Growth and Dissemination of Lewis Lung Carcinoma in Plasminogen-Deficient Mice

Abstract

Plasminogen activation has been proposed to play a critical role in cancer invasion and metastasis. The effects of complete ablation of plasminogen activation in cancer was studied by inoculation of a metastatic Lewis lung carcinoma expressing high levels of plasminogen activator into plasminogen-deficient (Plg−/−) mice and matched control mice. Primary tumors developed in all mice with no difference in the rate of appearance between Plg−/− and control mice. However, the primary tumors in Plg−/− mice were smaller and less hemorrhagic and displayed reduced skin ulceration. In addition, dissemination of the tumor to regional lymph nodes was delayed in Plg−/− mice. Surprisingly, no quantitative differences were observed in lung metastasis between Plg−/− and control mice. In addition, Plg deficiency was compatible with metastasis of the primary tumor to a variety of other organs. Nevertheless, Plg−/− mice displayed a moderately increased survival after primary tumor resection. These findings suggest that plasmin-mediated proteolysis contributes to the morbidity and mortality of Lewis lung carcinoma in mice, but sufficient proteolytic activity is generated in Plg−/− mice for efficient tumor development and metastasis.

Annexin A2 is a novel Cellular Redox Regulatory Protein involved in Tumorigenesis

“…Several studies have shown that plasmin activation does not play a major role in the subcutaneous growth of primary tumors. It has been shown that sub-cutaneous inoculation of plasminogen negative tumour cells (LLC) in plasminogen-null mice produced tumors only 10-35% smaller compared to control mice [ 38 ], while we observed a 70-85% decrease in tumor volume in the A549 and HT1080 ANXA2 depleted tumors compared to control tumors. Another study showed that both WT and plasminogen-null mice carrying the Polyoma middle T antigen under the control of the mouse mammary tumor virus long terminal repeat uniformly developed multiple bilateral mammary tumors that were indistinguishable [ 39 ].…”

Clinical significance of coagulation factors in operable colorectal cancer

“…Fibrin remodeling is involved in numerous steps of metastasis and has been shown to perform a crucial role in the formation of new vessels ( 42 ) Cross-linked fibrin in the ECM serves as a stable framework for endothelial cell migration during angiogenesis and for tumor cell migration during invasion ( 43 ). Knockout mouse models have also revealed the importance of fibrin remodeling in tumor growth and metastasis ( 44 ). In addition, multivariate modeling showed an association between the presence of elevated D-dimer levels and the presence of visceral metastases.…”

Cell Surface Remodeling by Plasmin: A New Function for an Old Enzyme

“…The dependence of tumor growth on host plasminogen was demonstrated also in the foot pad model with Lewis lung carcinoma and T241 fibrosarcoma [ 60 ]. Surprisingly, no quantitative differences were observed in lung metastasis between plasminogen knock-out and control mice if the Lewis lung carcinoma cells were implanted subcutaneously [ 61 ], pointing to complexity of plasminogen functions, manifestation of which in cancer can depend on the site of tumor development. Plasminogen-deficient mice also manifest a significantly decreased angiogenic response to vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF or FGF-2), which clearly indicates the importance of the plasmin system in angiogenesis in vivo [ 62 ].…”