Project description:PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment Tumor associated fibroblasts (TAF) from different tumors exhibit distinct angiogenic and tumorigenic properties. Unlike normal skin fibroblasts (NSF) or TAF (TAF-TIB6) from TIB6 tumors that are sensitive to anti-VEGF treatment, TAF (TAF-EL4) from resistant EL4 tumors can stimulate TIB6 tumor growth even when VEGF is inhibited. We show that platelet-derived growth factor (PDGF)-C is upregulated in TAFs from resistant tumors. PDGF-C neutralizing antibodies blocked the angiogenesis induced by such TAF in vivo and slowed the growth of EL4 and admixture (TAF-EL4 + TIB6) tumors and exhibited additive effects with anti-VEGF-A antibodies. Hence, our data reveal a novel mechanism for TAF mediated tumorigenesis and suggest that some tumors may overcome inhibition of VEGF-mediated angiogenesis through upregulation of PDGF-C
Project description:While angiogenesis inhibitors have provided significant clinical benefit as cancer therapeutics, the mechanisms of anti-VEGF resistance remain incompletely understood. We uncovered an interleukin-17 mediated paracrine network of signaling between the adaptive and innate immune system associated with resistance to anti-VEGF treatment in multiple tumor models. The expression of tumor-associated fibroblasts and tumor-associated granulocytes (defined as CD11b+Gr1+) and tumor-associated monocytic cells (defined as CD11b+Gr1-) were compared between wildtype and IL-17RC knockout tumor bearing mice.
Project description:A transcriptome study in mouse hematopoietic stem cells was performed using a sensitive SAGE method, in an attempt to detect medium and low abundant transcripts expressed in these cells. Among a total of 31,380 unique transcript, 17,326 (55%) known genes were detected, 14,054 (45%) low-copy transcripts that have no matches to currently known genes. 3,899 (23%) were alternatively spliced transcripts of the known genes and 3,754 (22%) represent anti-sense transcripts from known genes.
