Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, killing an estimated 35,000 Americans each year. Progression is typically asymptomatic, so the cancer is highly advanced and has often metastasized by the time of diagnosis, resulting in a five-year survival rate of less than 5%. To date, resources to fight pancreatic cancer are limited to standard chemotherapy, which only provides marginal relief. Current research priorities include determining how pancreatic tumors interact with their surrounding microenvironment; although the fibroinflammatory response in PDAC is well known, the mechanisms and importance of tumor-stromal signaling in pancreatic cancer progression are poorly understood, slowing the identification of new anti-tumor and anti-metastatic therapeutics.

Tumor cells often exhibit increases in reactive oxygen species (ROS), leading to oxidative stress. Excessive ROS build-up leads to apoptosis, which has been exploited in the development of chemotherapeutics that selectively kill tumors by enhancing their already elevated ROS levels to a fatal degree. Although much is known about the intrinsic mechanisms of ROS production in cancer cells, relatively little is known about the extrinsic mechanisms and the effect of oxidative stress in the tumor’s microenvironment.

In addition to providing structural support, the extracellular matrix (ECM) is a potent source of signaling molecules in both normal and tumor-supporting microenvironments. Here, the authors demonstrate that, when grafted with a tumorigenic pancreatic cell line, mice lacking the matricellular protein fibulin-5 (Fbln5) exhibited decreased pancreatic tumor growth, metastasis and angiogenesis, owing to increased levels of ROS and oxidative damage in the stromal microenvironment of the tumor. These effects resulted from the loss of a previously unknown function for fibulin-5, as a competitive inhibitor of fibronectin-mediated activation of integrin β1-containing receptors; when fibulin-5 was lost, or replaced with a mutant unable to bind to integrins, the activation of β1 integrin increased, causing overproduction of ROS and stromal cell death. Importantly, systemic treatment with an antioxidant restored tumor growth and angiogenesis to wild-type levels.

The identification of fibulin-5 as a novel regulator of ROS production marks a milestone in fibulin-5 biology, and shows a new way in which the tumor microenvironment can influence tumor growth and metastasis. Future work should define the molecular mechanisms through which fibulin-5 inhibits ROS production, and determine whether the fibulin-5–integrin pathway is a suitable target for anti-tumor therapy in pancreatic, and other, cancers.

2010