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The angiogenic response is dictated by beta3 integrin on bone marrow-derived cells.

Feng W, McCabe NP, Mahabeleshwar GH, Somanath PR, Phillips DR, Byzova TV - J. Cell Biol. (2008)

Bottom Line: Angiogenesis is dependent on the coordinated action of numerous cell types.Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization.Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

ABSTRACT
Angiogenesis is dependent on the coordinated action of numerous cell types. A key adhesion molecule expressed by these cells is the alpha(v)beta(3) integrin. Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization. Using knockin mice expressing functionally stunted beta(3) integrin, we show that bone marrow transplantation rescues impaired angiogenesis in these mice by normalizing BMDC recruitment. We demonstrate that alpha(v)beta(3) integrin enhances BMDC recruitment and retention at angiogenic sites by mediating cellular adhesion and transmigration of BMDCs through the endothelial monolayer but not their release from the bone niche. Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

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Localization of BMDCs in the area of blood vessels in tumor tissues. (A) Immunofluorescent detection of CD31 (red) and GFP (green) in B16F10 (top) and RM1 (bottom) tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 50 μm. (B) Immunofluorescent detection of laminin (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP donor marrow. Bar, 100 μm. (C) Immunofluorescent detection of SMA (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm.
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fig4: Localization of BMDCs in the area of blood vessels in tumor tissues. (A) Immunofluorescent detection of CD31 (red) and GFP (green) in B16F10 (top) and RM1 (bottom) tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 50 μm. (B) Immunofluorescent detection of laminin (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP donor marrow. Bar, 100 μm. (C) Immunofluorescent detection of SMA (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm.

Mentions: The localization of BMDCs in tumor neovasculature of DiYF/GFP→WT, WT/GFP→WT, and WT/GFP→DiYF mice was examined by double staining of tumor sections for GFP (to visualize recruited BMDCs) and CD31 or VE-Cadherin (endothelium markers), laminin (blood vessel basement membrane), or SMA. BMDCs were prominent in the vicinity of blood vessels of B16F10 and RM1 tumors but were distinctly separate from the endothelial lining stained by CD31 or VE-Cadherin (Fig. 4 A and Fig. S3 B, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1). GFP-positive cells were situated adjacent to both the basement membrane (Fig. 4 B) and SMA-positive cells (Fig. 4 C). Western analysis of B16 F10 tumor lysates (WT/GFP→WT and DiYF/GFP→WT) showed decreased expression levels of GFP in tumors with DiYF/GFP→WT compared with WT/GFP→WT (Fig. S3, C and D). Additionally, Western analysis of DiYF/GFP→WT also exhibited reduced expression levels of VE-Cadherin and CD31 compared with WT/GFP→WT (Fig. S3, C and D). Our results indicate that although BMDCs did not directly incorporate into the tumor neovasculature, they are situated in close proximity to blood vessels and might affect angiogenesis by secreting key effectors. This is further supported by several other studies emphasizing the role of promyeloid cells in tumor vasculature (Grunewald et al., 2006; Shojaei et al., 2007, 2008; Purhonen et al., 2008). These groups demonstrated that BMDCs do not incorporate into endothelium. A recent study using B16 melanoma clearly shows the lack of markers such as CD31, von Willebrand factor, and VEGFR2 on BMDCs (Purhonen et al., 2008). Moreover, several comprehensive studies conclusively show that it is the population of myeloid cells from BM that makes all the difference in tumor growth (Shojaei et al., 2007, 2008).


The angiogenic response is dictated by beta3 integrin on bone marrow-derived cells.

Feng W, McCabe NP, Mahabeleshwar GH, Somanath PR, Phillips DR, Byzova TV - J. Cell Biol. (2008)

Localization of BMDCs in the area of blood vessels in tumor tissues. (A) Immunofluorescent detection of CD31 (red) and GFP (green) in B16F10 (top) and RM1 (bottom) tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 50 μm. (B) Immunofluorescent detection of laminin (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP donor marrow. Bar, 100 μm. (C) Immunofluorescent detection of SMA (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2600740&req=5

fig4: Localization of BMDCs in the area of blood vessels in tumor tissues. (A) Immunofluorescent detection of CD31 (red) and GFP (green) in B16F10 (top) and RM1 (bottom) tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 50 μm. (B) Immunofluorescent detection of laminin (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP donor marrow. Bar, 100 μm. (C) Immunofluorescent detection of SMA (red) and GFP (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm.
Mentions: The localization of BMDCs in tumor neovasculature of DiYF/GFP→WT, WT/GFP→WT, and WT/GFP→DiYF mice was examined by double staining of tumor sections for GFP (to visualize recruited BMDCs) and CD31 or VE-Cadherin (endothelium markers), laminin (blood vessel basement membrane), or SMA. BMDCs were prominent in the vicinity of blood vessels of B16F10 and RM1 tumors but were distinctly separate from the endothelial lining stained by CD31 or VE-Cadherin (Fig. 4 A and Fig. S3 B, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1). GFP-positive cells were situated adjacent to both the basement membrane (Fig. 4 B) and SMA-positive cells (Fig. 4 C). Western analysis of B16 F10 tumor lysates (WT/GFP→WT and DiYF/GFP→WT) showed decreased expression levels of GFP in tumors with DiYF/GFP→WT compared with WT/GFP→WT (Fig. S3, C and D). Additionally, Western analysis of DiYF/GFP→WT also exhibited reduced expression levels of VE-Cadherin and CD31 compared with WT/GFP→WT (Fig. S3, C and D). Our results indicate that although BMDCs did not directly incorporate into the tumor neovasculature, they are situated in close proximity to blood vessels and might affect angiogenesis by secreting key effectors. This is further supported by several other studies emphasizing the role of promyeloid cells in tumor vasculature (Grunewald et al., 2006; Shojaei et al., 2007, 2008; Purhonen et al., 2008). These groups demonstrated that BMDCs do not incorporate into endothelium. A recent study using B16 melanoma clearly shows the lack of markers such as CD31, von Willebrand factor, and VEGFR2 on BMDCs (Purhonen et al., 2008). Moreover, several comprehensive studies conclusively show that it is the population of myeloid cells from BM that makes all the difference in tumor growth (Shojaei et al., 2007, 2008).

Bottom Line: Angiogenesis is dependent on the coordinated action of numerous cell types.Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization.Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

ABSTRACT
Angiogenesis is dependent on the coordinated action of numerous cell types. A key adhesion molecule expressed by these cells is the alpha(v)beta(3) integrin. Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization. Using knockin mice expressing functionally stunted beta(3) integrin, we show that bone marrow transplantation rescues impaired angiogenesis in these mice by normalizing BMDC recruitment. We demonstrate that alpha(v)beta(3) integrin enhances BMDC recruitment and retention at angiogenic sites by mediating cellular adhesion and transmigration of BMDCs through the endothelial monolayer but not their release from the bone niche. Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

Show MeSH
Related in: MedlinePlus