c-Met is a marker of pancreatic cancer stem cells and therapeutic target

Gastroenterology. 2011 Dec;141(6):2218-2227.e5. doi: 10.1053/j.gastro.2011.08.009. Epub 2011 Aug 22.


Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Anilides / therapeutic use
  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Drug Therapy, Combination
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis / prevention & control
  • Neoplastic Stem Cells / metabolism*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism*
  • Pyridines / therapeutic use


  • Anilides
  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Pyridines
  • Deoxycytidine
  • cabozantinib
  • gemcitabine
  • Proto-Oncogene Proteins c-met