An estimated 42,000 new cases of pancreatic cancer will occur in the USA in 2009. More than 75% of these will only be diagnosed after the cancer has invaded local tissues or metastasized, and this is a significant factor in the poor 5-year survival (<5%) of pancreatic cancer patients. These statistics underscore the urgent need to decipher the etiology of pancreatic cancer and to understand the factors regulating its progression to metastatic disease.

Historically, research into metastasis focused on the cell-autonomous behavior of cancer cells. Attention is now shifting to the interaction of cancer cells with their microenvironment. This is especially relevant in pancreatic cancer, in which the stromal response to the tumor leads to desmoplasia, a pervasive growth of fibrous tissue around the tumor mass. Crosstalk between malignant epithelial cells and the reactive stroma can promote extracellular matrix (ECM) remodeling, angiogenesis, immune cell recruitment and metastasis. The matricellular protein SPARC (secreted protein acidic and rich in cysteine) is a key component in regulating these elements of the tumor microenvironment. Importantly, SPARC expression is dysregulated in many human cancers, although it is currently unclear whether overexpression of SPARC is associated with promotion or suppression of tumor spread. Studying its function in an animal model may clarify this point and significantly increase our knowledge of how malignant disease develops and progresses.

In this paper, the authors demonstrate increased metastatic burden and local spread of orthotopic pancreatic tumors in mice lacking SPARC. This is due, in part, to decreased ECM deposition, reduced fibrillar collagen and enhanced vascular function, despite a decrease in microvessel density. Tumors grown in the absence of host SPARC display increased recruitment of fibroblasts, and of tumor-associated (M2) macrophages, which are thought to accelerate tumor progression through subversion of the adaptive immune response.

This study indicates that SPARC dictates the composition of the ECM during malignant progression and thus contributes directly to the control of tumor invasion and metastasis. The data also suggest that host SPARC maintains vascular integrity in the tumor microenvironment and at metastatic sites, such as the liver, and regulates immune tolerance. Future work should aim to clarify the molecular mechanisms by which SPARC acts. This paper, showing that loss of SPARC enhances tumor progression, highlights the complexity of the metastatic niche and raises concerns about the therapeutic targeting of SPARC.

2010