TGFβ1-Endo180-dependent collagen deposition is dysregulated at the tumour-stromal interface in bone metastasis
TGFβ1-Endo180-dependent collagen deposition is dysregulated at the tumour-stromal interface in bone metastasis
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DOI：
10.1002/path.3958
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发表时间：
2012-04-01
影响因子：
7.3
通讯作者：
Sturge, Justin
中科院分区：
文献类型：
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作者：
Caley, Matthew P.;Kogianni, Giolanta;Sturge, Justin
成人组织中的细胞小生境可以窝藏失调的微环境，成为疾病进展背后的驱动力。当转移细胞到达骨中时，主要的环境变化是矿化的I型胶原基质的破坏。一旦骨中建立转移性小生境，侵入的肿瘤细胞通过旁分泌信号的失调和正常骨吸收和产生的解偶联启动溶骨性病变形成的恶性循环。在这里，我们报告说，胶原蛋白受体Endo180（CD280，MRC2，uPARAP）参与胶原蛋白沉积的原代人成骨细胞在从头类骨质形成。在与前列腺肿瘤细胞共培养的异型直接细胞接触后，成骨细胞中Endo180的这种新识别的功能被抑制。在溶骨性前列腺肿瘤细胞（PC 3和DU 145）中的相互Endo180上调遵循它们与成骨细胞的直接接触并促进从头胶原内化，这是先前表征的组成性再循环Endo180受体的功能。成骨细胞的抑制和肿瘤细胞相关的增强Endo180表达同样持续在这些直接的共培养。这些发现首次证明，增加肿瘤细胞参与胶原降解和减少成骨细胞在溶骨性微环境中的胶原形成与胶原结合受体的不同调节有关。骨转移核心活检的免疫组化分析显示，肿瘤细胞灶中的Endo180表达水平高于周围基质中的细胞。在前列腺成纤维细胞共培养物中的其他实验表明，Endo180的不同调节是TGF β 1信号转导失调的结果。本研究的结果为Endo180在骨转移和其他胶原基质病变中靶向胶原重塑提供了依据。版权所有（c）2011大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Cellular niches in adult tissue can harbour dysregulated microenvironments that become the driving force behind disease progression. The major environmental change when metastatic cells arrive in the bone is the destruction of mineralized type I collagen matrix. Once metastatic niches establish in bone, the invading tumour cells initiate a vicious cycle of osteolytic lesion formation via the dysregulation of paracrine signals and uncoupling of normal bone resorption and production. Here we report that the collagen receptor Endo180 (CD280, MRC2, uPARAP) participates in collagen deposition by primary human osteoblasts during de novo osteoid formation. This newly recognized function of Endo180 was suppressed in osteoblasts following heterotypic direct cellcell contact in co-culture with prostate tumour cells. Reciprocal Endo180 up-regulation in osteolytic prostate tumour cells (PC3 and DU145) followed their direct contact with osteoblasts and promoted de novo collagen internalization, which is a previously characterized function of the constitutively recycling Endo180 receptor. The osteoblastic suppression and tumour cell-associated enhancement of Endo180 expression were equally sustained in these direct co-cultures. These findings are the first to demonstrate that increased tumour cell participation in collagen degradation and decreased collagen formation by osteoblasts in the osteolytic microenvironment are linked to the divergent regulation of a collagen-binding receptor. Immunohistochemical analysis of core biopsies from bone metastasis revealed higher levels of Endo180 expression in tumour cell foci than cells in the surrounding stroma. Additional experiments in prostate cellosteoblast co-cultures indicate that divergent regulation of Endo180 is the result of dysregulated TGF beta 1 signalling. The findings of this study provide a rationale for targeting collagen remodelling by Endo180 in bone metastases and other collagen matrix pathologies. Copyright (c) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.