Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID–ß2m–/– repopulating cells.

Kobune, Masayoshi; Ito, Yoshinori; Kawano, Yutaka; Sasaki, Katsunori; Uchida, Hiroaki; Nakamura, Kiminori; Dehari, Hironari; Chiba, Hiroki; Takimoto, Rishu; Matsunaga, Takuya; Terui, Takeshi; Kato, Junji; Niitsu, Yoshiro; Hamada, Hirofumi

doi:10.1182/blood-2003-09-3347

Cited by 52 publications

(58 citation statements)

References 40 publications

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“…We hypothesized that this tumor stem cell population, lacking in clinical CD138 ϩ bone marrow samples, was the locus of Hh pathway activation in MM. Consistent with previous reports (29,30), quantitative analysis of Hh pathway transcripts in normal human bone marrow populations revealed that CD34 ϩ bone marrow progenitors expressed the highest levels of SMO ( Fig. 2A), but showed relatively low expression of PTCH1.…”

Section: Hh Pathway Expression In MM In Vivosupporting

confidence: 76%

“…Consistent with this idea is our demonstration that Hh ligand can markedly expand the MM stem cell population when delivered exogenously. Because normal bone marrow stromal cells are a potential source of Hh ligand (29,30), it is also possible that MM progenitors activate Hh signaling through interactions with the bone marrow microenvironment. Testing this concept in lung, pancreas, and prostate cancers will require definitive identification of clonogenic progenitors.…”

Section: Discussionmentioning

confidence: 99%

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Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma

Peacock

Wang

Gesell

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

439

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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

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Section: Hh Pathway Expression In MM In Vivosupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma

Peacock

Wang

Gesell

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

439

347

View full text Add to dashboard Cite

show abstract

“…22,23 In this new coculture system, BM CD34 + cells were cocultured with human control-or AML/MDSderived MSCs in serum-free StemPro ® -34 medium in the presence of a cytokine cocktail consisting of 50 ng/mL human thrombopoietin (TPO), 10 ng/mL human stem cell factor (SCF), 50 ng/mL human Flk2/Flt3 ligand (FLT3LG) and 100 ng/mL human delta-like protein 4 (DLL4) (all from R&D Systems, Minneapolis, MN, USA). In this system, the primary MSC layer could be maintained for over 8 weeks even in a serum-free medium (Online Supplementary Methods).…”

Section: Coculture Of Bm Cd34 + Cells With Human Mscsmentioning

confidence: 99%

Extracellular vesicle miR-7977 is involved in hematopoietic dysfunction of mesenchymal stromal cells via poly(rC) binding protein 1 reduction in myeloid neoplasms

et al. 2016

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“…Furthermore, Indian Hh gene transfer can confer enhanced hematopoietic support ability to BM stromal cells, suggesting that it is involved in the interaction between HSC and the stromal cells. This leads to an increase in proliferation and repopulating capacity of primitive hematopoietic cells (Kobune et al, 2004). These results suggest a role for Hh signaling in balancing homeostasis and regeneration in vivo.…”

Section: The Hedgehog (Hh) Signalingmentioning

confidence: 77%