Role of the extracellular microenvironment and lymphatics in disease development and progression

The present project is focused on the tumour cell microenvironment, i.e. the interstitial fluid bathing the tumour cell and the lymph draining the tumour via the lymphatics. Lymphatic metastases are a major clinical problem for many cancer types, and stra tegies directed at halting this process are needed. Recent discoveries in the field of lymphatic vascular markers have been translated by genetical engineering into new animal models. By international collaboration we have access to and are breeding Chy a nd K14-VEGFR3-IgG mice, strains that have limited capacity for lymphangiogenesis and thus have lymphoedema. By implantation of syngenic tumours in Chy mice or mating K14-VEGFR3-IgG mice with GFP-NOD/SCID mice we will create new models to study lymphangiog enesis in vivo. Using these new models we will be able provide novel information on the role of lymphatics in tumour growth and metastasis as well as the role of stroma-host interactions. To quantify lymph flow in vivo in skin in lymphoedema as well as in tumours in mice we will determine washout of macromolecules conjugated to a fluorescent probe to generate new knowledge on lymphatic function in existing and newly generated lymph vessels and thereby the importance lymphatics for tumour growth and metast asis. We will also address microenvironmental signalling processes in spleen and bone marrow, two organs where access to interstitial fluid is limited because of lack of appropriate methods for fluid sampling. In these studies we will use newly developed techniques (tissue centrifugation and lymph sampling) to study local cytokine responses and cellular events during inflammation and leukaemia development. In the proposed experiments we intend to apply a broad spectrum of methodologies and approaches that will integrate molecular biology aspects with intact organ function. These are translational projects that make use of acquired basic and clinical science to evaluate key therapeutical approaches.