Anti-angiogenesis genes -
Moreover, inhibition of JMJD1A sustained the antitumoral properties of two anti-angiogenic treatments bevacizumab and sunitinib , limiting tumor resistance Osawa et al.
It also controls the turnover of HIF-1α as a cellular response to hypoxia. LSD1 promotes protein stability and tumor angiogenesis by demethylating the K residue and inhibiting HIF-1α downregulation with H 2 O 2 production, which inhibits the hydroxylating activity of PHD 2 on HIF-1α with its subsequent ubiquitination Lee J.
et al. An essential role in regulating the angiogenesis process has been attributed to microRNAs. These are non-protein-coding RNA, small molecules with around 22 nucleotides. MicroRNAs, generated from independent transcription units, can be either in polycistronic clusters or located within an intron of a protein-coding gene Bartel, ; Suárez et al.
The discovery of miRs that mediate post-transcriptional silencing of target genes has exposed exactly how non-coding RNAs play complex roles in angiogenesis. Initial evidence for the importance of miRs in regulating angiogenesis emerged from several experiments using a mutation in the Dicer gene, which is a ribonuclease essential for microRNA biogenesis Kuehbacher et al.
EC-specific Dicer inactivation in mice reveals embryonic lethality and fails to determine a vasculogenic phenotype. With weakened angiogenic capacity and reduced endothelial tube development, the mouse embryo showed an alteration of proangiogenic factors genes and reduced angiogenic response Yin et al.
An increasing number of endothelial miRNAs have been reported to control the angiogenesis signaling pathways, thus controlling endothelial proliferation, migration and vascular integrity Table 4 ; Yin et al. Table 4. Pro-angiogenic and anti-angiogenic miRNAs and their role in the angiogenesis process.
These miRs suppress argonaute 1 AGO1 , which is required for the microRNA-induced silencing complex miRISC to silence VEGF mRNA, resulting in the translational de-suppression of VEGF Chen et al. In ECs, miR and other miRs regulated under hypoxic conditions directly down-modulate the expression of Ephrin-A3, a receptor protein-tyrosine kinase with effects on tubulogenesis and chemotaxis Fasanaro et al.
As well as proteins, there are some anti-and pro-angiogenic effects on the angiogenesis process regulating genes and oncogenes.
They are presented below Table 2. Epigenetic inhibitors that affect the expression of angiogenic factors secreted into the tumor microenvironment have gained interest in developing anti-angiogenic agents.
VEGF-induced angiogenesis was analyzed in correlation with HDAC inhibitors known to relieve gene silencing Table 5. Trichostatin A TSA has anti-cancer and antifungal effects that selectively inhibits histone deacetylases HDACs. TSA considerably inhibits the transcription of endothelial receptors such as VEGFR1, VEGFR2 and neuropilin-1, along with the upregulation of SEMA3 semaphorin 3 in ECs Deroanne et al.
SEMA3 inhibits angiogenesis and metastatic dissemination of tumor cells by interfering with neuropilinmediated VEGF signaling Neufeld et al. It was observed that in the human tongue, squamous cell carcinoma cells have a robust anti-angiogenic activity by reducing HIF-1α protein accumulation and the levels of VEGF mRNA and protein expression Kang et al.
TSA treatment promotes the stabilization of HIF-1α under normal oxygen conditions, leading to VEGF overexpression. HIF-1α is stabilized and translocated into the nucleus to activate the VEGF promoter by TSA-mediated acetylation at lysine K The effectiveness of TSA is reduced by overexpression of HIF-1α or hypoxic conditions, which leads to drug resistance in tumor cells Lee J.
Moreover, it seems that under normoxic conditions, TSA treatment has a concomitant effect on drug resistance and anticancer effects by HIF-1α acetylation Geng et al.
Trichostatin A is mainly used in clinical trials and also in a phase I clinical trial investigating the safety and tolerability of trichostatin A in adults with relapsed or refractory hematologic malignancies.
Suberoylanilide hydroxamic acid SAHA inhibits the histone deacetylases activity of class I and II HDACs. SAHA selectively inhibits of the pathological development of a variety of transformed cells with relatively little toxicity Marks, Several studies have shown that SAHA has an important role in regulating the expression of the VEGFs pathway.
It was noted that in lung cancer cell lines, inhibition of HDACs by SAHA and TSA leads to vascular receptors expression reductions such as VEGFR1 and VEGFR2 and their co-receptors neuropilin1 NP1 and neuropilin2 NP2. Also, in breast cancer, the HDAC inhibitor SAHA reduces VEGF-C expression in a dose-dependent manner Cheng and Hung, Several studies have shown that SAHA sustains autophagy, tumoral cell viability reduction and demonstrates a strong anti-proliferative activity in tumoral cells Butler et al.
SAHA exerts selectivity toward HDAC6 and HDAC3. In breast cancer cells, HDAC6 has played a vital role in survivin deacetylation and nuclear export, which is an essential anti-apoptotic agent and thus increases the sensitivity of cells to chemotherapeutic drugs Lee et al.
Valproic acid VPA is a HDAC inhibitor, is evaluated for its anti-cancer properties due to its anti-angiogenic potential, inhibits in vitro and in vivo angiogenesis, involving a reduction in eNOS expression preceded by HDAC inhibition Michaelis et al. VPA-treatment significantly inhibits endothelial tube formation and stabilization, nitric oxide production, proliferation, and migration in ECs by promoting EMT states in cancer cells regulating the mesenchymal markers Vimentin-cadherin Murugavel et al.
Besides the antitumor effect, VPA affects the immune cells by suppressing the inflammatory response mediated by cytokines and oxidative stress molecules ROS, NO Soria-Castro et al. VPA has an inhibitory effect on pathological retinal angiogenesis in mice through HDAC inhibition, which reduces VEGF expression.
In the mouse retina, the mammalian target of rapamycin complex 1 mTORC1 is activated by VEGF, determining ECs proliferation, leading to angiogenesis Iizuka et al. Sodium butyrate NaB induces cell cycle arrest, cancer cell differentiation and apoptosis in colon cancer cells by modulating the expression of VEGF and HIF-1α in a dose-dependent manner Pellizzaro et al.
NaB suppresses hTERT gene expression and, therefore contributes to a low telomerase activity in human prostate cancer cells Rahman and Grundy, NaB is an HDAC inhibitor that reactivates epigenetically silenced genes in cancer cells by promoting apoptosis via p53 and Bax activation and cell-cycle arrest by induction of p21 Dashwood and Ho, On the other hand, the inhibition of HDAC by NaB had an anti-inflammatory effect by suppressing nuclear factor κB NFkB activation and inhibition of interferon γ production Hamer et al.
The effect of these inhibitors is only antiproliferative without affecting ECs, apoptosis and migration and also supporting their angiostatic activity Hellebrekers et al. Zebularine is a DNA methylation inhibitor that cooperates with DNMT creating a covalent complex. It shows antiangiogenic activity and significantly reduces vessel development in tumors Hellebrekers et al.
It has a good correlation between low toxicity and high efficacy, with potential contribution as an adjuvant agent for anticancer treatments and low-dose administration for a prolonged period Patnaik and Anupriya, GSK inhibits histone H3K27 methylation and increases expression of E-cadherin, p21 and PTEN.
Also, this drug suppresses the proliferation and tumoral invasion by inhibiting the expression of EZH2 Yu et al. LBH induces acetylation of histone H3 and alpha-tubulin protein on ECs, leading to tumor angiogenesis inhibition.
Complementary, in mice LBH treatment reduced angiogenesis and tumoral development Qian et al. Curcumin diferuloylmethane is well known as an anti-inflammatory agent, which also exhibits antiangiogenic properties, including downregulation of the proangiogenic factors VEGF, MMP-9, down-regulation of growth factor receptors EGFR, HER2, etc.
and inhibiting endothelial cell migration and invasion. The epigenetic regulatory roles consist in the inhibition of DNMTs, regulation of HATs, HDACs and miRNA. Curcumin is useful as an agent in cancer chemoprevention in the form of dietary phytochemicals, having the potential role of reversing epigenetic changes and efficient regulation of gene expression that causes tumorigenesis Hassan et al.
As a disadvantage, curcumin has poor solubility and a low absorption rate in the gastrointestinal tract after ingestion Aggarwal et al. Sulforaphane SFN is a natural compound found in cruciferous vegetables, which express antitumor effects without any toxic effect, inhibiting tumor growth, metastasis, and angiogenesis.
SFN suppress HDACs and mediate epigenetic regulation of apoptosis, cell cycle and inflammation in various cancers Alumkal et al. Emerging evidence suggests that SFN downregulate MMP-1, MMP-2, MMP-7, and MMP-9 and therefore intervenes in cancer cells invasion and angiogenesis Shankar et al.
Currently approved anti-angiogenic therapies includes several agents approved for clinical use Figure 3. Anti-angiogenic therapies focused on VEGF signaling pathways are demonstrating clinical benefits for an increasing number of cancer types. The difference in clinical benefits of treatment practice is manifested when is using multiple chemotherapy drugs.
However, only a proportion of patients have a prolonged favorable response to therapy, indicating treatment resistance in some cases Bergers and Hanahan, Figure 3. Schematic representation of currently approved anti-angiogenic inhibitors and their targets. Here we delimit the direct VEGF inhibitors and other targets from others, such as FGFs, oncogenes, remodeling and ECM degradation, cell adhesion molecules and conventional chemotherapeutic treatment.
For a long time, the development of antiangiogenic drugs has focused on VEGF inhibition and its receptors Figure 3. Bevacizumab is the first FDA approved monoclonal antibody against VEGF-A, which increased the overall survival of patients with metastatic colorectal cancer after 8 months of bevacizumab supplementation in chemotherapy Cao et al.
Also, sorafenib and sunitinib, tyrosine kinase inhibitors, have shown positive results in liver and kidney cancers Motzer et al. In some cases, anti-angiogenic strategies showed no benefit or induced initial responses followed by disease progression, thereby giving limited survival benefit Bergers and Hanahan, The failure of this therapeutic approach due to the acquired resistance of the tumors led to an increased understanding of VEGF-independent angiogenesis.
Similarly, cabozantinib can inhibit both the VEGF and c-Met in various solid tumors Bueno et al. Moreover, anti-angiogenic therapy may lead to the onset of hypoxia, resulting in the activation of HIF1a in tumor cells with a consequence of tumor cell adaptation to hypoxia and the promotion of tumor angiogenesis Bergers and Hanahan, Clinical findings from bevacizumab, sunitinib, and sorafenib provide valuable information for angiogenesis research, with survival benefits in some aggressive tumors, but in other cases failing to produce lasting clinical responses in most patients including those with metastatic cancer Mitchell and Bryan, Treatment failure frequently occurs in patients with metastatic cancer due to various mechanisms that support pathological angiogenesis and acquired resistance, phenomena in which the tumor microenvironment and communication between tumor cells and adjacent non-malignant cells play an essential role Bueno et al.
Elimination of resistance to therapeutic agents should be evaluated as a dynamic multifactorial process and inhibition of angiogenesis should be optimized by inhibiting alternative signaling pathways and integrating interaction changes between the tumor microenvironment and stromal cells.
The incidence of VEGF-resistant tumors targets alternative pathways, which include ANG-1, EGF, FGF, PDGF, and SDF-1 Bottsford-Miller et al. Thus, complementary methodologies have been studied, such as combining VEGF inhibitors with agents that target alternative blood vessel formation mechanisms Figure 3.
Volociximab inhibits angiogenesis by blocking the interaction between α5β1 and its ligand fibronectin Almokadem and Belani, Bortezomib, the first proteasome inhibitor targeting the ubiquitin-proteasome pathway, has shown a positive clinical benefit both alone and in combination therapy to produce tumor sensitization or to avoid drug resistance for multiple myeloma and mantle cell lymphoma.
Bortezomib up-regulate the pro-apoptotic protein NOXA, which interacts with Bcl-2 and results in apoptosis in malignant cells Chen et al. Nintedanib, a selective inhibitor of tumor angiogenesis by blocking receptors activities such as VEGFR1—3, PDGFR-α and -β, and FGFR1—3, was proposed to treat non—small cell lung adenocarcinoma and idiopathic lung fibrosis Hilberg et al.
Also, as a new targeted strategic approach, nanotechnology medical applications have been intensively studied to deliver anti-angiogenic drugs into the tumoral specific sites using nanomaterials as cerium oxide, gold, silver, copper, silica, based on carbon or hyaluronic acid and others Mukherjee and Patra, Besides their role in normal tissue maintenance, angiogenesis initiation may indicate a shift from tumor latency to malignant active growth and recurrence of the disease.
The precise functions of pro- and anti-angiogenic factors and the interactions between them in tumor angiogenesis are not fully understood and the important question is how anti-angiogenic medicine can be improved.
However, the mechanisms of induction of vascularization and subsequent development from precancerous lesions to micrometastases achieved by angiogenic strategies for vessel recruitment are not yet fully elucidated in all pathological cases.
Specific agents that can block tumor vascularization are required to inhibit angiogenesis and tumor growth. This review summarizes angiogenic factors involved in each step of vessel development to present an integrated overview of tumor vascularization models such as cooption, intussusception, sprouting angiogenesis, vasculogenic mimicry, and angioblasts which, depending on the context, can be helpful for targeted or combined anti-angiogenic therapies.
Moreover, we present the epigenetic changes in cancer which in contrast with genetic changes, are potentially reversible, increasing the prospect that epigenetic therapy will be able to mediate tumor fate. In addition to more disease-specific biomarkers, an important issue remains optimization of the dose and frequency of delivery of anti-angiogenic drugs.
Current efforts for biomarker discovery in cancer have primarily focused on multi-gene expression patterns, but complementary analysis of DNA methylation signatures may lead to diagnostic and prognostic improvement and better cancer therapy strategies.
The major limitations of drug delivery systems remain the lack of specificity. However, drug-specific therapies that use a lower dose of epi-drugs could improve the effectiveness and tolerability of treatments.
Another approach that might improve cancer therapy is the optimization of the dose and duration of release of anti-angiogenic drugs, with potential to alleviate colateral damage that conventional treatments that are toxic to both tumor and normal cells might produce.
Future directions for these treatments may include combined drug delivery systems that might target several types of anti-angiogenic factors for synergistic or additive therapeutic effects, and might increase the efficacy and specificity along with reduction of side effects.
VA and CD were involved in study conception. IS and CB were involved in study design. VA wrote the manuscript with support from IS, CB, and CD.
All authors reviewed and approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
We gratefully acknowledge the funding from the project Competitiveness Operational Programme COP A1. Adair, T. Chapter 1, Overview of Angiogenesis.
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It has been recently reported that a hypoxia visualization bio-imaging probe, protein transduction domain [PTD]-oxygen dependent degradation domain [ODD]-HaloTag POH , was able to detect HIF-1 active Takata et al.
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The authors believe that these studies show alternative therapeutic pathways, capable of inducing the differentiation and maturation of tumor blood vessels. In our opinion, the recruitment of pericytes must be taken into account for new strategies in the fight against those tumors, which are especially drug-resistant to traditional therapies.
These studies on new target tracers represent a useful tool for theranostic procedures. CA and GL designed the study. NC, MO, and MC collected the data reported in Table 1. CA and GL wrote the manuscript and drew the Figure 1.
FN, RA, VB, CM, and MS added the helpful discussions. CA, GL, and FN edited the manuscript, figure and table. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Angiogenesis is Angi-angiogenesis multi-stage process Fasting for diabetes control new blood vessel development from pre-existing vessels toward an Anti-angiogenwsis stimulus. The process is Anti-angiogenesix for tissue maintenance and homeostasis Fasting for diabetes control embryonic development Anti-qngiogenesis adult life as well as tumor growth. Under normal gened, angiogenesis Anti-angiogendsis involved in physiological Anti-agniogenesis, such as wound Anti-angiogenesis genes, cyclic Anti-agiogenesis of Anti-aangiogenesis endometrium, placental Energy-boosting bites and repairing certain Anti-amgiogenesis damage, in Anti-angiogenesis genes Fat intake and cholesterol, it is frequently associated Anti-angiogenesis genes cancer development Anit-angiogenesis metastasis. The control mechanisms of angiogenesis in carcinogenesis are tightly regulated at the genetic and epigenetic level. While genetic alterations are the critical part of gene silencing in cancer cells, epigenetic dysregulation can lead to repression of tumor suppressor genes or oncogene activation, becoming an important event in early development and the late stages of tumor development, as well. The global alteration of the epigenetic spectrum, which includes DNA methylation, histone modification, chromatin remodeling, microRNAs, and other chromatin components, is considered one of the hallmarks of cancer, and the efforts are concentrated on the discovery of molecular epigenetic markers that identify cancerous precursor lesions or early stage cancer. This review aims to highlight recent findings on the genetic and epigenetic changes that can occur in physiological and pathological angiogenesis and analyze current knowledge on how deregulation of epigenetic modifiers contributes to tumorigenesis and tumor maintenance. edu uses cookies to personalize content, tailor Anti-angiogenssis and improve the user experience. By using Pumpkin Seed Snacks Anti-angiogsnesis, you agree to our collection Anti-angiogenezis information through Pumpkin Seed Snacks use of cookies. To learn Holistic approaches to weight loss, Pumpkin Seed Snacks our Anti-agniogenesis Policy. edu no longer supports Internet Explorer. To browse Academia. edu and the wider internet faster and more securely, please take a few seconds to upgrade your browser. The discovery of endogenous inhibitors of angiogenesis has made it possible to test the hypothesis that blocking the angiogenic switch may keep tumor growth in check, and has added a new investigational arm to the field of cancer gene therapy.
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