Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al.. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458: 776-779

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature (Impact Factor: 41.46). 02/2009; 458(7239):776-9. DOI: 10.1038/nature07737
Source: PubMed


Although the role of Hedgehog (Hh) signalling in embryonic pattern formation is well established, its functions in adult tissue renewal and maintenance remain unclear, and the relationship of these functions to cancer development has not been determined. Here we show that the loss of Smoothened (Smo), an essential component of the Hh pathway, impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukaemia (CML) by the BCR-ABL1 oncoprotein. Loss of Smo causes depletion of CML stem cells--the cells that propagate the leukaemia--whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, we show that the cell fate determinant Numb, which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacological inhibition of Hh signalling impairs not only the propagation of CML driven by wild-type BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. These data indicate that Hh pathway activity is required for maintenance of normal and neoplastic stem cells of the haematopoietic system and raise the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway.

Download full-text


Available from: Hyog Young Kwon, Dec 17, 2013
47 Reads
  • Source
    • "However, CSCs possess several intrinsic mechanisms of resistance to current chemotherapeutic drugs. Among these mechanisms, the expression of ATP-Binding Cassette (ABC) transporters family (An and Ongkeko, 2009; Calcagno et al., 2010; Fuchs et al., 2010; Clevers, 2011; Moitra et al., 2011; Pietras, 2011) and the activation of different signaling pathways such as Wnt/β-catenin signaling (Teng et al., 2010; Yeung et al., 2010; Takebe et al., 2011; Janikowa and Skarda, 2012), Hedgehog (Hh), Notch (Kobune et al., 2009; Wang et al., 2009; Zhao et al., 2009; Takebe et al., 2011; Janikowa and Skarda, 2012; Jiang et al., 2012), Akt/PKB, ATR/CHK1 survival pathways (Ma et al., 2008; Korkaya et al., 2009; Jiang et al., 2012) and constitutive activation of NF-κB are reported (Zhou et al., 2008; Liu et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: CSCs are responsible for the high rate of recurrence and chemoresistance of different types of cancer. The current antineoplastic agents able to inhibit bulk replicating cancer cells and radiation treatment are not efficacious toward CSCs since this subpopulation has several intrinsic mechanisms of resistance. Among these mechanisms, the expression of ATP-Binding Cassette (ABC) transporters family and the activation of different signaling pathways (such as Wnt/β-catenin signaling, Hedgehog, Notch, Akt/PKB) are reported. Therefore, considering ABC transporters expression on CSCs membranes, compounds able to modulate MDR could induce cytotoxicity in these cells disclosing an exciting and alternative strategy for targeting CSCs in tumor therapy. The next challenge in the cure of cancer relapse may be a multimodal strategy, an approach where specific CSCs targeting drugs exert simultaneously the ability to circumvent tumor drug resistance (ABC transporters modulation) and cytotoxic activity toward CSCs and the corresponding differentiated tumor cells. The efficacy of suggested multimodal strategy could be probed by using several scaffolds active toward MDR pumps on CSCs isolated by tumor specimens.
    Frontiers in Pharmacology 07/2014; 5:163. DOI:10.3389/fphar.2014.00163 · 3.80 Impact Factor
  • Source
    • "HNSCC, head and neck squamous cell cancer. impaired the initiation of CML in BCR-ABL-transduced hematopoietic stem cells [30]. Aberrant Hh signaling has also been shown to contribute to tumor cell proliferation and survival, CSC maintenance, and resistance in other lymphomas, leukemias, and multiple myeloma [33] [80]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hedgehog (Hh) pathway is aberrantly activated in a number of tumors. In medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, mutations in Hh pathway genes lead to ligand-independent pathway activation. In many other tumor types, ligand-dependent activation of Hh signaling is potentiated through crosstalk with other critical molecular signaling pathways. Among such pathways, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest because agents that selectively inhibit these pathways are available and can be readily combined with agents such as vismodegib, sonidegib (LDE225), and BMS-833923, which target smoothened—a key Hh pathway regulator. Numerous preclinical studies have revealed the ways in which Hh intersects with each of these pathways, and combination therapies have resulted in improved antitumor efficacy and survival in animal models. Hh also plays an important role in hematopoiesis and in the maintenance of BCR-ABL–driven leukemic stem cells. Thus, combined inhibition of the Hh pathway and BCR-ABL has emerged as a promising potential therapeutic strategy in chronic myeloid leukemia (CML). A number of clinical trials evaluating combinations of Hh inhibitors with other targeted agents are now underway in CML and a variety of solid tumors. This review highlights these trials and summarizes preclinical evidence of crosstalk between Hh and four other actionable pathways—RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch—as well as the role of Hh in the maintenance of BCR-ABL–driven leukemic stem cells.
    Cancer Treatment Reviews 07/2014; 40(6). DOI:10.1016/j.ctrv.2014.02.003 · 7.59 Impact Factor
  • Source
    • "The Hh pathway is involved in the maintenance of CSCs in many tumors including gliomas, multiple myeloma, myeloid leukemias (Zhao et al. 2009), colorectal cancers, and gastric cancers (Merchant & Matsui 2010). Several studies have shown that Hh signaling activation is associated with chemotherapy or radiotherapy resistance (Sims-Mourtada et al. 2006), supporting that Hh signaling activation has a role in CSC functions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Thyroid cancer is one of the most rapidly increasing malignancies. The reasons for this increase is not completely known, but increases in the diagnosis of papillary thyroid microcarcinomas and follicular variant of papillary thyroid carcinomas along with the enhanced detection of well differentiated thyroid carcinomas are probably all contributing factors. Although most cases of well differentiated thyroid carcinomas are associated with an excellent prognosis, a small percentage of patients with well differentiated thyroid carcinomas as well as most patients with poorly differentiated and anaplastic thyroid carcinomas have recurrent and/or metastatic disease that is often fatal. The cancer stem cell model suggests that a small number of cells within a cancer, known as cancer stem-like cells, are responsible for resistance to chemotherapy and radiation therapy, as well as for recurrent and metastatic disease.. In this review we will focus on current studies about thyroid cancer stem-like cells, the processes of epithelial to mesenchymal transition, and mesenchymal to epithelial transition that provide plasticity to cancer stem-like cell growth in addition to the role of microRNAs in cancer stem cell development and regulation. Understanding the biology of cancer stem cells, epithelial to mesenchymal transition and the metastatic cascade should lead to the design of more rational targeted therapies for highly aggressive and fatal thyroid cancers.
    Endocrine Related Cancer 04/2014; 21(5). DOI:10.1530/ERC-14-0002 · 4.81 Impact Factor
Show more