The objective of this proposal is to examine the role of bone marrow (BM) - derived circulating endothelial precursor cells (CEPs) and hematopoietic cells (HCs) in the post natal regulation of angiogenesis. Despite recent identification of angiogenic factors regulating embryonic development, the role of such factors and effector cells in modulation of tumor angiogenesis is not clear. We intend to define the mechanisms whereby Id gene mediation along with the upregulation of vascular endothelial growth factor receptors, VEGFR1 (Flt-l) and VEGFR2 (FIK-1, KDR) regulate survival, proliferation, mobilization, and recruitment of CEPs and HCs. We have identified circulating CEPs, AC133 (+) VEGFR2 (+), capable of being recruited from BM to tumor vasculature bed, accelerating angiogenesis. We found that signaling through VEGFR2 is essential for CEP proliferation and that VEGF induces mobilization of a subset of VEGFR1 (+) HCs that affects initiation of the tumor vascular network. Also VEGF induced Id1 and Id3 expression in both BM derived CEPs and HCs. Further angiogenic defects (tumor growth, Matrigel vascularization) in Id1 and Id3 knock out (Id1+/-Id3-/-) mice were reversible by BM transplantation. Thus the primary angiogenic defect in (Id1+/-Id3-/-) mice may be due to dysregulated VEGF/VEGFR2 and perhaps VEGF/VEGFR1 signaling, causing mobilization failure. We hypothesize that VEGF-mediated upregulation of Id1 and/or Id3 is essential for mobilization of VEGFR1(+) HCs and VEGFR2(+) CEPs.
Specific aims are: Determine the temporal and spatial expression patterns of Id genes, VEGFR1, and VEGFR2 on neovessels during tumor angiogenesis, 2) Define the role of chemokine signaling pathways for the regulation of Id gene and VEGF receptor expression during the mobilization of CEPs and HCs, 3) Assess the physiological significance and contributions of BM-derived CEPs and/or HCs to tumor angiogenesis in vivo models. These experiments will lead to the understanding of the mechanisms involved in the recruitment of VEGF-responsive Id competent BM-derived precursors to the tumor vasculature bed and suggest new clinical strategies to block tumor growth.
| Gao, Sizhi P; Chang, Qing; Mao, Ninghui et al. (2016) JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci Signal 9:ra33 |
| Chang, Qing; Bournazou, Eirini; Sansone, Pasquale et al. (2013) The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 15:848-62 |
| Psaila, B; Lyden, D; Roberts, I (2012) Megakaryocytes, malignancy and bone marrow vascular niches. J Thromb Haemost 10:177-88 |
| Couto, Joana Pinto; Daly, Laura; Almeida, Ana et al. (2012) STAT3 negatively regulates thyroid tumorigenesis. Proc Natl Acad Sci U S A 109:E2361-70 |
| Peinado, Héctor; Ale?kovi?, Maša; Lavotshkin, Simon et al. (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883-91 |
| Psaila, Bethan; Lyden, David (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285-93 |
| Chan, April S; Jensen, Kristian K; Skokos, Dimitris et al. (2009) Id1 represses osteoclast-dependent transcription and affects bone formation and hematopoiesis. PLoS One 4:e7955 |
| Wels, Jared; Kaplan, Rosandra N; Rafii, Shahin et al. (2008) Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev 22:559-74 |
| Rafii, Daniel C; Psaila, Bethan; Butler, Jason et al. (2008) Regulation of vasculogenesis by platelet-mediated recruitment of bone marrow-derived cells. Arterioscler Thromb Vasc Biol 28:217-22 |
| Kaplan, Rosandra N; Psaila, Bethan; Lyden, David (2007) Niche-to-niche migration of bone-marrow-derived cells. Trends Mol Med 13:72-81 |
Showing the most recent 10 out of 15 publications
