title: Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness.
abstract: Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are characterized by extensive fibrosis. Importantly, in PDAC, this results in poor vascularization and impaired drug delivery to the cancer cells. Therefore, the combined targeting of pancreatic tumor stroma and chemotherapy should enhance response rates, but the negative outcome of a recent phase III clinical trial for the combination of chemotherapy and hedgehog pathway inhibition suggests that other means also need to be considered. Emerging data indicate that elimination of cancer stem cells as the root of the cancer is of pivotal importance for efficient treatment of pancreatic cancer. Recently, we demonstrated in a highly relevant preclinical mouse model for primary pancreatic cancers that the combination of cancer stem cell-targeting strategies in combination with a stroma-targeting agent, such as a hedgehog pathway inhibitor and chemotherapy, results in significantly enhanced long-term and progression-free survival. In the present study, we demonstrate mechanistically that Nodal-expressing pancreatic stellate cells are an important component of the tumor stroma for creating a paracrine niche for pancreatic cancer stem cells. Secretion of the embryonic morphogens Nodal/Activin by pancreatic stellate cells promoted in vitro sphere formation and invasiveness of pancreatic cancer stem cells in an Alk4-dependent manner. These data imply that the pancreatic cancer stem cell phenotype is promoted by paracrine Nodal/Activin signaling at the tumor-stroma interface. Therefore, targeting the tumor microenvironment is not only able to improve drug delivery but, even more importantly, destroys the cancer stem cell niche and, therefore, should be an integral part of cancer stem cell-based treatment strategies.
authors.affiliation: Stem Cells & Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Enza
authors.initials: E
authors.lastname: Lonardo
authors.forename: Javier
authors.initials: J
authors.lastname: Frias-Aldeguer
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hermann
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D005355:Fibrosis; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology*; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000502:physiology*; D050500:Pancreatitis, Chronic / Q000473:pathology; D055153:Stem Cell Niche / Q000187:drug effects / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: D053823:Hedgehog Proteins; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I