Role of Urokinase-Type Plasminogen Activator (uPA) in Progression of TSC Tumors
Abstract
We are studying a genetic disorder called tuberous sclerosis complex (TSC). The genetic defect causes overactivation of a molecule within cells called mTOR (mammalian Target Of Rapamycin), which sends excessive growth signals to cells, leading to the formation of "non-malignant" tumors in many organs. Our study focuses on two types of TSC tumors, which may be representative of other clinical outcomes: (1) lymphangioleimyomatosis (LAM), which occurs in the lung, and (2) angiomyolipoma (AML), which often occurs in the kidney. LAM is a devastating disease that primarily affects women of childbearing age. When LAM cells overgrow, they form cavities (cysts) that progressively enlarge and destroy surrounding normal lung tissue, obstruct airways and blood vessels, and eventually lead to respiratory failure. AML tumors contain abundant immature and leaky vessels, which can rupture and cause life-threatening bleeding. How LAM and AML cells overgrow and spread to the other organs, and how the tumors co-opt "healthy" fibroblasts and endothelial cells is a central feature, but is not well understood and is the subject of this research proposal. As of now, lung transplantation is the only definitive treatment for patients with LAM, but tumors can recur in the transplanted organ. The mTOR inhibitor rapamycin (Sirolimus), which is used to prevent immune rejection of donor tissue, has improved the otherwise poor prognosis in LAM by slowing down the decline in lung function and reducing the growth of AML. Unfortunately, some patients do not respond to rapamycin, treatment must be continued indefinitely, it is not well tolerated by many recipients and may need to be withdrawn, and a rebound increase in growth of AML is observed in some patients after drug withdrawal. We seek to understand how TSC-compromised cells respond to rapamycin, how they may eventually escape from its control, and how this information can be used to better clinical outcome. LAM and AML tumors are rich in a protein called urokinase-type plasminogen activator (urokinase), which cells use to dissect and migrate through tissue, penetrate blood and lymphatic vessels, and spread to other organs. Our data indicate that urokinase is involved in pathogenesis of TSC tumors, since mice lacking the gene encoding this protein develop significantly fewer TSC2-negative tumors in the lung. We recently discovered that the loss of function of TSC genes is itself directly responsible for this increase in urokinase production. To our surprise, we found that rapamycin actually stimulates production of urokinase specifically in cells lacking TSC function. We think that the effectiveness of rapamycin might be limited by this overproduction of urokinase, which increases the metastatic aggressiveness and tissue-destroying capacity of LAM and AML cells. This suggests that understanding how loss of TSC results in excessive urokinase production and how this enzyme stimulates the growth and migration of LAM and AML cells and co-opts "healthy" vascular cells by the tumor offers a new way to control this disease using urokinase inhibitors alone or when combined with rapamycin. We developed a mouse model of LAM, which allows us to study potential mechanisms that account for the adverse effects of urokinase. We will use this model to see if the analog of an orally available inhibitor of urokinase called Mesupron, alone or combined with rapamycin, might have potential to help halt the growth and spread of LAM and AML cells. Mesupron is well tolerated and has been shown to be effective in Phase II clinical trials in patients with breast cancer. These results are not surprising given the virtual absence of urokinase in most normal cells and the high levels found in most tumors, including LAM and AML. What is needed before such trials can be initiated in LAM patients is a solid experimental rationale for this approach and strong preclinical evidence of effectiveness and safety i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610187
Entities
People
- Victoria Stepanova
Organizations
- United States Army
- University of Pennsylvania