Global metabolic profiling in quiescent ECs underscores an upregulation of FAO gene sets, and a lower expression of glycolysis and oxidative phosphorylation genes [ 50 ]. Whether autophagy may contribute to promote EC quiescence through lipid droplet degradation and increased FAO is not known. Interestingly, in aging mice, a reduction in SIRT1 activity in ECs is associated to reduced FA uptake and oxidation, mitochondrial impairment, and increased oxidative stress [ 56 ], causing an overall impairment of EC function. Given the role of SIRT1 and redox signaling in the transcriptional control of autophagy genes in ECs [ 34 ], these findings further underpin a possible link between autophagy and FAO metabolism, a hypothesis warranting further investigations.
While this interesting connection still needs to be validated, under conditions of excessive accumulation of FAs i. In summary, these studies suggest that autophagy in ECs may contribute to the metabolic control of EC fate specification, an interesting connection urging future validation. Intercellular communication is achieved through ligand-receptor interactions involving surface-bound or secreted proteins that act on target cells in an auto- or paracrine manner. The spatio-temporal duration and intensity of receptor-mediated signaling events are regulated through the endocytic route and the lysosomes [ 58 ].
VEGFR2 internalization and turnover are reduced in the more quiescent and mature vessel plexus [ 60 ] supporting a mechanism of preservation of the resting state. Moreover, quiescent ECs establish bidirectional connections through junctional molecules like vascular endothelial-cadherin CDH5 , which strengthen their barrier function, and intercellularly, with pericytes, which are required to promote vessel stabilization.
Notably, these cell-to-cell interactions implicate an important role for vesicular trafficking mechanisms in controlling EC behavior [ 61 ]. Beyond the regulation of receptor availability via the endocytic route, autophagy genes in EC appear to have a fundamental role in secretion.
ECs contribute to the regulation of coagulation and fibrinolysis by expressing a variety of molecules regulating the activation of platelets and the coagulation cascade, thus preventing thrombus formation after vessel injury [ 63 ]. Endothelial-specific conditional deletion of Atg7 or Atg5 in mice does not affect vessel structure or capillary density, but limits VWF release upon epinephrine stimulation and consequently causes prolonged bleeding time.
These EC-intrinsic autophagy-mediated effects are caused by the incorrect processing and secretion of VWF via the WPBs in response to epinephrine [ 64 ].
Thus, shear stress-induced KLF2 and autophagy may congregate to regulate EC secretory profile thereby preserving the maturation state and function of vessels, an interesting connection that needs to be experimentally validated in future studies. In cancer, autophagy is considered a double-edged sword [ 67 ]; i. Once a tumor is formed, autophagy contributes to survival of cancer cells in areas deprived of nutrients or oxygen hypoxia [ 69 ], a common feature of solid tumors that contributes to tumor progression, therapy resistance, and metastasis formation [ 70 ].
In established tumors, elevated levels of autophagy are often found associated to poorly oxygenated regions where the demand for nutrients and the need to withstand several forms of metabolic stress in order to survive, are increased [ 68 , 69 ].
In line with this notion, in the context of advanced and aggressive tumors such as pancreatic cancer, autophagy is hijacked by oncogenes to support energy metabolism and allow growth under conditions of energy deficit and metabolic stress [ 72 , 73 ]. However, apart from cancer cells, the tumor microenvironment TME of a solid tumor contains a complex interstitial extracellular matrix and various stromal cells. These cells are recruited from the surrounding tissues or from the bone marrow and include fibroblasts, cells of the immune systems, pericytes, and ECs of the blood and lymphatic vasculature.
It is now increasingly accepted that the interface between malignant and non-transformed cells within the TME represents a highly plastic tumor ecosystem that supports tumor growth and dissemination through the various stages of carcinogenesis. In spite of this, whereas the role of autophagy in cancer cells is well-studied, its role in the tumor stroma is far from being understood. Some recent elegant studies have provided evidence for the differential role of autophagy mediators in cancer cell or stromal cells in regulating the TME and tumor control reviewed in [ 67 , 76 ].
For example, genetic loss of cancer cell autophagy and subsequent p62 accumulation leads to a chronic pro-inflammatory and pro-angiogenic microenvironment that assists tumor initiation and progression. Oppositely, increased expression of p62 in cancer-associated fibroblasts through blockade of autophagy reduces IL-6 secretion and is overall anti-inflammatory [ 77 , 78 ]. This example indicates the necessity to clarify the role of autophagy in shaping the cross talk between cancer cells and stromal cells in order to gain key insights in how autophagy intervention could impact stroma cell function, for better or worse regarding tumor development and therapy outcome.
In particular, studying the role of autophagy in the vascular compartment seems of vital relevance since the aberrant tumor vasculature provides not only a way to replenish nutrients to starved cancer cells, but represents a major escape route for the stressed cancer cells. Moreover, the tumor vasculature is crucially involved in the trafficking and activity of immune cells, thereby contributing to immunosurveillance mechanisms. In the next sections we will discuss some of the emerging features highlighting a role for autophagy and the endo-lysosomal system in tumor ECs TECs and cancer progression.
In solid tumors, angiogenesis is induced to receive nutrients e.
Tumor angiogenesis entails the development of new blood vessels from established vascular beds and as such is different from vasculogenesis de novo formation of vessels from bone marrow-derived endothelial precursor cells or vasculogenic mimicry the ability of tumor stem cells to form vessel-like networks. An angiogenic state should be reverted back to quiescence after the physiological challenge has been overcome.
These harsh TME conditions drive uncontrolled vessel sprouting and affect the vessel function and maturation. These structural and functional abnormalities of the vessel wall result in tumor-associated vessels that are structurally weak with varying diameters prone to collapse due to e.
These vascular abnormalities ultimately foster hypoxia, nutrient deprivation, acidity, and inflammation, which are all TME-related factors promoting tumor growth and cancer cell dissemination. ECs embedded in the TME are thus exposed to stressful conditions that typically result in heightened autophagic flux. Indeed, tumor-associated ECs upregulate autophagy compared to normal ECs that at least mediates resistance to hypoxia-induced cell death [ 81 ]. The compromised vascular barrier integrity observed in tumor vessels is a consequence of disrupted adherence and tight junctions between neighboring ECs commonly due to hyper-activation of VEGF signaling.
Indeed, in the endothelium, increased permeability is associated with a decreased expression of cell surface CDH5. Of note, blockade of lysosomal degradation by CQ in vivo augments CDH5 endothelial junctions and pericyte coverage of tumor vessels, resulting in tightening of the EC barrier in vivo [ 62 ].
This work describes the importance of tumor microenvironment in favouring tumor progression and isthrosazirppan.tk physiological conditions, angiogenesis. Angiogenesis is controlled by the balance between molecules that have positive and negative regulatory activity. This concept led to the notion.
This is likely the reason why cancer cell intravasation and the number of circulating cancer cells is decreased by CQ in this tumor model. Notably, although genetic loss of Atg5 in ECs delays melanoma growth, it does not affect metastasis and tumor oxygenation. On the contrary, genetic depletion of Atg5 in ECs worsens both structural and functional features of the vessels, exacerbating the chaotic and functionally abnormal tumor vasculature [ 62 ]. This underscores that the effects of pharmacological blockade of lysosomal function or genetic inhibition of key autophagy mediators, such as ATG5, have opposite effects on the tumor vasculature, which might have important consequences on therapeutic application, as discussed further in the next sections.
However, beyond its beneficial role in keeping redox homeostasis and EC permeability in check, heightened autophagy in TECs could also support the increased metabolic needs of the hyper-proliferating TECs and enhance adaptation to the metabolic stressors of the TME. For example, hypoxia is a known inducer of autophagy and tumor-associated ECs are more resistant to hypoxia-induced cell death than normal ECs [ 81 ].
Altogether these studies support the view that autophagy in tumoral ECs may confine—albeit not suppress—excessive angiogenesis. However, given that ATG5 and BECN1 regulate other pathways beyond canonical autophagy [ 83 ], it would be important to further evaluate the effects of the EC-specific genetic deletion of other autophagy mediators on tumor vessels and tumor growth, to get further insights into the role of autophagy in this crucial stromal compartment.
As mentioned above, angiogenesis imposes to ECs a metabolic shift to meet the augmented energy demand for migration and proliferation. However, whether autophagy fuels the high energy demand of these hyper-proliferating TECs, remains elusive. It is therefore possible that autophagy favors metabolic rewiring toward an EC quiescent phenotype, by maintaining mitochondria health via mitophagy and degrading lipid droplets.
As discussed previously, autophagy has emerging functions in unconventional secretion of cytokines [ 14 ] and angiogenesis-related factors [ 64 , 84 ]. For example, in ECs autophagy contributes to the secretion of high mobility group box 1 HMGB1 , which is highly upregulated in the tumor endothelium [ 85 ].
nesindymigre.ml Aside from its inflammatory role, HMGB1 also functions in tissue remodeling and angiogenesis [ 86 ]. Interestingly, HMGB1 is involved in resistance toward tumor vessel-targeted, monoclonal antibody-based immunotherapy [ 87 ]. The release of type I interferon IFN predominantly by tumoral ECs favors cytotoxic T-cell-mediated antitumor immunity in a melanoma mouse model [ 88 ], thus further indicating that the tumor endothelium is not just a passive player, but actively contributes in modifying the cross talk between stromal cells and cancer cells.
In conclusion, based on the limited studies available addressing the effects of genetic ablation of autophagy genes in ECs on the TME and tumor growth, it is tempting to propose that autophagy in TECs may support both cell-autonomous degradation, metabolism, and redox control and non-autonomous trafficking and secretion functions of the aberrant and inflamed endothelium. The abnormal tumor vasculature results in poor tumor perfusion, which not only favors cancer genetic instability, dissemination, and metastasis but also compromises drug delivery.
Choose Store. Pemetrexed plus cisplatin with or without bevacizumab. Principles of Bone Biology. David A. Non-Hodgkin Lymphomas.
In accordance, conditions and strategies alleviating tumor hypoxia represent an important aim in anticancer therapy [ 91 , 92 ]. The initial strategy for vessel-targeting therapy, aimed to inhibit new vessel formation and to destroy the tumor vasculature, thereby starving the tumor cells by reducing nutrient provision. However, anti-angiogenic therapies have been less successful than initially hoped for.
This is largely caused by the induction of hypoxia leading to resistance to chemotherapy or recruitment of myeloid cells that bypass tumor-inhibitory effects of therapy [ 93 ] and increased vascular permeability thereby increasing tumor cell intravasation [ 94 , 95 , 96 , 97 ]. In line with this, targeting tumor-associated ECs using monoclonal CD31 antibodies showed that the resulting hypoxia induces several changes in tumor cells, including increased epithelial-mesenchymal transition and vascular mimicry-related gene expression, allowing them to escape the anti-angiogenic therapy [ 98 ].
Accumulating evidence instead favor strategies causing a normalization of the tumor vasculature Fig. By normalizing the tumor vasculature, instead of pruning it, vessel functionality and perfusion are ameliorated, and as a consequence tumor hypoxia is reduced while transporting capability of vessels are improved, resulting in a better drug delivery and therapeutic responses [ 95 ]. Genetic blockade of autophagy in endothelial cells ECs fosters tumor angiogenesis while systemic treatment with chloroquine CQ induces vessel normalization.
Left: tumor vasculature is in a state of continuous remodeling due to imbalanced pro- and anti-angiogenic signaling in the tumor microenvironment. CQ treatment induces right vessel normalization in tumors, mainly by activating NOTCH1 signaling pathway during its endocytic route. As a result, vessel functionality and structure are improved. EC-specific genetic impairment of autophagy is associated with a highly angiogenic vascular phenotype. These differential effects on EC function should be taken into consideration when devising interventions aiming to modulate autophagy or the endo-lysososmal system in anticancer therapy.
Of note, inhibition of PFKFB3 induces vessel normalization [ 99 , ] suggesting that inhibition of glycolysis in TECs is sufficient per se to normalize the tumor vasculature, at least temporally. Interestingly, also inhibition of lysosomal function through CQ treatment of melanoma-bearing mice induces vessel normalization Fig. A recent study shows that CQ facilitates antitumor T-cell immunity by repolarizing tumor-promoting M2 macrophages in the TME to tumor-inhibiting M1 macrophages [ ], which can be an additional mechanism explaining the vessel normalization effects of this lysosomotropic drug [ ].