Essential role of stromally induced hedgehog signaling in B-cell malignancies
Essential role of stromally induced hedgehog signaling in B-cell malignancies
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DOI：
10.1038/nm1614
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发表时间：
2007-08-01
期刊：
影响因子：
82.9
通讯作者：
Warmuth, Markus
中科院分区：
文献类型：
--
作者：
Dierks, Christine;Grbic, Jovana;Warmuth, Markus
癌细胞与基质细胞产生的微环境的相互作用对于肿瘤细胞的存活至关重要，并影响肿瘤生长的定位。在这里，我们证明，骨髓、淋巴结和脾基质细胞分泌的hedgehog配体可作为源自转基因E mu-Myc小鼠或从患有这些恶性肿瘤的人中分离的恶性淋巴瘤和浆细胞瘤细胞的生存因子。淋巴瘤中的 Hedgehog 通路抑制通过下调 Bc12 诱导细胞凋亡，但与 p53 或 Bmi1 表达无关。体内阻断hedgehog信号传导可抑制同基因小鼠模型中小鼠淋巴瘤细胞的扩增，并减少患有完全疾病的小鼠的肿瘤质量。我们的数据表明，基质诱导的hedgehog信号传导可能为体外和体内的B细胞和浆细胞恶性肿瘤提供重要的生存信号。通过抑制hedgehog通路来破坏这种相互作用可以为淋巴瘤和多发性骨髓瘤治疗提供新策略。
Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic E mu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bc12, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.