Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice

Meehan, Brian; Garnier, Delphine; Dombrovsky, Alexander; Lau, Karrie; D’Asti, Esterina; Magnus, Nathalie; Rak, Janusz

doi:10.1016/j.mad.2014.07.003

Cited by 10 publications

(5 citation statements)

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“…Whilst this provides functional and mechanistic evidence for age-impaired wound healing and ischemia-mediated angiogenesis, the key triggers for these events have not been entirely elucidated. Recent data also indicate that processes fundamental to aging also play pivotal roles in cardiovascular disease associated with advanced age [7]. …”

Section: Introductionmentioning

confidence: 99%

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

et al. 2016

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BackgroundThe average population age is increasing and the incidence of age-related vascular complications is rising in parallel. Impaired wound healing and disordered ischemia-mediated angiogenesis are key contributors to age-impaired vascular complications that can lead to amputation. High-density lipoproteins (HDL) have vasculo-protective properties and augment ischemia-driven angiogenesis in young animals. We aimed to determine the effect of reconstituted HDL (rHDL) on aged mice in a murine wound healing model and the hindlimb ischemia (HLI) model.MethodsMurine wound healing model—24-month-old aged mice received topical application of rHDL (50 μg/wound/day) or PBS (vehicle control) for 10 days following wounding. Murine HLI model—Femoral artery ligation was performed on 24-month-old mice. Mice received rHDL (40 mg/kg) or PBS, intravenously, on alternate days, 1 week pre-surgery and up to 21 days post ligation. For both models, blood flow perfusion was determined using laser Doppler perfusion imaging. Mice were sacrificed at 10 (wound healing) or 21 (HLI) days post-surgery and tissues were collected for histological and gene analyses.ResultsDaily topical application of rHDL increased the rate of wound closure by Day 7 post-wounding (25 %, p < 0.05). Wound blood perfusion, a marker of angiogenesis, was elevated in rHDL treated wounds (Days 4–10 by 22–25 %, p < 0.05). In addition, rHDL increased wound capillary density by 52.6 %. In the HLI model, rHDL infusions augmented blood flow recovery in ischemic limbs (Day 18 by 50 % and Day 21 by 88 %, p < 0.05) and prevented tissue necrosis and toe loss. Assessment of capillary density in ischemic hindlimb sections found a 90 % increase in rHDL infused animals. In vitro studies in fibroblasts isolated from aged mice found that incubation with rHDL was able to significantly increase the key pro-angiogenic mediator vascular endothelial growth factor (VEGF) protein (25 %, p < 0.05).ConclusionrHDL can promote wound healing and wound angiogenesis, and blood flow recovery in response to ischemia in aged mice. Mechanistically, this is likely to be via an increase in VEGF. This highlights a potential role for HDL in the therapeutic modulation of age-impaired vascular complications.

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Section: Introductionmentioning

confidence: 99%

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

et al. 2016

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“…Other authors have shown that knockdown of RBP4 significantly reduces ovarian cancer cell migration and proliferation driven through the RhoA/Rock1 and extracellular signal-regulated kinase (ERK) pathways [26].The aim of our studies was to explain the role of RBP4 protein in the growth and metastatic spread of two murine breast cancer isogenic cell lines (derived from a single tumor of BALB/c mouse); metastatic 4T1 and nonmetastatic 67NR, representing basal-like and luminal-like phenotype, respectively [2,4]. Moreover, because, in many cases, cancer is associated with the aging process (largely reviewed in [27]) and aging affects the metastatic phenotype of cancer cells as well as tumor angiogenesis [28][29][30], we decided to include in our studies young and aged animals. To the best of our knowledge, no previous studies have investigated the effect of RBP4 protein on the metastatic spread of cancer.…”

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confidence: 99%

Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors

Papiernik

Urbaniak

Kłopotowska

et al. 2020

Cancers

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Retinol-binding protein 4 (RBP4) is proposed as an adipokine that links obesity and cancer. We analyzed the role of RBP4 in metastasis of breast cancer in patients and in mice bearing metastatic 4T1 and nonmetastatic 67NR mammary gland cancer. We compared the metastatic and angiogenic potential of these cells transduced with Rbp4 (4T1/RBP4 and 67NR/RBP4 cell lines). Higher plasma levels of RBP4 were observed in breast cancer patients with metastatic tumors than in healthy donors and patients with nonmetastatic cancer. Increased levels of RBP4 were observed in plasma, tumor tissue, liver, and abdominal fat. Moreover, the blood vessel network was highly impaired in mice bearing 4T1 as compared to 67NR tumors. RBP4 transductants showed further impairment of blood flow and increased metastatic potential. Exogenous RBP4 increased lung settlement by 67NR and 4T1 cells. In vitro studies showed increased invasive and clonogenic potential of cancer cells treated with or overexpressing RBP4. This effect is not dependent on STAT3 phosphorylation. RBP4 enhances the metastatic potential of breast cancer tumors through a direct effect on cancer cells and through increased endothelial dysfunction and impairment of blood vessels within the tumor.Cancers 2020, 12, 623 2 of 21 cancer pulmonary metastasis. These processes precede the onset of a phenotypic switch in the lung endothelium toward a mesenchymal phenotype (EndMT), which is parallel to the appearance of the first pulmonary metastatic colonies [7]. Therefore, therapeutic strategies that aim to normalize endothelial dysfunction can decrease the metastatic potential of this type of breast cancer [8][9][10].Apart from its involvement in cancer development, endothelial dysfunction plays an important role in the development of cardiovascular diseases and atherosclerosis. Moreover, in type 2 diabetes mellitus, endothelial dysfunction and insulin resistance often coexist at the earliest stage of atherosclerosis with elevation of serum retinol-binding protein 4 (RBP4), a specific retinol transporter in the blood [11]. It is documented that RBP4 induces inflammation of endothelial cells in vitro. This action is due to the stimulation of proinflammatory molecules involved in leukocyte recruitment and their adherence to endothelium, and it is independent of retinol and the RBP4 membrane receptor STRA6 [12]. Endothelial inflammation induced by RBP4 is largely mediated by toll-like receptor 4 (TLR4), and in part, through the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways [13]. Moreover, in isolated aorta rings, RBP4 treatment significantly increased NO production, stimulating the PI3K/Akt/eNOS pathway [14].RBP4, classified as adipokine [15], is proposed as the protein linking obesity and cancer [16]. Studies have shown various correlations between RBP4 plasma/tumor tissue levels and the development of certain types of cancer. For instance, Fei et al. reported lower RBP4 serum levels in patients with colon cancer than in healthy individu...

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“…Moreover, impairment of angiogenesis is described to be the cause of slower cancer growth in the elderly [3]. Further, tumour responsiveness to therapeutic agents differs in young and old animals [3,4]. Despite this evidence, the overwhelming majority of research focusing on the antitumour activity of various compounds is carried out on young animals.…”

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confidence: 99%

Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours

Anisiewicz¹,

Filip‐Psurska²,

Pawlik³

et al. 2019

Aging and disease

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Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.

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Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice

Cited by 10 publications

References 55 publications

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors

Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours

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