Dusp3 deletion in mice promotes experimental lung tumour metastasis in a macrophage dependent manner
Maud VandereykenSophie JacquesEva Van OvermeireMathieu AmandNatacha RocksCéline DelierneuxPratibha SinghManeesh SinghCamille GhuysenCaroline WathieuTinatin ZurashviliNor Eddine SounniMichel MoutschenChristine GillesCécile OuryDidier CataldoJo A. Van GinderachterSouad Rahmouni
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Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion prevents neo-angiogenesis and b-FGF-induced microvessel outgrowth. Considering the importance of angiogenesis in metastasis formation, our study aimed to investigate the role of DUSP3 in tumour cell dissemination. Using a Lewis Lung carcinoma (LLC) experimental metastasis model, we observed that DUSP3-/- mice developed larger lung metastases than littermate controls. DUSP3-/- bone marrow transfer to lethally irradiated DUSP3+/+ mice was sufficient to transfer the phenotype to DUSP3+/+ mice, indicating that hematopoietic cells compartment was involved in the increased tumour cell dissemination to lung tissues. Interestingly, we found a higher percentage of tumour-promoting Ly6Cint macrophages in DUSP3-/- LLC-bearing lung homogenates that was at least partially due to a better recruitment of these cells. This was confirmed by 1) the presence of higher number of the Ly6Bhi macrophages in DUSP3-/- lung homogenates and by 2) the better migration of DUSP3-/- bone marrow sorted monocytes, peritoneal macrophages and bone marrow derived macrophages (BMDMs), compared to DUSP3+/+ monocytes, macrophages and BMDMs, in response to LLC-conditioned medium. Our study demonstrates that DUSP3 phosphatase plays a key role in metastatic growth through a mechanism involving the recruitment of macrophages towards LLC-bearing lungs.Keywords:
Lewis lung carcinoma
Plaque angiogenesis promotes the growth of atheromas, but the functions of plaque capillaries are not fully determined. Neovascularization may act as a conduit for the entry of leukocytes into sites of chronic inflammation. We observe vasa vasorum density correlates highly with the extent of inflammatory cells, not the size of atheromas in apolipoprotein E-deficient mice. We show atherosclerotic aortas contain activities that promote angiogenesis. The angiogenesis inhibitor angiostatin reduces plaque angiogenesis and inhibits atherosclerosis. Macrophages in the plaque and around vasa vasorum are reduced, but we detect no direct effect of angiostatin on monocytes. After angiogenesis blockade in vivo , the angiogenic potential of atherosclerotic tissue is suppressed. Activated macrophages stimulate angiogenesis that can further recruit inflammatory cells and more angiogenesis. Our findings demonstrate that late-stage inhibition of angiogenesis can interrupt this positive feedback cycle. Inhibition of plaque angiogenesis and the secondary reduction of macrophages may have beneficial effects on plaque stability.
Angiostatin
Vasa vasorum
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Pathogenesis
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The concept of angiogenesis and consecutive stages of the neovascularization processes under physiological and pathological conditions have been described. Angiogenesis is regulated by the different mechanisms which are in dynamic balance. The regulating components of these processes are the stimulating and inhibiting factors, the mediators of these reactions under influence of the host cell-tumor cell interaction. The role of angiogenesis in cancer development is connected with obtaining the angiogenic phenotype by tumor when the transformation from prevascular to vascular phase of neoplasm goes on. The further tumor growth and metastasis processes depend on neovascularization. Actual research trends in the field of angiogenesis have been presented in this paper. We need to know such markers of angiogenesis would be the most useful for doing research work and monitoring neoplasm diseases in clinics. Antiangiogenic management seems to be a new promising therapeutic concept in oncology.
Neoplasm
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Summary: Angiogenesis, the process by which new blood vessels are generated, occurs during wound healing, in the female reproductive system during ovulation and gestation, and during embryonic development. The process is carefully controlled with positive and negative regulators, because several vital physiological functions require angiogenesis. The consequences of abnormal angiogenesis are either excessive or insufficient blood vessel growth. Ulcers, strokes, and heart attacks can result from the absence of angiogenesis normally required for natural healing, whereas excessive blood vessel proliferation may favor tumor growth and dissemination, blindness, and arthritis. In this review, the process of angiogenesis and the characteristics of the resulting tumor vasculature are outlined. Contrast-enhanced magnetic resonance imaging techniques that currently are available for basic research and clinical applications to study various aspects of tumor angiogenesis and neovascularization are discussed.
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Angiogenesis is the process of new blood vessel growth and is a critical biological process under both physiologic and pathologic conditions. Angiogenesis can occur under physiologic conditions that include embryogenesis and the ovarian/menstrual cycle. In contrast, pathologic angiogenesis is associated with chronic inflammation/chronic fibroproliferative disorders and tumorigenesis of cancer. Similarly, aberrant angiogenesis associated with chronic inflammation/fibroproliferative disorders is analogous to neovascularization of tumorigenesis of cancer. Net angiogenesis is determined by a balance in the expression of angiogenic compared with angiostatic factors. CXC chemokines are heparin-binding proteins that display unique disparate roles in the regulation of angiogenesis. Based on their structure, CXC chemokines can be divided into two groups that either promote or inhibit angiogenesis, and they are therefore uniquely placed to regulate net angiogenesis in both physiologic and pathologic conditions.
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Lewis lung carcinoma
Angiogenesis inhibitor
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The formation of new blood vessels from existing blood vessels has been referred to as angiogenesis to distinguish the process from de novo embryonic vessel formation or vasculogenesis (1). This chapter will describe an in vivo assay to measure angiogenesis. There are several important reasons to study and measure angiogenesis in vascular disease. First, it is necessary to try to understand proliferative angiogenesis as it occurs in tumors and in diabetic complications and devise strategies to inhibit it. Second, there is intense interest in improving angiogenesis after ischemia or in chronic wounds (2). Third, many potential modulators of angiogenesis need to be evaluated to determine their effects on blood vessel development.
Vasculogenesis
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A variety of pharmacological strategies are being subjected to clinical trial to inhibit neovascularization of solid tumors. Increased angiogenesis is also a key component of synovitis and bone modeling in arthritis. Molecular mechanisms and pathological consequences of blood vessel growth in arthritis are now being elucidated. Preclinical studies of angiogenesis inhibitors in animal models of inflammatory arthritis support the hypothesis that inhibition of neovascularization may reduce inflammation and joint damage. Clinical data are consistent with these models being predictive of efficacy in rheumatoid arthritis. However, controlled studies of specific anti-angiogenic agents in human arthritis remain limited. Further studies are required to demonstrate that pharmacological agents can effectively inhibit articular angiogenesis, and ameliorate inflammation and subsequent joint damage. Potential toxicity of angiogenesis inhibitors in reproduction, growth and development and wound repair may be circumvented by short-term or local application, or by targeting molecular mechanisms that are specific to pathological rather than physiological angiogenesis.
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