Dierks Christine, Grbic Jovana, Zirlik Katja, Beigi Ronak, Englund Nathan P, Guo Gui-Rong, Veelken Hendrik, Engelhardt Monika, Mertelsmann Roland, Kelleher Joseph F, Schultz Peter, Warmuth Markus
Kinase Biology/In-vivo Oncology, Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Nat Med. 2007 Aug;13(8):944-51. doi: 10.1038/nm1614. Epub 2007 Jul 15.
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 Emu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, 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.
癌细胞与由基质细胞产生的微环境之间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。在此，我们证明骨髓、淋巴结和脾基质细胞分泌的刺猬信号通路配体作为源自转基因Emu-Myc小鼠或从患有这些恶性肿瘤的人类中分离出的恶性淋巴瘤和浆细胞瘤细胞的存活因子。淋巴瘤中的刺猬信号通路抑制通过下调Bcl2诱导细胞凋亡，但与p53或Bmi1表达无关。在同基因小鼠模型中，体内阻断刺猬信号传导可抑制小鼠淋巴瘤细胞的扩增，并减少患有完全发展疾病的小鼠的肿瘤质量。我们的数据表明，基质诱导的刺猬信号传导可能在体外和体内为B细胞和浆细胞恶性肿瘤提供重要的存活信号。通过抑制刺猬信号通路破坏这种相互作用可能为淋巴瘤和多发性骨髓瘤治疗提供一种新策略。
