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Determining the interactions between murine melanoma cells and stroma. The addition of cancer-associated fibroblasts (red) to podoplanin-expressing melanoma cells (green) cultured within a 3-dimensional matrix stimulates invasive properties (lower panel) when compared with normal fibroblasts (red, top panel). After 2 days of culture with normal fibroblasts, podoplanin-expressing tumour cells retain their spheroid morphology. However, when alone or in the presence of cancer-associated fibroblasts, podoplanin- expressing cells outgrow the original spheroid structure and numerous podoplanin positive extensions can be seen penetrating the matrix.

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Complexities of the tumour microenvironment: the effects of lymphatic function on tumour-associated tissues. A) To ensure the maintenance of tissue homeostasis in normal tissues, plasma exudates from blood vessels are slowly transported through the interstitium towards lymphatic capillaries. Cell adhesion molecules such as CD31 maintain lymphatic endothelial cells junctions. B) In the tumor microenvironment, enhanced interstitial flow created by high interstitial fluid pressure drains to peritumoral lymphatics. In the process of passing over metabolically active tumor cells, interstitial fluid picks up growth factors (e.g. VEGF-C) and tumor cell components, which enter the lymphatic system towards the draining lymph node. Tumor derived growth factors can synergize with flow to act in an autocrine fashion increasing cell invasiveness, or paracrine manner on stromal cells such as cancer-associated fibroblasts and lymphatic endothelial cells. VEGF-C stimulates lymphatic growth (enhancing drainage capacity), and also the secretion of lymph homing chemokines such as CCL21. Flow itself is sufficient to induce environmental changes, stimulating remodelling of the stroma and modification of vessel functionality (via down-regulation of junction proteins and changes in surface expression). But how does flow impact stroma function?

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