Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11517-22. doi: 10.1073/pnas.1307100110. Epub 2013 Jun 25.
Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.
全长组织因子 (flTF) 是凝血的启动子，在乳腺癌 (BrCa) 中过度表达，但 flTF 表达与临床结果之间的关联仍存在争议。目前尚不清楚可溶性选择性剪接 TF 形式 (asTF) 是否在 BrCa 中表达或影响 BrCa 的进展。我们是唯一报道 asTF（而非 flTF）与肿瘤大小和分级强烈相关，并通过与β1 整合素结合诱导 BrCa 细胞增殖的人。asTF 促进致癌基因表达、非锚定依赖性生长，并在腔性 BrCa 模型中强烈上调肿瘤扩张。在持续表达两种 TF 同工型的基底 BrCa 细胞中，asTF 阻断可减少体内肿瘤的生长和增殖。我们提出，asTF 作为一种自分泌因子，在 BrCa 进展中发挥主要作用，促进肿瘤进展。靶向 asTF 可能构成一种以前未被探索的 BrCa 治疗策略，该策略可抑制肿瘤生长，而不会损害正常止血。
