Linking Fibrosis and Cancer through the Differentiation of Fibrocytes

Fibrosis is a disease in which scar tissue invades healthy organs and reduces their function. Fibrosis is involved in 45% of deaths in the United States, yet little is known about the signaling that underlies the early formation of a fibrotic lesion. Fibrocytes are fibroblast-like monocyte-derived cells, and are a key component of scar tissue. Monocytes can also differentiate into macrophages, and pro-fibrotic macrophages are an important component of scar tissue. Scar tissue is also essential for healing wounds. Chronic, non-healing wounds cost $25 billion annually to treat in the United States. How scar tissue starts to form in both healing wounds and fibrosis is poorly understood. A key question is what mechanism overrides the inhibitory signals present in wounds and at the site of fibrosis to trigger the differentiation of monocytes into fibrocytes. In this dissertation, I present evidence that proteases present in the early wound and scar tissue environment appear to be potent signals for fibrocyte, and pro-fibrotic macrophage, differentiation. Transient exposure of trypsin, tryptase, and thrombin to monocytes potentiates fibrocyte differentiation, even in the presence of fibrocyte inhibitors serum amyloid P (SAP) or interferon-gamma (IFN-γ), suggesting that proteases may be an early stage pro-fibrotic signal. Cancer is involved in 25% of deaths in the United States. The majority of these deaths are not caused by the primary tumor, but rather by metastases. Metastasis is a process whereby cancer cells migrate from a primary tumor to distant tissues. The tumor environment is heterogeneous, and contains cancer-associated macrophages and fibroblasts in addition to cancer cells. Tumors are frequently surrounded by scar tissue, and in order to metastasize, cancer cells must pass through this scar tissue. Little is known about the molecular mechanisms cancer cells use to disrupt the scar tissue and escape the surrounded tumor. In this dissertation, I present evidence that galectin-3 binding protein (LGALS3BP) is secreted by metastatic cancer cells, inhibits fibrocyte differentiation, and acts through the CD209/DCSIGN receptor. LGALS3BP is upregulated at the leading edge of tumors metastasizing into surrounding scar tissue. This data suggests a role for LGALS3BP in metastasis. This dissertation is focused on why fibrocytes differentiate and discovering novel methods for potentiating and inhibiting this differentiation, with an eye towards developing novel therapeutics for fibrosing diseases, chronic wounds, and cancer