Objective-Interleukin(IL)-17A, an inflammatory cytokine, has been implicated in atherosclerosis, in which inflammatory cells within atherosclerotic plaques express IL-17A. However, its role in the development of atheroscelrosis remains to be controversial. Methods and Results-To directly examine the role of IL-17A in atherosclerosis, we generated apolipoprotein E (ApoE)/IL-17A double-deficient (ApoE
Objective-Syndecan-4 (Syn4) is a heparan sulfate proteoglycan and works as a coreceptor for various growth factors. We examined whether Syn4 could be involved in the development of neointimal formation in vivo. Methods and Results-Wild-type (WT) and Syn4-deficient (Syn4 Ϫ/Ϫ ) mice were subjected to wire-induced femoral artery injury. Syn4 mRNA was upregulated after vascular injury in WT mice. Neointimal formation was attenuated in Syn4 Ϫ/Ϫ mice, concomitantly with the reduction of Ki67-positive vascular smooth muscle cells (VSMCs). Basic-fibroblast growth factor-or platelet-derived growth factor-BB-induced proliferation, extracellular signal-regulated kinase activation, and expression of cyclin D1 and Bcl-2 were impaired in VSMCs from Syn4 Ϫ/Ϫ mice. To examine the role of Syn4 in bone marrow (BM)-derived vascular progenitor cells (VPCs) and vascular walls, we generated chimeric mice by replacing the BM cells of WT and Syn4Ϫ/Ϫ mice with those of WT or Syn4 Ϫ/Ϫ mice. Syn4 expressed by both vascular walls and VPCs contributed to the neointimal formation after vascular injury. Although the numbers of VPCs were compatible between WT and Syn4 Ϫ/Ϫ mice, mobilization of VPCs from BM after vascular injury was defective in Syn4Ϫ/Ϫ mice. Conclusion-Syn4 deficiency limits neointimal formation after vascular injury by regulating VSMC proliferation and VPC mobilization. Therefore, Syn4 may be a novel therapeutic target for preventing arterial restenosis after angioplasty. oth excessive proliferation and migration of vascular smooth muscle cells (VSMCs) from arterial media to neointima and mobilization of bone marrow (BM)-derived vascular progenitor cells (VPCs) are the major causes of neointimal hyperplasia, which contributes to the development and progression of various vascular pathologies, such as atherosclerosis and restenosis after angioplasty. [1][2][3][4] Although drug-eluting stents can inhibit smooth muscle cell proliferation and reduce the rate of restenosis, 5 their clinical benefits are still limited because of the critical problems, such as causing late stent thrombosis and the need for continuing dual antiplatelet therapy. 6,7 Therefore, the elucidation of the molecular mechanisms by which neointimal hyperplasia develops after vascular injury is necessary to establish the development of novel approaches for improving the safety and efficacy of angioplasty. See accompanying article on page 952Proliferation and migration of VSMCs after vascular injury are modulated by various components of the extracellular matrix, particularly heparin and the related heparan sulfate proteoglycans. 8 Heparan sulfate proteoglycans are distributed ubiquitously as a component of the extracellular matrix or at the cell surface. Among the heparan sulfate proteoglycans, both perlecan and syndecan-1, a member of the syndecan family that works as a coreceptor and reservoir for growth factors, cytokines, and extracellular matrix proteins through its heparan sulfate chains, 9 have been shown to inhibit VSMC proliferation and neointimal hy...
Osteopontin (OPN) has been implicated in various stages of cancer progression such as malignant transformation, invasion and metastasis. Several groups independently demonstrated that plasma OPN level is a potential diagnostic and prognostic marker for several human malignancies (Bellahcene A et al, Nat Rev Cancer 8:212, 2008 and Anborgh PH, et al Clin Chem 55:895, 2009). Interestingly, a human breast cancer cell with an aggressive lymph node metastatic ability has been established, which demonstrated strong expression of α9β1 integrin and OPN (Vantyghem SA et al Clin & Exp Meta 22:351, 2005). Of note, α9β1 integrin is a receptor for not only OPN, but also VEGF-C and -D, known lymphatic vessel growth factors. To address whether and how α9β1 integrin is involved in tumorigenesis, growth, invasion and lymph node metastasis, we took advantage of using an inhibitory anti-human α9 integrin antibody (clone: K33N), which does not cross react with murine α9 integrin and an α9β1 integrin-positive human breast cancer cell line, MDA-MB-231 luc-D3H2LN (D3H2LN), in in vitro functional assays and an in vivo orthotopic xenotransplantation model. We found that K33N inhibited in vitro migration and invasion of D3H2LN cells, indicating that the interaction of α9β1 integrin with its ligands was involved in the breast cancer cells motility. Next, we inoculated D3H2LN cells into the mammary fat pad of nude mice at day 0, and K33N or control IgG was given to them twice per week from day 15 to day 50 after tumor inoculation. K33N significantly reduced both primary tumor growth and draining lymph node metastasis. To gain an understanding of the mechanism by which K33N suppressed the primary tumor growth and lymph node metastasis, we examined the expression of various molecules which are associated with the cancer progression. We found significant matrix metalloproteinase (MMP) up-regulation in K33N-treated primary tumor tissues, consistent with a recent report demonstrating an indirect involvement of MMPs involved in tumor growth. Of note, upon orthotopic injection of human D3H2LN cells, plasma level of host-derived murine OPN, but not tumor-derived human OPN was significantly elevated. Surprisingly, host-derived murine OPN was significantly reduced in the mice treated with K33N. These results suggest that the interaction between α9β1 integrin on breast cancer cells and its ligands favors the generation of tissue microenvironments which contribute to primary tumor growth and lymph node metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 417. doi:10.1158/1538-7445.AM2011-417
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