ECM remodeling and the recruitment of immune cells and endothelial precursors. Here, we demonstrated that ablation of the LOX gene in Lewis lung carcinoma (LLC) cells diminishes tumor growth and metastasis compared to wild-type LLC cells in a syngeneic mouse model. Although the role of tumor-derived LOX in tumor formation and metastasis is well established, little is known regarding the possible contribution of LOX produced by the parenchymal tissue of metastatic organs. Thus, this report describes our findings that host-derived LOX produced by the lung contributes to the pulmonary metastasis of LLC cells in mice. The suppression of pulmonary lysyl oxidase expression reduces the metastatic potential of Lewis Lung Carcinoma cells in mice, revealing a previously unknown influence of LOX expression in the parenchymal tissue of metastatic target organs on the seeding of tumor cells.
铜通过多种机制促进肿瘤生长和转移，最显著的是作为分泌性铜酶赖氨酰氧化酶（LOX）家族中的一种辅助因子。该家族成员包括LOX和LOX样酶LOXL1 - 4，可催化细胞外基质（ECM）中胶原蛋白和弹性蛋白的铜依赖性交联。LOX表达升高与多种癌症（包括结直肠癌、乳腺癌、胰腺癌和头颈癌）的更高发病率和更差预后相关。在本研究中，我们证明LOX表达升高与肺癌患者的总生存期缩短和首次进展的中位时间缩短相关。先前的研究表明，肿瘤分泌的LOX通过促进ECM重塑以及免疫细胞和内皮前体细胞的募集，对转移前生态位的形成至关重要。在此，我们证明在同基因小鼠模型中，与野生型LLC细胞相比，Lewis肺癌（LLC）细胞中LOX基因的缺失会减少肿瘤生长和转移。尽管肿瘤来源的LOX在肿瘤形成和转移中的作用已得到充分证实，但关于转移器官实质组织产生的LOX可能的贡献却知之甚少。因此，本报告描述了我们的发现，即肺产生的宿主来源的LOX有助于LLC细胞在小鼠中的肺转移。肺赖氨酰氧化酶表达的抑制降低了Lewis肺癌细胞在小鼠中的转移潜能，揭示了转移靶器官实质组织中LOX表达对肿瘤细胞播种的先前未知的影响。
