Allgayer Heike, Aguirre-Ghiso Julio A
Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Medical Faculty Mannheim, University of Heidelberg, and DKFZ German Cancer Research Center Heidelberg, Germany.
APMIS. 2008 Jul-Aug;116(7-8):602-14. doi: 10.1111/j.1600-0463.2008.00997.x.
Minimal residual disease (MRD) is hypothesized to be the major cause of tumor recurrence and metastasis even years and decades after primary cancer diagnosis and curative solid tumor resection. In these patients disseminated tumor cells reflecting MRD can be detected in the bone marrow years after treatment. It is to be assumed that genetic determinants and a complex interplay between the disseminated tumor cells and their microenvironment in the bone marrow are responsible for tumor cell dormancy and the final reactivation towards metastasis. The urokinase receptor (u-PAR), a critical regulator of invasion, intravasation, and metastasis, is found to be a key player in regulating the shift between single cell tumor dormancy and proliferation. This has mainly been attributed to a regulation by u-PAR of integrins, and the ability of the latter to propagate signals from fibronectin through the EGF-receptor, ERK, and p38 signaling. Interestingly, u-PAR is found in disseminated tumor cells in the bone marrow of solid cancer patients, and is associated with the expansion of these cells and clinical prognosis. Here we summarize and discuss findings on disseminated tumor cells in the bone marrow, MRD and the role of u-PAR in tumor biology, especially focusing on its specific role in providing a switch between tumor cell proliferation and dormancy. Finally, we discuss the hypothesis that u-PAR might be an essential molecule in bone marrow disseminated tumor cells for long-term survival during dormancy, and/or reactivation of their proliferation years after primary treatment.
微小残留病（MRD）被认为是肿瘤复发和转移的主要原因，即使在原发性癌症诊断和实体肿瘤根治性切除后的数年甚至数十年亦是如此。在这些患者中，治疗数年之后可在骨髓中检测到反映MRD的播散肿瘤细胞。据推测，遗传决定因素以及骨髓中播散肿瘤细胞与其微环境之间的复杂相互作用是导致肿瘤细胞休眠以及最终重新激活并发生转移的原因。尿激酶受体（u-PAR）是侵袭、血管内渗和转移的关键调节因子，被发现是调节单细胞肿瘤休眠与增殖之间转换的关键因素。这主要归因于u-PAR对整合素的调节作用，以及整合素通过表皮生长因子受体（EGF受体）、细胞外信号调节激酶（ERK）和p38信号传导途径传递来自纤连蛋白信号的能力。有趣的是，在实体癌患者骨髓中的播散肿瘤细胞中发现了u-PAR，并且它与这些细胞的扩增以及临床预后相关。在此，我们总结并讨论有关骨髓中播散肿瘤细胞、MRD以及u-PAR在肿瘤生物学中的作用的研究结果，尤其关注其在肿瘤细胞增殖与休眠之间转换中所起的特定作用。最后，我们讨论这样一种假说，即u-PAR可能是骨髓播散肿瘤细胞在休眠期间长期存活和/或在初次治疗数年之后重新激活其增殖所必需的分子。
