The Urokinase Receptor (u-PAR)--a Link Between Tumor Cell Dormancy and Minimal Residual Disease in Bone Marrow?

Minimal residual disease (MRD) is hypothesized to be the major cause of tumor recurrence and metastasis even years and decades after primary cancer diagnosis and curative solid tumor resection. In these patients disseminated tumor cells reflecting MRD can be detected in the bone marrow years after treatment. It is to be assumed that genetic determinants and a complex interplay between the disseminated tumor cells and their microenvironment in the bone marrow are responsible for tumor cell dormancy and the final reactivation towards metastasis. The urokinase receptor (u-PAR), a critical regulator of invasion, intravasation, and metastasis, is found to be a key player in regulating the shift between single cell tumor dormancy and proliferation. This has mainly been attributed to a regulation by u-PAR of integrins, and the ability of the latter to propagate signals from fibronectin through the EGF-receptor, ERK, and p38 signaling. Interestingly, u-PAR is found in disseminated tumor cells in the bone marrow of solid cancer patients, and is associated with the expansion of these cells and clinical prognosis. Here we summarize and discuss findings on disseminated tumor cells in the bone marrow, MRD and the role of u-PAR in tumor biology, especially focusing on its specific role in providing a switch between tumor cell proliferation and dormancy. Finally, we discuss the hypothesis that u-PAR might be an essential molecule in bone marrow disseminated tumor cells for long-term survival during dormancy, and/or reactivation of their proliferation years after primary treatment.