The spread of bad neighborhoods Our genomes have complex three-dimensional (3D) arrangements that partition and regulate gene expression. Cancer cells frequently have their genomes grossly rearranged, disturbing this intricate 3D organization. Hnisz et al. show that the disruption of these 3D neighborhoods can bring oncogenes under the control of regulatory elements normally kept separate from them (see the Perspective by Wala and Beroukim). These novel juxtapositions can result in the inappropriate activation of oncogenes. Science, this issue p. 1454; see also p. 1398 Disrupting the boundaries between three-dimensional neighborhoods in the genome can activate cancer-promoting genes. [Also see Perspective by Wala and Beroukim] Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.

Activation of proto-oncogenes by disruption of chromosome neighborhoods

In the present review, we describe the causes and consequences of loss of vascular smooth muscle cells (VSMCs) or their function in advanced atherosclerotic plaques and discuss possible mechanisms such as cell death or senescence, and induction of autophagy to promote cell survival. We also highlight the potential use of pharmacological modulators of these processes to limit plaque progression and/or improve plaque stability. VSMCs play a pivotal role in atherogenesis. Loss of VSMCs via initiation of cell death leads to fibrous cap thinning and promotes necrotic core formation and calcification. VSMC apoptosis is induced by pro-inflammatory cytokines, oxidized low density lipoprotein, high levels of nitric oxide and mechanical injury. Apoptotic VSMCs are characterized by a thickened basal lamina surrounding the cytoplasmic remnants of the VSMC. Inefficient clearance of apoptotic VSMCs results in secondary necrosis and subsequent inflammation. A critical determinant in the VSMC stress response and phenotypic switching is autophagy, which is activated by various stimuli, including reactive oxygen and lipid species, cytokines, growth factors and metabolic stress. Successful autophagy stimulates VSMC survival, whereas reduced autophagy promotes age-related changes in the vasculature. Recently, an interesting link between autophagy and VSMC senescence has been uncovered. Defective VSMC autophagy accelerates not only the development of stress-induced premature senescence but also atherogenesis, albeit without worsening plaque stability. VSMC senescence in atherosclerosis is likely a result of replicative senescence and/or stress-induced premature senescence in response to DNA damaging and/or oxidative stress-inducing stimuli. The finding that VSMC senescence can promote atherosclerosis further illustrates that normal, adequate VSMC function is crucial in protecting the vessel wall against atherosclerosis.

/pdf/vascular-smooth-muscle-cell-death-autophagy-and-senescence-27h5e60yuq.pdf

Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis

Autophagy is a reparative, life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. Growing evidence reveals that basal autophagy is an essential in vivo process mediating proper vascular function. Moreover, autophagy is stimulated by many stress-related stimuli in the arterial wall to protect endothelial cells and smooth muscle cells against cell death and the initiation of vascular disease, in particular atherosclerosis. Basal autophagy is atheroprotective during early atherosclerosis but becomes dysfunctional in advanced atherosclerotic plaques. Little is known about autophagy in other vascular disorders, such as aneurysm formation, arterial aging, vascular stiffness, and chronic venous disease, even though autophagy is often impaired. This finding highlights the need for pharmacological interventions with compounds that stimulate the prosurvival effects of autophagy in the vasculature. A large number of animal studies and clinical trials have indicated that oral or stent-based delivery of the autophagy inducer rapamycin or derivatives thereof, collectively known as rapalogs, effectively inhibit the basic mechanisms that control growth and destabilization of atherosclerotic plaques. Other autophagy-inducing drugs, such as spermidine or add-on therapy with widely used antiatherogenic compounds, including statins and metformin, are potentially useful to prevent vascular disease with minimal adverse effects.

Autophagy in Vascular Disease

There is increasing interest in the role of autophagic flux in maintaining normal vessel wall biology and a growing suspicion that autophagic dysregulation may be a common pathway through which vascular aging and associated pathologies develop. Within endothelial and smooth muscle cells, diverse but important triggers that range from oxidized lipids to β-amyloid seem to stimulate autophagosome formation potently. In addition, emerging evidence links autophagy to a wide array of vascular processes ranging from angiogenesis to calcification of the vessel wall. Alterations in autophagic flux are also increasingly being implicated in disease processes that include both atherosclerosis and pulmonary hypertension. Finally, recent insights point toward an important role of autophagy in the paracrine regulation of vasoactive substances from the endothelium. Here, we review the progress in understanding how autophagy can contribute to vascular biology and the emerging strategies to target this process for therapeutic benefit.

The Role of Autophagy in Vascular Biology

Autophagy is a subcellular process that plays an important role in the degradation of proteins and damaged organelles such as mitochondria (a process termed “mitophagy”) via lysosomes. It is crucial for regulating protein and mitochondrial quality control and maintaining cellular homeostasis, whereas dysregulation of autophagy has been implicated in a wide range of diseases including atherosclerosis. Recent evidence has shown that the autophagic process becomes dysfunctional during the progression of atherosclerosis, regardless of whether there are many autophagy-stimulating factors (e.g., reactive oxygen species, oxidized lipids, and cytokines) present within the atherosclerotic plaque. This review highlights the recent insights into the causes and consequences of defective autophagy in atherosclerosis, with a special focus on the role of autophagy and mitophagy in plaque macrophages, vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). It has been shown that defective autophagy can promote apoptosis in macrophages but that it accelerates premature senescence in VSMCs. In the ECs, defective autophagy promotes both apoptosis and senescence. We will discuss the discrepancy between these three cell types in their response to autophagy deficiency and underline the cell type-dependent role of autophagy, which may have important implications for the efficacy of autophagy-targeted treatments for atherosclerosis.

/pdf/defective-autophagy-in-atherosclerosis-to-die-or-to-senesce-4un3y8s4bg.pdf

Defective Autophagy in Atherosclerosis: To Die or to Senesce?

Background: Arterial calcification is a major event in the progression of atherosclerosis. It is reported that statins exhibit various protective effects against vascular smooth muscle cell (VSMC) inflammation and proliferation in cardiovascular remodeling. Although statins counteract atherosclerosis, the molecular mechanisms of statins on the calcium release from VSMCs have not been clearly elucidated. Methods: Calcium content of VSMCs was measured using enzyme-linked immunosorbent assay (ELISA). The expression of proteins involved in cellular transdifferentiation was analyzed by western blot. Cell autophagy was measured by fluorescence microscopic analysis for acridine orange staining and transmission electron microscopy analysis. The autophagic inhibitors (3-MA, chloroquine, NH4Cl and bafilomycin A1) and β-catenin inhibitor JW74 were used to assess the effects of atorvastatin on autophagy and the involvement of β-catenin on cell calcification respectively. Furthermore, cell transfection was performed to overexpress β-catenin. Results: In VSMCs, atorvastatin significantly suppressed transforming growth factor-β1 (TGF-β1)-stimulated calcification, accompanied by the induction of autophagy. Downregulation of autophagy with autophagic inhibitors significantly suppressed the inhibitory effect of atorvastatin on cell calcification. Moreover, the beneficial effect of atorvastatin on calcification and autophagy was reversed by β-catenin overexpression. Conversely, JW74 supplement enhanced this effect. Conclusion: These data demonstrated that atorvastatin protect VSMC from TGF-β1-stimulated calcification by inducing autophagy through suppression of the β-catenin pathway, identifying autophagy induction might be a therapeutic strategy for use in vascular calcification.

/pdf/atorvastatin-protects-vascular-smooth-muscle-cells-from-tgf-3a1o2hnm48.pdf

Atorvastatin protects vascular smooth muscle cells from TGF-β1-stimulated calcification by inducing autophagy via suppression of the β-catenin pathway.

Renal cell carcinoma (RCC) is a malignant tumor and the third most common urinary disease. It was estimated that RCC affected over 350,000 individuals in 2013, and there are nearly 140,000 deaths annually due to this disease. The initial masses in RCC patients are mostly confined to a single organ. However, due to the metastatic spread of cancer cells through the circulatory system, more than 30% of RCC patients relapse after surgery. The appearance of distant metastases often means that patients enter the advanced stage of cancer with low quality of life and a short expected survival time. This review aims to describe the extant research on advanced RCC, including its pathophysiology, heterogeneity, diagnosis, treatment, and prospects. We try to highlight the most suitable means of treating advanced RCC patients, focusing on comprehensive personalized treatments.

https://journals.sagepub.com/doi/pdf/10.1177/0300060520924265

Research progress on advanced renal cell carcinoma

Inflammation is the body's response to cell damage. Cancer is a general term that describes all malignant tumours. There are no confirmed data on cancer-related inflammation, but some research suggests that up to 50% of cancers may be linked to inflammation, which has led to the concept of 'cancer-associated inflammation'. Although some cancer patients do not appear to have a chronic inflammatory background, there might be inflammatory cell infiltration in their cancer tissues. The continuation of the inflammatory response plays an important role in the initiation, promotion, malignant transformation, invasion and metastasis of cancer. Anti-inflammatory therapy has been shown to have some effects on the prevention and treatment of cancer, which supports a pathogenic relationship between inflammation and cancer. This review describes the interaction between inflammation and tumour development and the main mechanism of regulation of the inflammatory response during tumour development.

https://journals.sagepub.com/doi/pdf/10.1177/0300060519895347

Advances in research on the interaction between inflammation and cancer.

Objective Atorvastatin reduces the incidence of cardiovascular events. However, the effects of atorvastatin on platelet aggregation are unknown. Methods Blood samples were obtained from 126 healthy volunteers. Prepared isolated platelet suspensions were adjusted with saline to three different concentrations of 100 × 109, 300 × 109, and 600 × 109 platelets/L. Platelet samples were incubated with atorvastatin (10-7 mol/L, 10-6 mol/L or 10-5 mol/L), and stimulated with ADP (10 µmol/L), arachidonic acid (0.5 mmol/L), collagen (2 µg/mL), and epinephrine (1 mg/mL). The maximal amplitude of aggregation and the curve slope were measured by electric impedance aggregometry. Results Atorvastatin inhibited platelet aggregation at moderate (300 × 109/L) and high (600 × 109/L) concentrations. However, an inhibitory effect of atorvastatin at low concentrations (100 × 109/L) was not observed. Conclusions The study shows that atorvastatin inhibits platelet aggregation in vitro, and this inhibitory effect is related to platelet concentrations.

https://journals.sagepub.com/doi/pdf/10.1177/0300060516675681

Bin Liu

Papers

Atorvastatin protects vascular smooth muscle cells from TGF-β1-stimulated calcification by inducing autophagy via suppression of the β-catenin pathway.

Research progress on advanced renal cell carcinoma

Advances in research on the interaction between inflammation and cancer.

Effects of atorvastatin on ADP-, arachidonic acid-, collagen-, and epinephrine-induced platelet aggregation.

dl-3-n-butylphthalide suppresses PDGF-BB-stimulated vascular smooth muscle cells proliferation via induction of autophagy.