title: Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers.
abstract: In the context of pancreatic cancer, metastasis remains the most critical determinant of resectability, and hence survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in pancreatic cancer invasion and metastasis because this is likely to have profound clinical implications. In pancreatic cancer cell lines, Hh inhibition with cyclopamine resulted in down-regulation of snail and up-regulation of E-cadherin, consistent with inhibition of epithelial-to-mesenchymal transition, and was mirrored by a striking reduction of in vitro invasive capacity (P < 0.0001). Conversely, Gli1 overexpression in immortalized human pancreatic ductal epithelial cells led to a markedly invasive phenotype (P < 0.0001) and near total down-regulation of E-cadherin. In an orthotopic xenograft model, cyclopamine profoundly inhibited metastatic spread; only one of seven cyclopamine-treated mice developed pulmonary micrometastases versus seven of seven mice with multiple macrometastases in control animals. Combination of gemcitabine and cyclopamine completely abrogated metastases while also significantly reducing the size of "primary" tumors. Gli1 levels were up-regulated in tissue samples of metastatic human pancreatic cancer samples compared with matched primary tumors. Aldehyde dehydrogenase (ALDH) overexpression is characteristic for both hematopoietic progenitors and leukemic stem cells; cyclopamine preferentially reduced "ALDH-high" cells by approximately 3-fold (P = 0.048). We confirm pharmacologic Hh pathway inhibition as a valid therapeutic strategy for pancreatic cancer and show for the first time its particular efficacy against metastatic spread. By targeting specific cellular subpopulations likely involved in tumor initiation at metastatic sites, Hh inhibitors may provide a new paradigm for therapy of disseminated malignancies, particularly when used in combination with conventional antimetabolites that reduce "bulk" tumor size.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD 21231, USA. gfeldma4@jhmi.edu
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Surajit
authors.initials: S
authors.lastname: Dhara
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Robert
authors.initials: R
authors.lastname: Beaty
authors.forename: Michael
authors.initials: M
authors.lastname: Mullendore
authors.forename: Collins
authors.initials: C
authors.lastname: Karikari
authors.forename: Hector
authors.initials: H
authors.lastname: Alvarez
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014704:Veratrum Alkaloids / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; D003841:Deoxycytidine; C000541:cyclopamine; D000093542:Gemcitabine