title: A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development.
abstract: There is an enormous gap between the antiproliferative and in vivo antitumor efficacy of gemcitabine in cell line-based models and its clinical efficacy. This may be due to insensitiveness of the precursor, cancer stem cell (CSC) compartment to cytotoxic agents. The hedgehog pathway is associated with CSC signaling and control. We used a direct xenograft model of pancreatic cancer and a two-stage approach was used to test the hypotheses that targeting CSC could increase the efficacy of gemcitabine. Tumors from a gemcitabine-sensitive xenograft were treated with gemcitabine first, and randomized, after tumor regression to continuing treatment with gemcitabine, a hedgehog inhibitor alone or in combination with gemcitabine. We tested markers described as associated with CSC such as CD24, CD44, ALDH, nestin, and the hedgehog pathway. After induction with gemcitabine, treated tumor showed an enrichment in CSC markers such as ALDH and CD24. Subsequently, a release from gemcitabine prompted a repopulation of proliferating cells and a decrease in such markers to equilibrate from pretreatment levels. Combined treatment with gemcitabine and cyclopamine induced tumor regression and decrease in CSC markers and hedgehog signaling. Cytoplasmic CD24 and ALDH were inversely and strongly associated with growth and were expressed in a minority of cells that we propose constitute the CSC compartment. Hedgehog inhibitors as part of a dual compartment therapeutic approach were able to further reduce tumor growth and decreased both static and dynamic markers of CSC. Direct tumor xenografts are a valid platform to test multicompartment therapeutic approaches in pancreatic cancer.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21231-1000, USA. Antonio.Jimeno@UDenver.edu
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Ana
authors.initials: A
authors.lastname: Suárez-Gauthier
authors.forename: Zeshaan
authors.initials: Z
authors.lastname: Rasheed
authors.forename: Anna
authors.initials: A
authors.lastname: Solomon
authors.forename: Gang-Ming
authors.initials: GM
authors.lastname: Zou
authors.forename: Belen
authors.initials: B
authors.lastname: Rubio-Viqueira
authors.forename: Elena
authors.initials: E
authors.lastname: García-García
authors.forename: Fernando
authors.initials: F
authors.lastname: López-Ríos
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000628:therapy*; D050697:Retinal Dehydrogenase; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D003841:Deoxycytidine; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D000093542:Gemcitabine