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Background Vascularized lymph node transfer (VLNT) is one of the surgical options in the treatment of lymphedema, but its mechanism of action has not yet been firmly clarified. In the VLNT mouse models described so far, the lymph node flap is performed between two different sites in the same lymphedematous paw. In this study, we describe an optimized VLNT mouse model using the contralateral paw as donor site, thus removing the bias of transferring a lymph node already damaged by irradiation and/or surgery required to induce lymphedema. Methods A lymphedema was induced on the left posterior paw in four experimental groups of mice (n = 8). Two weeks later, group 1 was the sham one, group 2 underwent a VLNT from the right inguinal region to the left, in group 3 a vascular endothelial growth factor (VEGF)-C sponge was placed alone in the left inguinal region, and in group 4 a VEGF-C sponge was associated to the VLNT. The 32 mice were followed during 3 months. Outcomes included paws volume, skin quality, inflammation in the lymphedematous tissue, and lymphatic network density and function. Results Group 4 displayed significantly higher (p Conclusions This optimized mouse model of VLNT shows to be handy and effective. It could be exploited to perform further experimental studies about the influence of VLNT on lymphedema. Moreover, the local association between VLNT and biological compounds in this model allows it to be a good preclinical model to identify new potential drugs in lymphedema.

Angiogenesis and lymphangiogenesis have become important research areas in the biomedical field. The outgrowth of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels from preexisting ones is involved in many pathologies including cancer. In-depth investigations of molecular determinants such as proteases in these complex processes require reliable in vivo models. Here we present the ear sponge assay as an easy, rapid, quantitative and reproducible model of angiogenesis and lymphangiogenesis. In this system, a gelatin sponge soaked with tumor cells, cell-conditioned medium, or a compound to be tested is implanted, for 2-4 weeks, between the two mouse ear skin layers. The two vascular networks are next examined through histological procedures.

Lymphangiogenesis, the formation of new lymphatic vessels, occurs in primary tumors and in draining lymph nodes leading to pre-metastatic niche formation. Reliable in vivo models are becoming instrumental for investigating alterations occurring in lymph nodes before tumor cell arrival. In this study, we demonstrate that B16F10 melanoma cell encapsulation in a biomaterial, and implantation in the mouse ear, prevents their rapid lymphatic spread observed when cells are directly injected in the ear. Vascular remodeling in lymph nodes was detected two weeks after sponge implantation, while their colonization by tumor cells occurred two weeks later. In this model, a huge lymphangiogenic response was induced in primary tumors and in pre-metastatic and metastatic lymph nodes. In control lymph nodes, lymphatic vessels were confined to the cortex. In contrast, an enlargement and expansion of lymphatic vessels towards paracortical and medullar areas occurred in pre-metastatic lymph nodes. We designed an original computerized-assisted quantification method to examine the lymphatic vessel structure and the spatial distribution. This new reliable and accurate model is suitable for in vivo studies of lymphangiogenesis, holds promise for unraveling the mechanisms underlying lymphatic metastases and pre-metastatic niche formation in lymph nodes, and will provide new tools for drug testing., info:eu-repo/semantics/published

Solid tumors comprise cancer cells and different supportive stromal cells, including mesenchymal stem cells (MSCs), which have recently been shown to enhance tumor growth and metastasis. We provide new mechanistic insights into how bone marrow (BM)-derived MSCs co-injected with Lewis lung carcinoma cells promote tumor growth and metastasis in mice. The proinvasive effect of BM-MSCs exerted on tumor cells relies on an unprecedented juxtacrine action of BM-MSC, leading to the trans-shedding of amphiregulin (AREG) from the tumor cell membrane by tumor necrosis factor-α-converting enzyme carried by the BM-MSC plasma membrane. The released soluble AREG activates cancer cells and promotes their invasiveness. This novel concept is supported by the exploitation of different 2D and 3D culture systems and by pharmacological approaches using a tumor necrosis factor-α-converting enzyme inhibitor and AREG-blocking antibodies. Altogether, we here assign a new function to BM-MSC in tumor progression and establish an uncovered link between AREG and BM-MSC., info:eu-repo/semantics/published