Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma

Abstract

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.cancer stem cells ͉ cancer therapy ͉ cyclopamine

Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2

“…It is also well known that chronic tissue injury caused by inf lammation is associated with tumorigenesis (1). Moreover, recently, it was also shown that Hh signaling maintains a tumor stem cell compartment (34). Therefore, it is possible that, in the early stage of tumorigenesis, Hh signaling promotes cell growth and partially inhibits p53 function, thereby enabling these cells to survive and grow.…”

Two Distinct Sites in Sonic Hedgehog Combine for Heparan Sulfate Interactions and Cell Signaling Functions

“…In addition, ectopic expression of Gli1 or Gli2 in mice results in tumor formation, indicating that activating downstream components of the pathway is sufficient to initiate tumor growth (12). Shh signaling also plays a role in the patho- genesis of chronic myelogenous leukemia, gliomas, and multiple myeloma (13)(14)(15). Shh signaling is active during pancreatic organogenesis, and low level expression of Hip1, Ptch1, Smo, Ihh, and Dhh has been detected within mature islets and cultured cell lines (16,17).…”

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

“…In addition, the Gli1 gene is amplified in many sarcomas (16,17) and is expressed at high level in association with the EWS/FLI fusion oncogene that causes Ewing sarcoma (18,19), thus causing activation of Hh pathway targets. Hh pathway activity also appears to be required for the maintenance of cancer stem cells in multiple myeloma (20), chronic myeloid leukemia (21,22), and perhaps other hematologic malignancies (23).…”