Tumor Cell–Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis

Endo, Motoyoshi; Nakano, Masahiro; Kadomatsu, Tsuyoshi; Fukuhara, Shigetomo; Kuroda, Hiroaki; Mikami, Shuji; Hato, Tai; Aoi, Jun; Horiguchi, Haruki; Miyata, Keishi; Odagiri, Haruki; Masuda, Tetsuro; Harada, Masahiko; Horio, Hirotoshi; Hishima, Tsunekazu; Nomori, Hiroaki; Ito, Takaaki; Yamamoto, Yutaka; Minami, Takashi; Okada, Seiji; Takahashi, Takashi; Mochizuki, Naoki; Iwase, Hirotaka; Oike, Yuichi

doi:10.1158/0008-5472.can-11-3878

Cited by 113 publications

(170 citation statements)

References 33 publications

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“…Our previous report showing chronic inflammation in skin tissue of K14-Angptl2 Tg mice demonstrated infiltration of skin tissue by inflammatory cells, including activated macrophages and neutrophils (7), both of which are sources of ROS (36). Angptl2 reportedly activates NFkB proinflammatory signaling in various cell types (3)(4)(5)(6)(7)37), which also enhances ROS production (38). Taken together, Angptl2 secreted from skin tissue of K14-Angptl2 Tg mice may increase ROS production due to activity of infiltrated and activated inflammatory cells.…”

Section: Discussionmentioning

confidence: 93%

“…Since then, epidemiologic studies have confirmed the idea that chronic inflammation underlies many cancers (2). Recently, we reported that Angiopoietin-like protein 2 (Angptl2) acts as a chronic inflammatory mediator in several pathologic settings (3)(4)(5)(6), and demonstrated that increased Angptl2 expression in skin tissues promotes inflammation and accelerates carcinogenesis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model by increasing susceptibility to "preneoplastic change" and "malignant conversion" (7). In normal cells, initiating oncogenic mutation is considered essential to promote a "preneoplastic change," which, if unrepaired, is then followed by proliferation and acquisition of cellular survival capacity, allowing accumulation of additional mutations (8)(9)(10).…”

Section: Introductionmentioning

confidence: 92%

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Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aoi

Endo

Kadomatsu

et al. 2014

Molecular Cancer Research

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Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 92%

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aoi

Endo

Kadomatsu

et al. 2014

Molecular Cancer Research

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“…28,36,37 Moreover, we reported that ANGPTL2 signaling through integrin α5β1 enhances cell motility by activating the Rho family GTPase Rac1 and by stimulating remodeling of the extracellular matrix (ECM) through activation of p38 mitogen-activated protein kinase (MAPK)-dependent matrix metalloproteinases (MMPs) (Figure 1). 19,20,24 ANGPTL2 signaling also induces expression of inflammation-related NFκB target genes by increasing degradation of IκB, a factor that inhibits NFκB nuclear localization. 17, 24 More recently, we reported that ANGPTL2 promotes intestinal epithelial regeneration (Figure 1).…”

Section: Angptl2 Function In Cvd Development and Progressionmentioning

confidence: 99%

ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

Oike

Tian

Miyata

et al. 2017

Circ J

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inflammation, 11,12 and emerging evidence reveals that senescent cells secrete factors that cause chronic local tissue inflammation associated with age-associated diseases. [13][14][15] This newly identified cellular senescence condition, termed the senescence-associated secretory phenotype (SASP), is now recognized as creating a common pathological environment that encourages development of age-associated diseases, including CVD. 13,15, 16 Many of our previous studies have revealed that the expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiologic stimuli such as hypoxia, reactive oxidative species, and pressure overload. 17-21 ANGPTL2 expression also increases in cells undergoing senescence, 22 suggesting that ANGPTL2 is a SASP factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathologic states and contributes to the development of aging-associated diseases such as CVD. 23-25 Thus, to understand the mechanisms underlying these conditions, we focus our discussion here on the role of ANGPTL2 in CVD. What Is ANGPTL2?Around 2000, several groups independently reported secreted glycoproteins that exhibit an N-terminal coiled-coil W orldwide, the number of patients with heart disease is increasing as populations of elderly people expand. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are associated with adverse health outcomes that decrease a patient's wellbeing and productivity. 1,2 Prevention of these conditions is desirable to promote healthy aging and improve patients' lifestyle.The pathologic basis of CVD is atherosclerosis caused by ectopic accumulation of cholesterol in vessel walls; 3 thus advent of therapies aimed at reducing low-density lipoprotein (LDL)-cholesterol levels has succeeded in decreasing the number of CVD events. 4,5 However, these events continue to occur, even in patients whose LDLcholesterol levels have been lowered by antidyslipidemia treatment, 1,2,4,5 indicating that the pathologies underlying CVD are highly complex. In addition to dyslipidemia, other factors such as smoking, hypertension, diabetes, ventral obesity, male sex, aging, genetic factors, and family history of CVD are well-established risk factors, 6-8 and the number of patients with dyslipidemia, diabetes, and hypertension also increases with age. 9 Recently, it was shown that chronic vascular inflammation accelerates atherosclerosis development. 10 Interestingly, aging, smoking, diabetes, and dyslipidemia all induce chronic In parallel with the increase in the number of elderly people worldwide, the number of patients with heart disease is also rapidly increasing. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are strongly associated with adverse health outcomes that decrease productivity in later years. Recently, ANGPTL2, a secreted glycoprotein and member of the angiopoietin-like protein family, has received attention as a causal player in the development of CVD and HF. Prolonged ANGPTL2 auto...

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“…Most recent studies have shown that Angptl2 also contributes to other chronic inflammatory disorders such as carcinogenesis and metastasis, dermatomyositis, and rheumatoid arthritis. [19][20][21][22] Enhanced expression of Angptl2 has been observed in the sera or lesions of patients with obesity-related metabolic and cardiovascular diseases. 18,[23][24][25] These recent findings suggest robust evidence that Angptl2 mediates chronic inflammation.…”

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confidence: 99%

Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

Kanda

Noda

Oike

et al. 2012

Laboratory Investigation

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Angiopoietin-like protein (Angptl) 2 is a key mediator linking obesity to chronic adipose-tissue inflammation and systemic insulin resistance, and increasing evidence has shown that Angptl2 is associated with various chronic inflammatory diseases such as cancer and dermatomyositis; however, it remains unclear that Angptl2 functions in acute inflammation. In this study, we investigate whether Angptl2 has a role in acute inflammation in the eye with endotoxin-induced uveitis (EIU). Angptl2 was widely expressed in the normal mouse retina, while Angptl2^[-/-] mice did not exhibit any changes in retinal cell marker expression and morphological analyses. Treatment with lipopolysaccharide (LPS) stimulated retinal Angptl2 mRNA expression in vivo and in vitro. We generated EIU in wild-type (C57BL/6) and Angptl2^[-/-] mice by injecting LPS intraperitoneally. Compared to wild-type animals, Angptl2^[-/-] mice significantly reduced various EIU-associated cellular and molecular parameters including leukocyte adhesion to the retinal vessels and infiltration into the vitreous cavity and retinal mRNA expression levels of monocyte chemotactic protein-1, intercellular adhesion molecule-1, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, together with nuclear translocation of nuclear factor (NF)-κB p65 subunit. In vitro, antibody-based inhibition of α5β1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-α, both of which are the major inflammatory cytokines derived from macrophages. The present findings indicate that Angptl2 mediates endotoxin-induced retinal inflammation through the activation of NF-κB signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation

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Tumor Cell–Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis

Cited by 113 publications

References 33 publications

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

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Tumor Cell–Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis

Cited by 113 publications

References 33 publications

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

ANGPTL2 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

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ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―