title: Targeting embryonic signaling pathways in cancer therapy.
abstract: BACKGROUND
  The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed.
  
  
  METHODS
  This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field.
  
  
  CONCLUSIONS
  CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.
authors.affiliation: National Cancer Institute, Bethesda, MD 20892-7426 , USA.
authors.forename: Pamela Jo
authors.initials: PJ
authors.lastname: Harris
authors.forename: Giovanna
authors.initials: G
authors.lastname: Speranza
authors.forename: Claudio
authors.initials: C
authors.lastname: Dansky Ullmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D051880:Receptors, Notch; D051153:Wnt Proteins