Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents
Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents
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DOI：
10.1002/path.2436
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发表时间：
2009-01-01
影响因子：
7.3
通讯作者：
Shipley, J.
中科院分区：
文献类型：
--
作者：
Gilbert, D. C.;Chandler, I.;Shipley, J.
趋化因子CXCL12(SDF1)和G蛋白偶联受体CXCR4之间的相互作用负责维持成体干细胞的生态位，并在子宫内原始生殖细胞的迁移中发挥重要作用。我们证明了CXCL12在支持细胞中的表达，并通过成人睾丸的生殖细胞群证实了CXCR4的表达。众所周知，CXCR4还可以在一系列常见癌症中介导器官特异性转移模式。我们发现CXCR4mRNA和蛋白在睾丸生殖细胞肿瘤(TGCT)中表达一致，这是已知CXCL12表达部位复发模式的原因。腺外原发生殖细胞肿瘤表达CXCR4，其发生部位与已知的宫内CXCL12表达区域一致。我们发现，CXCL12在体外以依赖于CXCR4的方式刺激TGCT细胞系的侵袭性迁移，并激活ERK。此外，我们证明CXCL12在I期非精原细胞瘤中的表达与切除后器官受限疾病和降低复发风险显著相关(P=0.003)。这可能是由于CXCL12梯度的丧失，否则可能会吸引细胞远离原发肿瘤。我们建议将CXCL12的表达作为潜在的复发预测因子，从而避免不必要的治疗和相关的晚期毒副作用。我们的观察结果支持CXCL12/CXCR4在成人生殖细胞群体中的作用，并证明了在生殖细胞肿瘤的发生和转移中的病理作用，这可能具有临床实用价值。版权所有(C)2008年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Interaction between the chemokine CXCL12 (SDF1) and the G-protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ-specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4-dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non-seminomas is significantly associated with organ-confined disease post-orchidectomy and reduced risk of relapse (P = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.