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090 a| RS431.A64;

100 1 a| Joshi, Molishree Umesh.?| UNAUTHORIZED;

245 14 a| The role of SDF-1[alpha] as a vasculogenic chemokine and endothelium-associated cell adhesion molecule for the recruitment of bone marrow-derived progenitor cells to developing tumors /c| by Molishree Umesh Joshi.;

260 a| [Greenville, N.C.] :b| East Carolina University,c| 2010.;

300 a| 245 pages :b| illustrations (some color), digital, PDF file;

336 a| text2| rdacontent;

337 a| computer2| rdamedia;

338 a| online resource2| rdacarrier;

500 a| Presented to the faculty of the Department of Interdisciplinary Doctoral Program in Biological Sciences.;

500 a| Advisor: Kathryn Verbanac.;

500 a| Title from PDF t.p. (viewed Jan. 31, 2011).;

502 b| Ph.D.c| East Carolina Universityd| 2010.;

504 a| Includes bibliographical references.;

520 3 a| Tumor vascularization is an important control point in cancer progression and its inhibition is a promising approach to cancer therapy. Stromal-derived factor-1 alpha (SDF-1 alpha or CXCL12) is a chemoattractant for lymphocytes, hematopoietic progenitor cells, and vascular endothelial cells. SDF-1 alpha binds to the CXCR4 receptor on cell surfaces and to heparan sulfate in cell membranes and the extracellular matrix. We hypothesized that SDF-1 alpha is an important mediator of tumor vasculogenesis, recruiting bone marrow-derived endothelial progenitor cells to tumors. We evaluated the role of SDF-1 alpha in the adhesion of bone marrow-derived lineage-negative cells to the murine Lewis lung adenocarcinoma (LLCaB subclone), both in vitro and in vivo. LLCaB lung and liver metastases expressed significantly elevated levels of SDF-1 alpha compared to normal tissue from naive controls and primary tumors. SDF-1 alpha expression inversely correlated with tumor size, implicating involvement in early tumor development. SDF-1 alpha was detected on ~30% of blood vessels in primary and metastatic tumors by double immunocytochemistry staining and on endothelial cells within primary cultures of dissociated LLCaB tumors (DTC). Lineage-negative BMC enriched for Sca1+cKit+ (LSK) cells, including endothelial progenitors and CXCR4+ cells, were used for subsequent adhesion studies. LSK cells preferentially adhered in vitro to DTC, compared to other target cell types. Pre-incubation with anti-CXCR4 antibody or the CXCR4 antagonist AMD3100 decreased adhesion of LSK cells by 50%. Biolocalization of adoptively-transferred EGFP-Lineage-negative BMC in tumor-bearing wild-type mice was evaluated by qPCR for the egfp-transgene. A significantly greater number of Lineage-negative BMC localized to metastases 2-3 days after intravenous injection than to adjacent healthy tissue, normal organs, or primary tumors. Control CXCR4-negative EGFP-dermal fibroblasts showed significantly less tumor localization. One-week post-injection, Lineage-negative BMC were still detected in every metastasis, suggesting that BMC were retained and/or had replicated. These data support the hypothesis that the biolocalization of circulating Lineage-negative BMC to tumors is SDF-1 alpha-mediated. We have also put forth the novel proposal that SDF-1 alpha promotes early tumor vasculogenesis as a tumor endothelium-associated adhesion molecule for circulating CXCR4+ Lineage-negative BMC. These findings may aid our understanding of the mechanism of tumor vascularization and the design of tumor-targeted therapy.;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

650 0 a| Neovascularization inhibitors.=| ^A715048;

650 0 a| Tumorsx| Growth.=| ^A787392;

653 a| Biology, Animal Physiology;

653 a| Biology, Physiology;

653 a| Biology, Cell;

700 1 a| Verbanac, Kathryn M.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Biology.=| ^A637467;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/2953;

949 o| jgml;

994 a| C0b| ERE;

596 a| 1 4;

998 a| 2329418;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 2329418-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 11/3/2010x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 2329418-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 11/3/2010x| ETDz| HERESOURCE;

The role of SDF-1[alpha] as a vasculogenic chemokine and endothelium-associated cell adhesion molecule for the recruitment of bone marrow-derived progenitor cells to developing tumors / by Molishree Umesh Joshi.

Author/creator	Joshi, Molishree Umesh
Other author	Verbanac, Kathryn M.
Other author	East Carolina University. Department of Biology.
Format	Theses and dissertations
Publication Info	[Greenville, N.C.] : East Carolina University, 2010.
Description	245 pages : illustrations (some color), digital, PDF file
Supplemental Content	Access via ScholarShip
Subjects	Neovascularization inhibitors. Tumors--Growth.

Summary	Tumor vascularization is an important control point in cancer progression and its inhibition is a promising approach to cancer therapy. Stromal-derived factor-1 alpha (SDF-1 alpha or CXCL12) is a chemoattractant for lymphocytes, hematopoietic progenitor cells, and vascular endothelial cells. SDF-1 alpha binds to the CXCR4 receptor on cell surfaces and to heparan sulfate in cell membranes and the extracellular matrix. We hypothesized that SDF-1 alpha is an important mediator of tumor vasculogenesis, recruiting bone marrow-derived endothelial progenitor cells to tumors. We evaluated the role of SDF-1 alpha in the adhesion of bone marrow-derived lineage-negative cells to the murine Lewis lung adenocarcinoma (LLCaB subclone), both in vitro and in vivo. LLCaB lung and liver metastases expressed significantly elevated levels of SDF-1 alpha compared to normal tissue from naive controls and primary tumors. SDF-1 alpha expression inversely correlated with tumor size, implicating involvement in early tumor development. SDF-1 alpha was detected on ~30% of blood vessels in primary and metastatic tumors by double immunocytochemistry staining and on endothelial cells within primary cultures of dissociated LLCaB tumors (DTC). Lineage-negative BMC enriched for Sca1+cKit+ (LSK) cells, including endothelial progenitors and CXCR4+ cells, were used for subsequent adhesion studies. LSK cells preferentially adhered in vitro to DTC, compared to other target cell types. Pre-incubation with anti-CXCR4 antibody or the CXCR4 antagonist AMD3100 decreased adhesion of LSK cells by 50%. Biolocalization of adoptively-transferred EGFP-Lineage-negative BMC in tumor-bearing wild-type mice was evaluated by qPCR for the egfp-transgene. A significantly greater number of Lineage-negative BMC localized to metastases 2-3 days after intravenous injection than to adjacent healthy tissue, normal organs, or primary tumors. Control CXCR4-negative EGFP-dermal fibroblasts showed significantly less tumor localization. One-week post-injection, Lineage-negative BMC were still detected in every metastasis, suggesting that BMC were retained and/or had replicated. These data support the hypothesis that the biolocalization of circulating Lineage-negative BMC to tumors is SDF-1 alpha-mediated. We have also put forth the novel proposal that SDF-1 alpha promotes early tumor vasculogenesis as a tumor endothelium-associated adhesion molecule for circulating CXCR4+ Lineage-negative BMC. These findings may aid our understanding of the mechanism of tumor vascularization and the design of tumor-targeted therapy.
General note	Presented to the faculty of the Department of Interdisciplinary Doctoral Program in Biological Sciences.
General note	Advisor: Kathryn Verbanac.
General note	Title from PDF t.p. (viewed Jan. 31, 2011).
Dissertation note	Ph.D. East Carolina University 2010.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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The role of SDF-1[alpha] as a vasculogenic chemokine and endothelium-associated cell adhesion molecule for the recruitment of bone marrow-derived progenitor cells to developing tumors / by Molishree Umesh Joshi.

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