title: c-Met is a marker of pancreatic cancer stem cells and therapeutic target.
abstract: OBJECTIVE
  Growth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target.
  
  
  METHODS
  We studied growth of primary human pancreatic adenocarcinoma in NOD SCID mice. The self-renewal capability of pancreatic cancer cells that expressed high levels of c-Met (c-Met(high)) was assessed using in vitro sphere assays and compared with those that were c-Met negative or expressed low levels of c-Met. The tumorigenicity of c-Met(high) pancreatic cancer cells was evaluated in NOD SCID mice.
  
  
  RESULTS
  c-Met(high) cells readily formed spheres, whereas c-Met-negative cells did not. Use of the c-Met inhibitor XL184 or c-Met knockdown with small hairpin RNAs significantly inhibited tumor sphere formation. c-Met(high) cells had increased tumorigenic potential in mice; those that expressed c-Met and CD44 (0.5%-5% of the pancreatic cancer cells) had the capability for self-renewal and the highest tumorigenic potential of all cell populations studied. In pancreatic tumors established in NOD SCID mice, c-Met inhibitors slowed tumor growth and reduced the population of CSCs when given alone or in combination with gemcitabine. Administration of XL184 for 2 weeks after cardiac injection of cancer cells prevented the development of metastases.
  
  
  CONCLUSIONS
  c-Met is a new marker for pancreatic CSCs. It is required for growth and metastasis of pancreatic tumors in mice and is a therapeutic target for pancreatic cancer.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Chenwei
authors.initials: C
authors.lastname: Li
authors.forename: Jing-Jiang
authors.initials: JJ
authors.lastname: Wu
authors.forename: Mark
authors.initials: M
authors.lastname: Hynes
authors.forename: Joseph
authors.initials: J
authors.lastname: Dosch
authors.forename: Bedabrata
authors.initials: B
authors.lastname: Sarkar
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Welling
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca di Magliano
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000627:therapeutic use; D000093542:Gemcitabine
chemical_list: D000813:Anilides; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D011725:Pyridines; D003841:Deoxycytidine; C558660:cabozantinib; D019859:Proto-Oncogene Proteins c-met; D000093542:Gemcitabine