Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma

被引:373
作者
Peacock, Craig D.
Wang, Qiuju
Gesell, Gregory S.
Corcoran-Schwartz, Ian M.
Jones, Evan
Kim, Jynho
Devereux, Wendy L.
Rhodes, Jonathan T.
Huff, Carol A.
Beachy, Philip A. [1 ]
Watkins, D. Neil
Matsui, William
机构
[1] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21231 USA
[2] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA
[3] Stanford Univ, Sch Med, Howard Hughes Med Inst, Dept Dev Biol,Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA
关键词
cancer stem cells; cancer therapy; cyclopamine;
D O I
10.1073/pnas.0611682104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The cancer stem cell hypothesis suggests that malignant growth depends on a subset of tumor cells with stem cell-like properties of self-renewal. Because hedgehog (Hh) signaling regulates progenitor cell fate in normal development and homeostasis, aberrant pathway activation might be involved in the maintenance of such a population in cancer. Indeed, mutational activation of the Hh pathway is associated with medulloblastoma and basal cell carcinoma; pathway activity is also critical for growth of other tumors lacking such mutations, although the mechanism of pathway activation is poorly understood. Here we study the role and mechanism of Hh pathway activation in multiple myeloma (MM), a malignancy with a well defined stem cell compartment. In this model, rare malignant progenitors capable of clonal expansion resemble B cells, whereas the much larger tumor cell population manifests a differentiated plasma cell phenotype that pathologically defines the disease. We show that the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment. The Hh ligand promotes expansion of MM stem cells without differentiation, whereas the Hh pathway blockade, while having little or no effect on malignant plasma cell growth, markedly inhibits clonal expansion accompanied by terminal differentiation of purified MM stem cells. These data reveal that Hh pathway activation is heterogeneous across the spectrum of MM tumor stem cells and their more differentiated progeny. The potential existence of similar relationships in other adult cancers may have important biologic and clinical implications for the study of aberrant Hh signaling.
引用
收藏
页码:4048 / 4053
页数:6
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