title: Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis.
abstract: Pancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here, we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of patients with pancreatic cancer.
authors.affiliation: Division of Medical Oncology, IU Simon Cancer Center, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Gu
authors.forename: Hailan
authors.initials: H
authors.lastname: Liu
authors.forename: Gloria H
authors.initials: GH
authors.lastname: Su
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Helen
authors.initials: H
authors.lastname: Chin-Sinex
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.forename: Marc S
authors.initials: MS
authors.lastname: Mendonca
authors.forename: Harlan E
authors.initials: HE
authors.lastname: Shannon
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Jingwu
authors.initials: J
authors.lastname: Xie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D063646:Carcinogenesis / Q000235:genetics* / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D059010:Single-Cell Analysis; D014704:Veratrum Alkaloids / Q000494:pharmacology*; D014965:X-Rays
chemical_list: D053823:Hedgehog Proteins; C509246:IHH protein, human; C509239:SHH protein, human; D014704:Veratrum Alkaloids; C000541:cyclopamine