1. Department of Urology, University of Pittsburgh School of Medicine, Shadyside Medical Center, 5200 Centre Avenue, Pittsburgh, PA15232, USA.
2. Prostate and Urological Cancers Program, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA 15232, USA.
3. Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Ringstr.52, D-66421 Homburg/Saar, Germany.
*LMK and LAG contributed equally.
Fibrin plays an important role in lung metastasis. Here we show that fibrin promotes colony formation in primary kidney tumor cells from patients with kidney metastasis. In addition, we found that inhibition of fibrin formation with the thrombin inhibitor hirudin in nude mice in vivo significantly reduced the metastatic outgrowth of kidney tumor cells. Colony formation was significantly more efficient in tumor cells embedded in fibrin compared to matrigel and this effect correlates with the capacity of tumor cells to assemble a fibronectin matrix and generate stress fibers. Interestingly, stress fiber formation in fibrin was a specific function of metastatic kidney tumor cells while non-metastatic cells remained round. Inhibition of stress fiber formation with the Rho kinase inhibitor Y-27632, in turn, reduced fibronectin matrix assembly and colony formation in fibrin suggesting that spreading is a critical mechanism for the outgrowth of metastatic kidney tumor cells. Overall, our results indicate that adhesive interactions with fibrin play an important role for the progression of renal cell carcinoma and that inhibiting these interactions could be a promising strategy for treatment and prevention of kidney cancer metastasis.
Keywords: Fibronectin, Metastasis, Fibrin.