{"id":{"repo_id":"ecu","oai_identifier":"oai:thescholarship.ecu.edu:10342/2953"},"canonical_url":"https://search.dev.ndltd.org/etd/ecu/oai:thescholarship.ecu.edu:10342/2953","repository":{"repo_id":"ecu","name":"East Carolina University","base_url":"https://thescholarship.ecu.edu/server/oai/request"},"display":{"title":"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","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Joshi, Molishree Umesh"],"institution":"East Carolina University","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Biology","school":null,"contributors":[],"advisors":["Verbanac, Kathryn M."],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010","date_published":"2010","updated_at":"2026-07-24T02:13:41Z","subjects":["Biology, Animal physiology","Biology, Physiology","Biology, Cell","Animal physiology","Physiology","Cell Biology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10342/2953","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Verbanac, Kathryn M."]},{"key":"dc:contributor.department","label":"Department","values":["Biology"]},{"key":"dc:creator","label":"Author","values":["Joshi, Molishree Umesh"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2010-09-16T13:25:14Z","2011-05-17T14:41:18Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2012-07-31T13:08:19Z"]},{"key":"dc:date.issued","label":"Date","values":["2010"]},{"key":"dc:publisher","label":"Institution","values":["East Carolina University"]},{"key":"dc:type","label":"Dc Type","values":["Doctoral Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biology, Animal physiology","Biology, Physiology","Biology, Cell","Animal physiology","Physiology","Cell Biology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10342/2953"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["dissertations, academic"]},{"key":"dc:title","label":"Title","values":["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"]}]}],"canonical_facts":{"dc:contributor.advisor":["Verbanac, Kathryn M."],"dc:contributor.department":["Biology"],"dc:creator":["Joshi, Molishree Umesh"],"dc:date.accessioned":["2010-09-16T13:25:14Z","2011-05-17T14:41:18Z"],"dc:date.available":["2012-07-31T13:08:19Z"],"dc:date.issued":["2010"],"dc:description.abstract":["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."],"dc:description.degree":["Ph.D."],"dc:format.medium":["dissertations, academic"],"dc:identifier.uri":["http://hdl.handle.net/10342/2953"],"dc:publisher":["East Carolina University"],"dc:subject":["Biology, Animal physiology","Biology, Physiology","Biology, Cell","Animal physiology","Physiology","Cell Biology"],"dc:title":["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"],"dc:type":["Doctoral Dissertation"]},"updated_at":"2026-07-24T02:13:41Z"}