Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice
Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice
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DOI：
10.1172/jci43757
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发表时间：
2011-02-01
影响因子：
15.9
通讯作者：
McAllister, Sandra S.
中科院分区：
文献类型：
--
作者：
Elkabets, Moshe;Gifford, Ann M.;McAllister, Sandra S.
全身性激发是一个过程，通过该过程，从某些肿瘤（激发者）发出的内分泌信号刺激BM细胞（BMC），BM细胞被动员到循环中，随后促进位于远处解剖部位的惰性癌细胞（应答者）的生长。BMC的身份及其对应答者肿瘤生长的特定贡献或贡献一直难以捉摸。在这里，我们已经证明了携带诱发肿瘤的小鼠宿主的Scal（+）cKit（-）造血BMC促进了由富含肌纤维母细胞的促结缔组织增生基质形成的应答肿瘤的生长。这种间质几乎总是在恶性人类腺癌中观察到，并且是预后不良的指标。然后，我们鉴定了颗粒蛋白（GRN）作为相对于对应对照细胞在激发Scal（+）cKit（-）BMC中上调最多的基因。募集到应答肿瘤的GRN（+）BMC诱导驻留组织成纤维细胞表达促进恶性肿瘤进展的基因;事实上，单独用重组GRN治疗足以促进促结缔组织增生应答肿瘤生长。此外，对来自一组乳腺癌患者的肿瘤组织的分析显示，高GRN表达与最具侵袭性的三阴性基底细胞样肿瘤亚型相关，并降低了患者的生存率。我们的数据表明，GRN和产生它的独特的造血BMCs可能作为新的治疗靶点。
Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Scal(+)cKit(-) hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Scal(+)cKit(-) BMCs relative to counterpart control cells. The GRN(+) BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets.