title: Human colon cancer stem cells are enriched by insulin-like growth factor-1 and are sensitive to figitumumab.
abstract: Cancer stem cells (CSCs) are recognized as contributors to cancer progression and therapeutic resistance in liquid and solid malignancies. We analyzed a panel of human colon cancer cell lines for CSC populations by side population and aldehyde dehydrogenase activity. IGF-1 enriches these putative colon CSC populations in a β-catenin-dependent manner. Chemical inhibition of Akt depletes SP cells, and conversely, the overexpression of a constitutively active mutant version of Akt is sufficient to enrich CSC populations. CP-751,871, a fully human antibody with specificity to the IGF-1 receptor, is currently being tested in clinical trials for a variety of solid tumors. CP-751,871 reduces CSC populations in colon cancer cell lines in vitro and reduces tumor growth in vivo. We have identified a novel role for IGF-1 in the enrichment of chemo-resistant CSC populations. Our results suggest that CP-751,871 has preferential activity against putative CSC populations and, therefore, may complement current standard chemotherapeutic regimens that target cycling cells.
authors: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Lori S
authors: LS
authors: Hart
authors: Nathan G
authors: NG
authors: Dolloff
authors: David T
authors: DT
authors: Dicker
authors: Constantinos
authors: C
authors: Koumenis
authors: James G
authors: JG
authors: Christensen
authors: Adda
authors: A
authors: Grimberg
authors: Wafik S
authors: WS
authors: El-Deiry
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D034741:RNA, Small Interfering; D051176:beta Catenin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C525021:figitumumab