Stromal biology and therapy in pancreatic cancer.
ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.
Article: Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness.[show abstract] [hide abstract]
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.Cell cycle (Georgetown, Tex.) 04/2012; 11(7):1282-90. · 5.36 Impact Factor