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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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Reduced tumor growth and delayed wound healing in DiYF mice are BM dependent. (A) Weights of subcutaneous B16F10 tumors in WT and DiYF mice (11 d after implantation) or mice undergoing BMT (13 d) with WT or DiYF donor marrow. Data represent mean ± SEM (n = 10 per group). (B) Weights of subcutaneous RM1 tumors in WT and DiYF mice (9 d after implantation) or mice undergoing BMT with WT donor marrow (11 d after implantation). Representative tumors are depicted above their respective dataset. Data represent mean ± SEM (without BMT, n = 14 per group; with BMT, n = 18 per group). (C) Analysis of wound healing in WT and DiYF mice. Gross visualization of healing wounds 3 (top left) and 7 (bottom left) d after wound creation in WT and DiYF mice not undergoing (top left) and undergoing (bottom left) BMT with WT or DiYF donor marrow. Percentage of wound closure in WT and DiYF mice (top right) and WT and DiYF mice (bottom right) undergoing BMT. Data represent mean ± SEM (WT and DiYF, n = 10 per group; WT→WT, n = 16; WT→DiYF, n = 12). *, P < 0.05.
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fig1: Reduced tumor growth and delayed wound healing in DiYF mice are BM dependent. (A) Weights of subcutaneous B16F10 tumors in WT and DiYF mice (11 d after implantation) or mice undergoing BMT (13 d) with WT or DiYF donor marrow. Data represent mean ± SEM (n = 10 per group). (B) Weights of subcutaneous RM1 tumors in WT and DiYF mice (9 d after implantation) or mice undergoing BMT with WT donor marrow (11 d after implantation). Representative tumors are depicted above their respective dataset. Data represent mean ± SEM (without BMT, n = 14 per group; with BMT, n = 18 per group). (C) Analysis of wound healing in WT and DiYF mice. Gross visualization of healing wounds 3 (top left) and 7 (bottom left) d after wound creation in WT and DiYF mice not undergoing (top left) and undergoing (bottom left) BMT with WT or DiYF donor marrow. Percentage of wound closure in WT and DiYF mice (top right) and WT and DiYF mice (bottom right) undergoing BMT. Data represent mean ± SEM (WT and DiYF, n = 10 per group; WT→WT, n = 16; WT→DiYF, n = 12). *, P < 0.05.

Mentions: In accord with our previous findings (Mahabeleshwar et al., 2006), the growth of implanted B16F10 melanoma was reduced about twofold in DiYF mice compared with WT counterparts. Transplantation of WT BM into irradiated DiYF hosts (WT→DiYF) normalized tumor growth to that of control WT mice receiving WT marrow (WT→WT; Fig. 1 A). These results were corroborated using murine RM1 prostate carcinoma cells (Fig. 1 B). Alternatively, transplantation of DiYF BM into irradiated WT hosts (DiYF→WT) resulted in stunted B16F10 and RM1 tumor growth, a difference similar to that observed in mice not undergoing BMT. These data suggest that reduced tumor growth in DiYF mice is at least partially a consequence of altered BMDC β3 integrin function.


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)

Reduced tumor growth and delayed wound healing in DiYF mice are BM dependent. (A) Weights of subcutaneous B16F10 tumors in WT and DiYF mice (11 d after implantation) or mice undergoing BMT (13 d) with WT or DiYF donor marrow. Data represent mean ± SEM (n = 10 per group). (B) Weights of subcutaneous RM1 tumors in WT and DiYF mice (9 d after implantation) or mice undergoing BMT with WT donor marrow (11 d after implantation). Representative tumors are depicted above their respective dataset. Data represent mean ± SEM (without BMT, n = 14 per group; with BMT, n = 18 per group). (C) Analysis of wound healing in WT and DiYF mice. Gross visualization of healing wounds 3 (top left) and 7 (bottom left) d after wound creation in WT and DiYF mice not undergoing (top left) and undergoing (bottom left) BMT with WT or DiYF donor marrow. Percentage of wound closure in WT and DiYF mice (top right) and WT and DiYF mice (bottom right) undergoing BMT. Data represent mean ± SEM (WT and DiYF, n = 10 per group; WT→WT, n = 16; WT→DiYF, n = 12). *, P < 0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2600740&req=5

fig1: Reduced tumor growth and delayed wound healing in DiYF mice are BM dependent. (A) Weights of subcutaneous B16F10 tumors in WT and DiYF mice (11 d after implantation) or mice undergoing BMT (13 d) with WT or DiYF donor marrow. Data represent mean ± SEM (n = 10 per group). (B) Weights of subcutaneous RM1 tumors in WT and DiYF mice (9 d after implantation) or mice undergoing BMT with WT donor marrow (11 d after implantation). Representative tumors are depicted above their respective dataset. Data represent mean ± SEM (without BMT, n = 14 per group; with BMT, n = 18 per group). (C) Analysis of wound healing in WT and DiYF mice. Gross visualization of healing wounds 3 (top left) and 7 (bottom left) d after wound creation in WT and DiYF mice not undergoing (top left) and undergoing (bottom left) BMT with WT or DiYF donor marrow. Percentage of wound closure in WT and DiYF mice (top right) and WT and DiYF mice (bottom right) undergoing BMT. Data represent mean ± SEM (WT and DiYF, n = 10 per group; WT→WT, n = 16; WT→DiYF, n = 12). *, P < 0.05.
Mentions: In accord with our previous findings (Mahabeleshwar et al., 2006), the growth of implanted B16F10 melanoma was reduced about twofold in DiYF mice compared with WT counterparts. Transplantation of WT BM into irradiated DiYF hosts (WT→DiYF) normalized tumor growth to that of control WT mice receiving WT marrow (WT→WT; Fig. 1 A). These results were corroborated using murine RM1 prostate carcinoma cells (Fig. 1 B). Alternatively, transplantation of DiYF BM into irradiated WT hosts (DiYF→WT) resulted in stunted B16F10 and RM1 tumor growth, a difference similar to that observed in mice not undergoing BMT. These data suggest that reduced tumor growth in DiYF mice is at least partially a consequence of altered BMDC β3 integrin function.

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