Tumor lymphangiogenesis was increased in VEGF-C MCF7 tumors injected in nude mice and lymph node metastasis were found more frequently. Similar results were reported with VEGF-C Evofosfamide overexpressing MDA-MB-435. In the present study, MCF7 cells overexpressing or not VEGF-C were inoculated into RAG-12/2 immunodeficient mice crossed with PAI-1 WT or PAI-1 deficient mice. In accordance with previous reports, we confirmed the increased growth rate of VEGF-C expressing tumors. The pro-tumoral effect of VEGF-C was previously attributed to a better oxygenation due to a slight angiogenic response or a decreased intratumoral pressure because of the increased number of lymphatic vessels. It is worth noting that the mice background and the immunodeficiency rate are essential factors influencing the lymph node dissemination. Indeed, the propensity of VEGF-C expressing cells to disseminate into lymph node was higher in nude micethan in SCID miceor RAG-12/2 mice. Since these mice differ in their B-lymphocyte status, it suggests that B lymphocytes might contribute to lymph node dissemination of cancerous cells. Accordingly, the requirement of B-lymphocytes was also observed in a lymphangiogenesis model of mycoplasma infection of the pulmonary tract. In agreement with previous studies, PAI-1 deficiency was associated with decreased tumor development. We further analysed the lymphatic invasion of these tumors and their dissemination into lymph nodes. Although VEGF-C expression led to an enhancement of lymphatic vessel numbers, no difference was observed in PAI-1 WT and PAI-12/2 mice. Moreover, both genotypes showed a similar rate of lymph node metastasis. These data clearly demonstrate that PAI-1 is not implicated in tumoral lymphangiogenesis. Moreover, our data are in line with a previous study on PyMT transgenic mice showing that the primary tumor growth was not significantly affected by PAI-1 deficiency and neither was the lung metastatic burden. We now demonstrate that PAI-1 is dispensable for tumoral lymphangiogenesis by using the PyMT and PAI-1 double transgenic mice. Knowing that inflammation influences cancer progressionand that lymphangiogenesis and inflammation processes are closely related, we applied a model of lymphangioma to PAI12/2 mice. This system consists in a benign hyperplasia of lymphatic vessels induced by the injection of Freund adjuvant and is often used to isolate lymphatic endothelial cells. In this system, the inflammatory reaction induced by Freund adjuvant relies on the recruitment of leukocytes by cytokines secreted by cells of the peritoneum. In PAI-1 deficient mice, we observed a macroscopic decrease of the lymphangioma formation as compared to PAI-1 WT mice. This effect could be ascribed to a reduction of fibrosis rather than to a decrease in lymphatic vessel recruitment. Accordingly, PAI-1 deficiency slowed down the fibrotic reaction in different modelsby accelerating plasmin-mediated proteolysisor by influencing macrophage or AP24534 myofibroblast recruitment. The lack of PAI-1 effect on inflammation related lymphangiogenesis was further confirmed by similar injury-induced corneal lymphangiogenesis observed in PAI-12/2 and PAI-1 WT mice. The increased lymphatic vessel size observed in lymphangioma of PAI-12/2 mice is intriguing. However, note that this variation in vessel structure is associated with a reduction of matrix deposition which may influence vessel branching. Studies on mammary gland morphogenesis revealed that the collagen deposition inhibition reduced developing tubular structure bifurcations. The matrix proteolytic breakdown could compromise the scaffold mechanical integrity necessary to counter endothelial cells-generated forces during the tube formation process.