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• W1520231443 abstract "Cancer is a class of diseases in which a group of cells display uncontrolled growth (division beyondthe normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimesmetastasis (spread to other locations in the body via the circulatory system). In addition to tumorcell-intrinsic genetic and epigenetic alterations, the tumor stroma, i.e. endothelial cells, pericytes,fibroblasts and a diverse immune cell infiltrate, might substantially contribute to tumor progression,metastatic potential and resistance to therapy.I therefore investigated the influence of immune cells on the growth of tumors in theRip1Tag2 mouse insulinoma model of multistage carcinogenesis. I detected a strong infiltration ofmyeloid cells, i.e. macrophages and granulocytes, into insulinomas. Functional experiments in vivorevealed that depletion of macrophages in tumors led to reduced angiogenesis but did not affecttumor growth.During the characterization of the immune cell contribution to tumor growth in the Rip1Tag2tumor model, I detected bone marrow-derived cells at unexpected sites. In particular, when Ianalyzed the spatial contribution of GFP-tagged bone marrow cells in tumors of lymphangiogenicRip1Tag2;RipVEGF-C mice, I detected bone marrow-derived cells in lymphatic endotheliumsurrounding the tumors.Detailed analysis of the integrated GFP+-cells revealed the expression of a complete set ofmarkers that are characteristic for lymphatic endothelial cells, the cell surface proteins LYVE-1 andPodoplanin, as well as the homeo-box transcription factor Prox-1. Depending on the analysistechnique applied, either confocal microscopy followed by 3D reconstitution or flow cytometry,between 3 and 9% of lymphatic endothelial cells in tumors are derived from the bone marrow.These studies were expanded to a second tumor model, the subcutaneous growth of TRAMP-C1prostate cancer cells in syngenic mice, which confirmed the findings made in Rip1Tag2;RipVEGF-C mice, and allowed to further substantiate the suggested ontogeny of the integrated,bone marrow-derived cells.Cell sorting and genetic lineage tracing experiments indicated that the bone marrow-derivedtumor lymphatic endothelial cells were at least partially derived from the myeloid lineage. Tumormice were adoptively transferred with labeled myeloid (progenitor) cells, and subsequentintegration of these cells into tumor lymphatic endothelium was detected. Cre/Lox technologyresulting in myeloid-specific marker gene expression was employed to come to similar conclusionsin a pure genetic experimental system without bone marrow cell-transfer or irradiation.In a loss-of-function approach, macrophages were pharmacologically depleted inRip1Tag2;RipVEGF-C mice. Peritumoral lymphatic vessel coverage was found to be reduced in 2macrophage-depleted mice as compared to control mice. Expression level analysis of thelymphangiogenic factors VEGF-C and VEGF-D by tumor-infiltrating macrophages indicated thattheir contribution to lymphangiogenesis by supplying growth factors is negligible and that thereduced lymphangiogenesis might indeed come from the reduced availability of macrophages asbuilding blocks of lymphatic endothelia.The same plasticity of myeloid cells I detected in vivo was also observed in vitro, wherebone marrow-derived macrophages start forming tube like structures and also start expressinglymphatic endothelial markers, when cultured under pro-inflammatory and endothelial specificconditions.In conclusion, this data indicates a myeloid origin of cells that trans-differentiate intolymphatic endothelial cells in an inflammatory tumor environment.The increasing use of non-invasive imaging technologies prompted us to evaluate anapproach resulting in bioluminescent pancreatic insulinoma, principally an improved Rip1Tag2tumor model of multistage pancreatic β-cell carcinogenesis. I therefore constructed a bicistronicexpression cassette in which SV40 early region is followed by an internal ribosomal entry site anda firefly luciferase coding sequence, under the transcriptional control of the Rat insulin promoter 1.Transgenic expression in mice resulted in β-cell carcinogenesis that could be monitored noninvasivelyby in vivo bioluminescence. Numerous tumors of different malignancy stages can bedetected in individual mice, indicating that this model recapitulates multistage carcinogenesis. Inaddition, in this mouse strain called RL-1 (RipTag-IRES-Luciferase line 1), due to the very stringent expression exclusively in the β-cells of Langerhans islets, we could determine micro-metastasis inliver via luciferase expression of metastatic cells. This mouse line will be of value to study antitumoraltherapeutic approaches in real-time, as well as to define roles for tumor-promoting as wellas metastasis-related genes when crossed to other transgenic or gene-targeted mice." @default.
• W1520231443 created "2016-06-24" @default.
• W1520231443 creator A5048615168 @default.
• W1520231443 date "2009-01-01" @default.
• W1520231443 modified "2023-09-26" @default.
• W1520231443 title "The contribution of bone marrow-derived cells to angiogenesis and lymphangiogenesis in murine models of carcinogenesis" @default.
• W1520231443 doi "https://doi.org/10.5451/unibas-004811343" @default.
• W1520231443 hasPublicationYear "2009" @default.
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