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Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species

Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2023, 13(6), 886;
Submission received: 4 April 2023 / Revised: 19 May 2023 / Accepted: 24 May 2023 / Published: 25 May 2023
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers)


Blood vessels are the most important way for cancer cells to survive and diffuse in the body, metastasizing distant organs. During the process of tumor expansion, the neoplastic mass progressively induces modifications in the microenvironment due to its uncontrolled growth, generating a hypoxic and low pH milieu with high fluid pressure and low nutrients concentration. In such a particular condition, reactive oxygen species play a fundamental role, enhancing tumor proliferation and migration, inducing a glycolytic phenotype and promoting angiogenesis. Indeed, to reach new sources of oxygen and metabolites, highly aggressive cancer cells might produce a new abnormal network of vessels independently from endothelial cells, a process called vasculogenic mimicry. Even though many molecular markers and mechanisms, especially in gastric cancer, are still unclear, the formation of such intricate, leaky and abnormal vessel networks is closely associated with patients’ poor prognosis, and therefore finding new pharmaceutical solutions to be applied along with canonical chemotherapies in order to control and normalize the formation of such networks is urgent.

1. Introduction

Tumor vascularization plays a fundamental role in cancer progression and metastasis, allowing tumor cells to reach a continuous source of oxygen and nutrients and to evade host immunosurveillance. Sprouting angiogenesis, intussusception, vasculogenesis, vessel co-option, and vasculogenic mimicry (VM) are the main processes that contribute to tumor vascularization, generating an intricate net of vessels, some of which are composed of a mosaic of endothelial and tumor cells. While angiogenesis is commonly described as a complex mechanism including the remodeling of the extracellular matrix, the formation of the Tip-Stalk cells hierarchy and the involvement of pericytes, VM is typically characterized by highly perfused vessels with a significant deposition of matrix proteins, and it is often associated with highly invasive and metastatic tumors, frequently paired with a poor patient prognosis [1]. In previous years, periodic acid-Schiff (PAS)-CD31 was deemed to be the golden standard to distinguish between the two biological processes [2], but recently an alternative method of vascularization, the Epithelial-to-Endothelial Transition (EET), has been observed [3,4]. EET is the acquisition by epithelial cancer cells of endothelial markers, such as CD31, VE-Cadherin, Ephrin A2 and others [3]. Although not completely understood, it has been found that EET is induced by several microenvironmental factors and is established in highly plastic cancer cells, the so-called cancer stem cells (CSCs). One of the master inducers of all the above-described phenomena is hypoxia, which is undoubtedly one of the most typical features of the tumor microenvironment, determining the activation of the hypoxia-inducible factors (HIF) which were first discovered and elucidated by Semenza in 1992, who won the 2019 Nobel Prize in Physiology or Medicine along with Ratcliffe and Kaelin [5,6,7]. In particular, HIF proteins also enhance the stem features of cancer cells and contribute to their differentiation through the EET, by losing cell polarity, increasing the invasive ability and upregulating Twist and Snail, causing the consequent downregulation of the tight junction proteins, E-cadherin and Occludin, together with the upregulation of angiogenesis-related molecules such as VE-cadherin, vitronectin and fibronectin [8]. During severe hypoxic conditions, generated by tumor expansion, the impaired electron transport chain reactions and, more generally, mitochondrial dysfunctions, induce high reactive oxygen species (ROS) production [9] which, consequently, affects cancer cells’ proliferation, migration and metabolism. It is noteworthy that ROS may also be generated during tumor growth by the increased activity of peroxisomes, oxidases, cyclooxygenases, lipoxygenases and thymidine phosphorylase [10]. Gastric cancer (GC), which is currently the fourth leading cause of cancer-related death and the sixth for incidence globally [11,12], is closely dependent on vascularization. Indeed, several studies have showed that Helicobacter pylori, which is related to more than half of GC cases, is able to penetrate normal, metaplastic and neoplastic epithelia, triggering an immune-inflammatory response, and thus not only promoting gastric carcinogenesis, but also stimulating the release of cytokines, matrix metalloproteinases and angiogenic factors by gastric epithelial cells upon NF-kB activation [13]. It is well established that H. pylori-infected GC patients showed increased tumor vascularization compared to those who underwent H. pylori eradication [14]. Moreover, elevated gastrin secretion was also associated with NF-kB activation, as well, enhancing ROS generation and vasculogenesis [15]. When ROS levels were reduced by the use of N-Acetylcysteine, metastatic capability and chemoresistance resulted in inhibition, demonstrating that ROS play a central role in GC pathogenesis. Moreover, it was observed that inoperable GC patients subjected to chemotherapy demonstrated a ‘U-like’ association of mortality rate with vascular density, suggesting that very low and very high vascularization are both linked to poor outcomes [16].

2. Tumor Angiogenesis and Vasculogenesis

Angiogenesis is a multistep process that involves the formation of new blood vessels starting from pre-existing ones. During cancer development, the tumor mass constantly grows until the oxygen concentration is too low and the catabolic products of the accelerated glycolysis affect the microenvironmental pH. In particular, hypoxia often triggers the early endothelial response by activating the production of pro-angiogenic factors such as the vascular endothelial growth factor (VEGF), angiopoietin-2 (ANG-2), or fibroblast growth factor-2 (FGF-2) [17]. These signals wake up the pericytes, detaching them from the vessel wall and allowing the endothelial cells to degrade the basement membrane through the activation of matrix metalloproteinases (MMPs). After such events, the endothelial cells lose their junctions, the vessel dilates and several plasma proteins extravasate, creating a new temporary matrix layer for ECs migration [17]. The endothelial cell closest to the higher VEGF concentration gradient is then selected by the Notch-Dll4 axis as the “Tip” cell [18], which will lead to the building of the nascent vessel, while neighbor cells will be consequently selected as “Stalk” cells and they will divide to follow the Tip. Once the vessel is mature, all the junctions between ECs have been restored, pericytes have covered the vessel again and the basement membrane has been deposited, the blood will flow and the new vessel will be completely perfused. However, while in physiological conditions Dll4 selects the Tip cell only, activating the Notch pathway, in tumor-induced angiogenesis Dll4 expression was observed in the majority of tumor vessels [19]. Sprouting angiogenesis is a complex and long process, especially in tumors, where ECs often compete for the leading positions, generating a continuous change between Tip and Stalk status. Therefore, endothelial tip and stalk cells’ fate determination is not fixed by the initial conditions, but rather there is a constant dynamic phenotype switch [20]. Despite some interesting clinical trials aimed at treating and controlling angiogenesis in GC, their efficacy in improving patients’ Overall Survival (OS) remains limited. In 2011 and 2014, the trials AVAGAST and AVATAR [21,22] demonstrated that the use of Bevacizumab, a monoclonal antibody inhibiting VEGF-mediated angiogenesis by binding and inactivating the VEGF-A ligand, was able to modestly increase the Overall Response Rate (ORR) and the Progression-Free Survival (PFS) but with no significant improvement in the OS. Moreover, it clearly appeared that the efficacy was dissimilar depending on territorial differences, which might be due to different hospitalization conditions or genetic discrepancies [23]. Better results were achieved through the trials REGARD and RAINBOW [24,25], which tested Ramucirumab, a human monoclonal antibody binding to the extracellular region of VEGFR-2 and blocking the downstream effects of VEGF, improving PFS and OS, especially when combined with Paclitaxel. Such a promising result induced the American Society of Clinical Oncology to confirm Ramucirumab as the second-most-effective targeted drug after Trastuzumab [26]. Although tyrosine kinase inhibitors (TKi) are not widely used in the treatment of GC, here we report Sunitinib, one of the first TKi approved for use in imatinib-resistant GISTs. Indeed, it not only blocks VEGFRs, PDGFR-α, PDGFR-β and c-Kit [27] molecules involved in the vasculogenic process, but also exerts a possible ROS-mediated cytotoxic effect, albeit one that is still not completely clear [28]. We also need to mention that such anti-angiogenic therapies often result in only a transitory improvement of the clinical picture. Resistance to such regimens is divided into two main categories: the first is defined as the evasive or adaptive resistance to angiogenesis inhibitors, which involves revascularization due to the upregulation of alternative pro-angiogenic signals, the protection of the tumor vasculature by recruiting pro-angiogenic inflammatory cells or by increasing protective pericyte coverage, the increased invasiveness of tumor cells into adjacent tissues to co-opt normal vasculature and the augmented metastatic relapse and tumor cell growth in lymph nodes and distant organs. The second one is called intrinsic resistance, and includes those individuals who had never benefited from the anti-angiogenic treatments due to an innate indifference, probably due to the redundancy of several pro-angiogenic signals, an inflammatory cell-mediated vascular protection, and the invasive angiogenic-independent co-option of normal vessels [29].

3. Vasculogenic Mimicry

Described for the first time in uveal melanoma by Maniotis et al., VM is a biological mechanism exploited by several cancer histotypes to generate PAS-positive vessels lined by tumor cells [30]. Although early evidence indicated that the inner wall of such vessels was composed of only tumor cells, Chang et al. demonstrated that the luminal surface might indeed be lined by an intricate mosaic of tumor and endothelial cells [31]. The intricate transformation that leads cancer cells to perform VM is, to date, not fully understood, but accumulating evidence points to a close correlation between CSCs and VM formation. Indeed, during VM, high plasticity cancer cells that do not express any typical endothelial markers behave like proper endothelial cells to achieve new sources of oxygen and nutrients. To distinguish between the two histotypes, the golden standard is the immunohistochemical analysis of two endothelium-related proteins (CD31/CD34) coupled with the PAS reaction [2]. Currently, very little is known about the formation of VM in GC. A close association has been reported between GC patients with VM and the formation of hematogenous metastasis, probably due to the aggressive features developed by cancer cells and to the fact that, when lining the luminal surface of the vessels, cancer cells are directly exposed to the bloodstream, increasing their proficiency to detach and form distant metastases [32]. MMP-2 and MMP-9 have been positively correlated with VM, conferring on cancer cells the capability to remodel the extracellular matrix and degrade the vascular basement membrane [33], while EphA2 has been reported to be directly involved in the formation of tubular networks [34]. These phenomena were confirmed by Sun et al., who demonstrated that out of a collection of 84 specimens of gastrointestinal stromal tumors (GIST), 21 were found to be VM positive, with a high production of MMP-2 and MMP-9 [35]. Although GISTs are typically not aggressive tumors, patients with VM-enriched vessels experienced a worse prognosis with respect to the ones with low VM-dependent vascularization. VM is commonly associated with advanced-stage GCs and with patients’ poor prognosis, although the vast majority of the data are available only in Eastern countries [36]. Moreover, one of the main issues in identifying VM in GC samples is the heterogeneous mucous tissues of the gastrointestinal tract, which might lead to false PAS-positive results, thus overestimating the VM histological grade. It is today well-known that cells resistant to anti-angiogenic therapies, such as those reported above, are often more prone to generate VM networks in vivo and in vitro, and therefore research into new therapeutic strategies to target both phenomena at the same time is urgently needed.

4. Epithelial-to-Endothelial Transition

Under particular microenvironmental conditions, i.e., hypoxia, high tumor interstitial fluid pressure and altered extracellular matrix, VM-prone cells begin to express typical endothelial antigens through the so-called Epithelial-to-Endothelial transition. Hypoxia is the best-known and most potent VM inducer, activating HIF-1α and HIF-2α, which in turn bind to the hypoxia-response elements of target genes such as VEGF, VEGF receptors, EMT inducers and stem-associated genes [37]. Under hypoxic conditions, Twist1 translocates into the nucleus and promotes VE-Cadherin expression, triggering the transition of epithelial cells to an endothelial-like phenotype [38,39]. Indeed, VE-Cadherin activates PI3K via EphA2 phosphorylation, promoting the matrix metalloproteinases secretion and thus extracellular matrix remodeling [40]. In particular, HIF-1α involvement was reported to promote the stabilization of Notch, a typical endothelial antigen, by binding to its intracellular domain and consequently promoting Nodal transcription [41]. It was recently reported that the onset of chemoresistance, and in particular to 5-Fluorouracil, might induce the EET in AGS cells via the upregulation of TYMP, EphA2 and VEGFR2 [42]. However, the EET is still a poorly understood phenomenon, with narrow limits that denote the difference with a proper VM process. Additionally, from the clinical point of view, the treatment of such a biological event is currently debated as all the above-described anti-angiogenic therapies might induce the onset of VM cells due to the generation of hypoxic regions. Even after discontinuing treatments, endothelial vessels might rebound and link to the neo-formed VM channels [39]. To date, the only therapeutic options evaluated in vivo are the use of Doxycycline, a tetracycline derivative, acting by the inhibition of the degradation of E-Cadherin preventing in this way both the EET and VM [43], anti-Notch4 antibodies which downregulate Nodal expression [41] and dual antiplatelet therapy, a gamma-secretase inhibitor, which was found to inhibit glioblastoma CSCs from differentiating into endothelial-like progenitor cells through blockade of Dll4-Notch signaling [44]. However, no therapies nor experimental drugs are currently reported for GC treatment.

5. Innovative Pharmacological Approaches

Even though no clinical trials with anti-VM drugs have been reported, we describe here the use of Rapamycin, Genistein and Thalidomide. Rapamycin, a macrolide compound used to coat coronary stents and to prevent organ transplant rejection, has a strong immunosuppressive effect and acts by targeting mTOR, which is a crucial VM and angiogenic effector, especially when induced by hypoxic conditions [45,46]. Similarly to Rapamycin, Everolimus, and Temsirolimus act as mTOR inhibitors for GIST treatment, although it has still not been clarified whether their antitumor effect might be produced by ROS mediation [47]. The use of EF24, a new curcumin analog, was evaluated by Chen et al. in combination with Rapamycin for the treatment of advanced GC. Indeed, they demonstrated that EF24 acted as an ROS inducer, sensitizing GC cells to Rapamycin-induced growth inhibition, decreasing the mitochondrial membrane potential and leading cancer cells to apoptosis [48]. The co-treatment of GC cells with MK-2206, an Akt inhibitor, and EF24 induces ROS generation via the stimulation of the endoplasmic reticulum through the activation of CHOP and ATF-4, thus decreasing the mitochondrial membrane potential and inducing apoptosis via the Bcl-2/Bax protein ratio dysregulation [49]. Recently, another curcuminoid analog, the B63 targeting TrxR1, has been reported to induce ROS-mediated paraptosis-like cell death in GC cells, leading to the reduction of tumor growth in vivo [50]. Genistein is a phytoestrogenic compound derived from soybean and is already used in many in vitro experimentations in GC to induce apoptosis in a dose and time-dependent manner by downregulating the expression of the antiapoptotic Bcl-2 protein and upregulating the expression of proapoptotic Bax [51]. Physiologically, Genistein is mainly metabolized through oxidation, sulfation, glucuronidation, hydroxylation or methylation, and therefore its derivatives’ effects are still not well evaluated (although it was speculated that the 5,7,39,49-tetrahydroxyisoflavone (THIF) and 2 glutathinyl conjugates of THIF might be responsible for the angiogenesis inhibition and reduction in endothelial cell proliferation) [52]. Moreover, it has been shown that THIF may induce the cycle arrest, activate the p38 MAPK signaling pathway and induce DNA strand breakage via ROS formation [53]. Moreover, increasing evidence suggests that gastric CSCs may be particularly sensitive to a low dose of genistein (15 mM), leading to inhibited self-renewal ability, drug resistance and tumorigenicity due to the suppression of ABCG2 expression and ERK1/2 activity [54], and to the downregulation of Gli1 and CD44 paired with a reduced migration capability [55]. Thalidomide, involved in the 1950 scandal of several birth defects, is still used for the treatment of some multiple myeloma cases even though its pharmacologic action and targets are not completely clear. Kita et al. reported that several N(α)-phthalimide glutarimide derivatives, similar to Thalidomide, are able to selectively target the platelet-derived endothelial cell growth factor (PD–ECGF), which is structurally identical to the thymidine phosphorylase (TYMP), an important enzyme for purine synthesis and one closely involved in angiogenesis response [56]. It was also demonstrated that Thalidomide in GC cells might partially revert chemoresistance to 5-Fluorouracil and inhibit invasion, migration and VM capabilities [42]. All the above-described anti-angiogenesis and anti-VM therapies are summarized in Table 1.

6. Gastric MALT Lymphoma

A particular and noteworthy case is gastrointestinal lymphomas (indolent B-cell non-Hodgkin), of which the so-called MALT lymphoma (mucosa-associated-lymphoid tissue) is the most common type. Such a kind of lymphoma may arise from any mucosal tissue, but often is associated with the gastric one, where memory B cells may be subjected to chronic inflammation and infection in the extranodal marginal zone of the mucosa-associated lymphoid tissue [57]. Etiological agents such as the H. pylori may play an important role in the pathogenesis of this disease. Indeed, H. pylori exposition leads to an increased MALT accumulation and to the stimulation of tumor-infiltrating T cells, which generate the chronically inflamed microenvironment [58]. The continuous antigenic stimulation, which promotes B cell proliferation and neutrophils retrieval, induces the B cell population to develop oligoclonal and/or monoclonal sub-populations, leading to the oncogenic event [59]. Moreover, the release of ROS by neutrophils might spread a wide genotoxic effect, allowing the amplification of genetic aberrations [60]. Currently, the gold standard therapy for H. pylori-positive gastric MALT lymphoma is based on a combination of three drugs, a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole, while in the case of failure or for H. pylori-negative MALT, patients commonly undergo involved-site radiation therapy (ISRT) or Rituximab [61]. The MALT being histologically characterized by an abundant distribution of the microvascular network, comprising immature capillaries, lymphatics, and venules, Nakamura M et al. proposed a new pharmaceutical approach based on an anti-VEGF antibody, such as bevacizumab or aflibercept, and celecoxib, a cyclooxygenase-2 inhibitor with promising results [62].

7. Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal cancers of the gastrointestinal tract, albeit accounting for less than 1% of all gastrointestinal tumors [63]. They are classified as soft tissue sarcomas, and frequently arise from Cajal cells along the digestive tube or, less frequently, from telocytes or smooth muscle cells [64,65,66]. Over the years, GIST have been more and more precisely characterized from a molecular point of view, and thus now they are enclosed in two main categories depending on the proto-oncogene (KIT) or the platelet-derived growth factor receptor alpha gene (KIT/PDGFRA) mutations. The ones (5–7.5% of all GIST) with KIT/PDGFRA wild-types are then sub-classified depending on the functionality of the succinate dehydrogenase enzyme (SDH B/C/D), which might be deficient due to mutation or epigenetic regulation. In the rare cases when no KIT/PDGFRA mutations are detected and the SDH complex is functional, several very rare driver alterations could have occurred in genes such as the RAS gene family, BRAF, NF1, NTRK1–3, and FGFR1–4 [67]. To date, surgery is the only therapeutic option in combination with adjuvant chemotherapy based on the tyrosine kinase inhibitor (TKi) Imatinib mesylate for KIT/PDGFRA-mutated patients [68]. Xu et al. recently revealed that the chronic administration of Imatinib might induce ROS accumulation over time, leading to an increase and stabilization of HIF-1α, which in turn stimulates the phosphogluconate dehydrogenase (PGD), resulting in a metabolic switch from a typical tricarboxylic acid cycle with high oxidative phosphorylation to the exploitation of the pentose phosphate pathway. PGD was observed to be upregulated in GIST, and especially in GIST cell lines resistant to Imatinib when compared with sensitive ones, promoting cell proliferation and apoptosis avoidance [69]. Indeed, a higher PGD expression produces an abundant quantity of NADPH, providing reducing intermediates for the glutathione and thioredoxin systems and, at last, reducing the ROS-dependent apoptosis and cell cycle arrest. Angiogenesis is another important force affecting GIST malignancy [70]. For example, it was reported that BRD4 upregulation enhanced GIST migration and invasion by regulating angiogenesis through the NF-kB/CCL2 signaling pathway, while CCL2 is also useful to recruit tumor-associated macrophages, increasing the cancer microvessel density and secreting several pro-angiogenic molecules such as VEGFA, LOX and MMP9 [32,71]. Moreover, mutations in the PPP2R1A gene are associated with a more aggressive tumor phenotype causing an increased growth rate via stimulating the phosphorylation of c-kit, Akt1/2, ERK1/2 and WNK1, of which the latter one regulates the angiogenetic response [72,73]. Furthermore, GIST has also demonstrated a high capability for assessing vasculogenic mimicry, as demonstrated by Sun B et al., observing that, in a retrospective study of 84 patients with GIST, VM is associated with tumor size, mitotic rate and liver metastasis [35]. VM-positive GIST patients correlate with a high risk of metastatic progression and with poor prognosis according to the survival Kaplan–Meier curves. They also found an upregulation and activation of MMP-2 and MMP-9, whilst not detecting any significant change in VEGF expression. It was recently observed that epigenetic regulation might also play a major role in GIST vascularization control, as the upregulation of the histone demethylase KDM4D was demonstrated to affect promoters of the H3K9me3 and H3K36me3 genes, enhancing the angiogenesis in vivo through the HIF1β/VEGFA pathway stimulation, leading to the overexpression of CD31 [74]. It is also noteworthy that several TKi exert an anti-angiogenic effect, too. Indeed, Cabozantinib, as well as sorafenib, targets VEGFR2, Flt-3 and c-Kit, leading to a diminished tumor microvascular density [75,76].

8. ROS-Induced Vascularization

Hypoxia in varying degrees commonly generates Reactive Oxygen Species (ROS), probably affecting the complexes I, II and III of the mitochondrial electron transport chain (ETC), even though the mechanism is still debated [77]. ROS are molecular oxygen-derived molecules that are formed by reduction-oxidation reactions or by electronic excitation. They contain one or more unpaired electrons, and are characterized by a highly reactive status [78]. Cellular endogenous ROS are generated physiologically in the process of mitochondrial oxidative phosphorylation [79], as well as in cellular responses to xenobiotics, cytokines, viruses and bacterial invasion, or they may arise from interactions with exogenous sources [80]. When ROS concentration overwhelms the cellular antioxidant defense system, oxidative stress occurs, inducing damage to proteins, lipids and nucleic acids, contributing in this way to the pathogenesis of several human diseases such as neurodegenerative [81,82], cardiovascular [83,84], and inflammatory diseases [85], infertility [86,87], aging [88,89] and cancer [90]. Three main classes of ROS are commonly produced: hydroxyl radicals characterized by a high reactivity and short half-life, superoxides with low reactivity and the capacity to diffuse through anionic channels and hydroperoxides with moderate reactivity and the capability of diffusing via aquaporins [9]. Superoxide, hydrogen peroxide and peroxyl induce membrane lipid peroxidation, generating unstable fatty acid radicals (lipid hydroperoxides) which rapidly degrade into cytotoxic ketones, epoxides and reactive aldehydes released in the gastrointestinal compartment [91]. Their plasma and urinary levels are indeed elevated due to the absorption in the intestines, leading to a higher risk of mutagenesis and cancer progression [92,93]. Moreover, ROS’ intracellular accumulation results in the stabilization and activation of HIF-1α and the degradation of SIRT3, leading to the transcription of VEGF, LDHA and PDK1, even under normoxic conditions, promoting in such a way tumor angiogenesis and progression in GC [94]. In particular, HIF-1α and HIF-2α regulate tumor cell proliferation, migration, glycolysis and angiogenesis via endogenous ROS production [95]. Moreover, Park et al. demonstrated that endogenously produced ROS or stimulation by H. pylori stabilize HIF-1α protein in human GC cells even under normoxic conditions via non-mitochondrial ROS [96]. Indeed, H. pylori is capable of producing ROS and reactive nitrogen species (RNS) or inducing their production in neutrophils, endothelial cells, and gastric mucosal cells [97]. Such particular bacteria are capable of survive in the host stomach, inducing the expression of inducible NO synthase (iNOS) in gastric mucosal epithelial cells, vascular endothelial cells, or infiltrated inflammatory cells [98]. H. pylori then translocates into the cells through the cytotoxin-associated gene A (CagA), inducing the production of ROS and triggering, in turn, a cascade response including the stimulation of cell cycle progression, and therefore proliferation [99], and damages to mitochondrial and nuclear DNA [100]. Cation transport regulator 1 overexpression in AGS cell lines infected with CagA-positive H. pylori has also been demonstrated to reduce cellular glutathione levels via the glutamylcyclotransferase, leading to the rapid accumulation of ROS [101]. Such damages, which rapidly induce mutations and carcinogenesis, are also generated through ROS promotion by another important H. pylori-associated virulence factor [102], the vacuolating cytotoxin A (VacA) [103]. The combined effect of CagA and VacA is thus reported to decrease cell autophagy in gastric epithelial cells by reducing intracellular glutathione levels, increasing ROS accumulation, enhancing the resilience of H. pylori infection in the stomach, and therefore promoting GC development [104]. On the other hand, VacA inhibits the expression of integrin-linked kinase and endothelial nitric oxide synthase, leading to decreased ROS production in macrophage/monocyte lineages in order to evade immune system surveillance [105]. Recently, proton pump inhibitors have been used for the treatment of peptic ulcers and for the H. pylori eradication therapy, being capable of suppressing the effect of the bacterial-induced acid secretion. Rabeprazole has been reported to reduce H. pylori-induced gastric mucosal damage by increasing the concentration of reduced glutathione [106], while lansoprazole and omeprazole have been observed to inhibit inflammatory cytokines’ production by stimulating gastric epithelial cells and endothelial cells via the blockage of redox-sensitive transcription factor activation [107]. Lian et al. demonstrated the complex interplay between ROS and angiogenesis in GC, exposing the AGS cell line to nicotine and treating endothelial cells with the resulting tumor cell-derived conditioned media. Indeed, they observed that nicotine promoted endothelial cells’ growth and tube-like formation, induced by IL-8 expression via the stimulation of ROS/NF-κB and ROS/MAPK (ERK1/2, p38)/AP-1 axes [108]. Gastrin, a major component of the gastric juice, promotes angiogenesis by activating HIF-1α/β-catenin/VEGF signaling in GC [109] and metastasis via the β-catenin-TCF4 pathway [110]. Liu et al. demonstrated that gastrin regulates IκBα and NF-κB in GC cells, enhancing ROS generation and controlling the anti-apoptotic Bcl-2 and pro-apoptotic Bax expression in a ROS-dependent manner [15]. It has also been reported that EMT and metabolism alterations may depend on the ROS/NF-κB/HIF-1α axis. Indeed, Qin et al. demonstrated that N-acetylcysteine-dependent ROS scavenging diminished NF-κB and HIF-1α activation in autophagy-deficient GC cells, preventing the metabolic switch (from mitochondrial oxidative phosphorylation to aerobic glycolysis), which is closely associated with malignity and chemoresistance in GC [111]. Radiotherapy, as well as platinum-based drugs, might induce ROS generation by high energy ionizing radiation [112] or via NADPH oxidase, respectively [113,114]. In this context, it has been already demonstrated that Oleocanthal, a minor polar compound extracted by extra-virgin olive, causes cell cycle inhibition and ROS accumulation in AGS cells resistant to 5-Fluorouracil and Paclitaxel, but not to Cisplatin. Indeed, Cisplatin-resistant cells seem to be characterized by higher levels of antioxidant enzymes that are capable of counteracting the Oleocanthal-induced ROS accumulation [115]. Endogenous ROS, which are able to directly affect GC cells, can also modulate tumor microenvironmental components. Indeed, it was observed that tumor-infiltrating lymphocytes might be attracted by ROS, exerting their typical antitumor effect [116]. Radiotherapy can damage cancer cells’ DNA, dramatically increasing ROS levels, inducing vascular trauma, tissue self-healing, edema and immune cell infiltration, and generating, in turn, an increased demand for oxygen with consequent HIFs activation [117]. The immune cell infiltration, commonly composed of tumor-associated macrophages, T-cells, B-cells, and myeloid-derived suppressor cells, is influenced and recruited by severe hypoxic conditions [118]. The interaction among ROS, angiogenesis and inflammation is an important pathogenic factor for GC progression, as inflammatory mediators can regulate ROS/RNS production [119]. ROS-activated TNF-α has been reported to downregulate IκBα, mediating, in turn, the release of inflammatory mediators such as NOX2, IL-6, IL-2, IL-8 and CXCL12 [120]. Several enzymes contribute to their production in three main cellular districts (mitochondria, cytosol and single membrane-bound organelles (peroxisomes, endosomes and phagosomes)), and thus ROS may diffuse through specific channels or be delivered by exosomes [121]. ROS play also a major role in tumor angiogenesis by controlling VEGF expression. As reported by Xia et al. the NADPH oxidase inhibitor DPI and the complex I inhibitor Rotenone are capable of inhibiting VEGF protein and mRNA levels, probably via HIF-1α, reducing neovascularization and tumor growth [122].

9. ROS Scavenging Activity

There are three main enzymatic components of the antioxidant defense system: the metal ion-dependent superoxide dismutases (SODs) [123], the catalase and the glutathione peroxidase (GPx) [124]. To the first family belongs two copper/zinc-containing members: CuZnSOD (SOD1), localized within the cytosol, mitochondrial intermembrane space and nucleus, and the extracellular SOD (EcSOD or SOD3), which is the predominant antioxidant enzyme secreted into the extracellular space and the manganese-containing MnSOD (SOD2), active into the mitochondrial matrix. Such particular enzymes require specific metal cofactors for catalyzing the redox process of dismutation, i.e., the conversion of superoxide molecules into oxygen and hydrogen peroxide. Of particular interest is that EcSOD is commonly reported to be down-regulated in almost all cancer histotypes, albeit increased in gastric adenocarcinoma and prolactinoma, a benign pituitary gland tumor [125,126]. However, the cause of such an increase in serum EcSOD remains unclear. Another fundamental enzyme with scavenging activity against intracellular ROS is the catalase, localized in the peroxisomes, which converts hydrogen peroxide into water and oxygen. While SOD and catalase do not need co-factors to function, GPx requires the co-factors and proteins belonging to the glutathione system (glutathione reductase and glucose-6-phosphate dehydrogenase) to convert the hydrogen peroxide in water [127]. Even though the importance of such a scavenging system is clearly remarkable, to date no scientific articles have been produced about gastric cancer, and here lies the urgent need to stimulate the worldwide community to improve the research on such an interesting topic.

10. The Role of NADPH Oxidase in GC

NADPH oxidases, one of the major ROS sources, are multi-subunit enzyme complexes catalyzing the production of a superoxide-free radical by transferring one electron to oxygen from NADPH with the extrusion of an H+ molecule. This highly conserved protein family includes seven oxidases, namely NADPH oxidase 1 (NOX1), NOX2, NOX3, NOX4, NOX5, Dual oxidase 1 (DUOX1) and DUOX2. It has been reported that p22phox expression, an essential component of the membrane-associated enzyme NADPH-oxidase NOX1, NOX2 and NOX4, is more highly expressed in actively proliferating endothelial cells than in quiescent cells, demonstrating that ROS produced by NADPH oxidase might sustain endothelial cells’ proliferation [128]. NOX1 plays an important role in endothelial cell proliferation, sprouting and migration by increasing ROS-sensitive transcription factors and ROS-dependent phosphatases that block PPAR-α activity, which in turn is responsible for NF-kB inhibition [129]. On the other hand, NOX2 is a critical ROS source in endothelial cells and an important regulator of their function, as its genetic deficiency, i.e., the loss of gp91phox expression, leads to the chronic granulomatous disease causing enhanced endothelium-dependent vasorelaxation, the reduction of vascular aging markers and oxidative stress by limiting NO bioavailability [130], whilst NOX5 is actively involved in ROS-mediated proliferation and the formation of capillary-like structures in human microvascular endothelial cells [131]. NOX3, DUOX1 and DUOX2’s involvement in cancer angiogenesis has not yet been fully established (Figure 1). You et al. demonstrated that NOX1/2/4 mRNA expression levels in GC tissues were higher than in normal tissues, while NOX5 and DUOX1/2 expression levels were lower. Moreover, they observed that a high NOX2 mRNA expression was associated with better OS, whilst NOX4 and DUOX1 were closely correlated with a worse outcome, in particular in intestinal-type GC patients [132]. Similarly, Qiao and colleagues investigated the role of NOX4 in GC by observing its upregulation in the tumor mass compared with adjacent non-tumor tissues, which was correlated with higher invasive capability and a worse TNM stage [133]. Indeed, studies indicated that lipopolysaccharides from H. pylori induced NOX1-derived ROS through TLR4 in guinea pig gastric pit cells, in this way exploiting NOX1 as the trigger of the innate immune responses against H. pylori [134]. Moreover, high levels of NOX1 were detectable in GC cells (intestinal, diffuse or signet-ring cell type) but not in normal gastric mucosa cells [135]. This points to an intriguing possibility that GC undergoes aberrant control of NOX1 expression. Even though all these proofs clearly determine the deep involvement of the NOX family, and in particular NOX1, in ROS-mediated GC progression, few works in the literature are available to date. Of particular interest is the biological process termed “ROS-induced ROS release” (RIRR), in which one cellular compartment generates and releases ROS, stimulating ROS production by another adjacent compartment or organelle. This phenomenon was initially described in cardiomyocytes, demonstrating that upon the mitochondrial permeability transition pore opening the mitochondrial membrane potential rapidly dissipates, triggering the so-called “burst phase” of ROS generation, which caused a synchronous phenomenon in the contiguous mitochondria [136]. Indeed, this event might be considered a natural safety valve that prevents excessive ROS accumulation inside the mitochondria, through the occasional opening of their pores to release ROS. During pathologic conditions, i.e., cancer, such a release might trigger irreversible positive feedback, leading to the activation of apoptotic or autophagic pathways [137]. Moreover, Young-Mee et al. reported that, in endothelial cells, NOX2 is capable of sensing NOX4-derived H2O2, inducing mitochondrial ROS production via pSer36-p66Shc and, lastly, enhancing VEGFR2 activation, thus amplifying the angiogenesis signaling program [138]. Amongst the currently available clinical approaches, we report the use of Apatinib, which is thought to be one of the most promising drugs, being a well-known anti-angiogenic agent as a VEGFR2 selective inhibitor. Already approved for the treatment of metastatic GC by the FDA [139], it is reported to affect ROS production via GPX4 and SREBP-1a [140].

11. Conclusions

To date, the relationship between ROS and tumor vascularization is still debated, but the urgency of learning how to treat and control cancer-induced angiogenesis, especially when particular hostile conditions, such as hypoxia, start to be established in the tumor microenvironment, is clear. Several attempts have been made to counteract tumor angiogenesis, for example through treatment with Bevacizumab and Ramucirumab, which have proven to be effective in the early tumor stages, but which often induce hypoxic regions, selecting, in such a way, a pool of cancer cells with an endothelial behavior that in turn might replace the proper endothelium. VM and EET molecular processes also need to be further clarified in order to fully understand their genesis and the real contribution of external factors and stimuli which might induce each kind of phenotype.

Author Contributions

Original paper preparation, review and writing, A.B., S.P., G.V., C.F., M.B., L.M. and L.P. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.


Figure 1 was created with

Conflicts of Interest

The authors declare no conflict of interest.


  1. Wei, X.; Chen, Y.; Jiang, X.; Peng, M.; Liu, Y.; Mo, Y.; Ren, D.; Hua, Y.; Yu, B.; Zhou, Y.; et al. Mechanisms of Vasculogenic Mimicry in Hypoxic Tumor Microenvironments. Mol. Cancer 2021, 20, 7. [Google Scholar] [CrossRef]
  2. Biagioni, A.; Andreucci, E. Immunohistochemistry for VM Markers. Methods Mol. Biol. Clifton NJ 2022, 2514, 141–152. [Google Scholar] [CrossRef]
  3. Sun, B.; Zhang, D.; Zhao, N.; Zhao, X. Epithelial-to-Endothelial Transition and Cancer Stem Cells: Two Cornerstones of Vasculogenic Mimicry in Malignant Tumors. Oncotarget 2017, 8, 30502–30510. [Google Scholar] [CrossRef] [Green Version]
  4. El Hallani, S.; Boisselier, B.; Peglion, F.; Rousseau, A.; Colin, C.; Idbaih, A.; Marie, Y.; Mokhtari, K.; Thomas, J.-L.; Eichmann, A.; et al. A New Alternative Mechanism in Glioblastoma Vascularization: Tubular Vasculogenic Mimicry. Brain J. Neurol. 2010, 133, 973–982. [Google Scholar] [CrossRef] [Green Version]
  5. Semenza, G.L.; Nejfelt, M.K.; Chi, S.M.; Antonarakis, S.E. Hypoxia-Inducible Nuclear Factors Bind to an Enhancer Element Located 3’ to the Human Erythropoietin Gene. Proc. Natl. Acad. Sci. USA 1991, 88, 5680–5684. [Google Scholar] [CrossRef] [Green Version]
  6. Kibel, A.; Iliopoulos, O.; DeCaprio, J.; Kaelin, W. Binding of the von Hippel-Lindau Tumor Suppressor Protein to Elongin B and C. Science 1995, 269, 1444–1446. [Google Scholar] [CrossRef] [PubMed]
  7. Pugh, C.W.; Tan, C.C.; Jones, R.W.; Ratcliffe, P.J. Functional Analysis of an Oxygen-Regulated Transcriptional Enhancer Lying 3’ to the Mouse Erythropoietin Gene. Proc. Natl. Acad. Sci. USA 1991, 88, 10553–10557. [Google Scholar] [CrossRef] [Green Version]
  8. Liu, Q.; Qiao, L.; Liang, N.; Xie, J.; Zhang, J.; Deng, G.; Luo, H.; Zhang, J. The Relationship between Vasculogenic Mimicry and Epithelial-Mesenchymal Transitions. J. Cell. Mol. Med. 2016, 20, 1761–1769. [Google Scholar] [CrossRef] [PubMed]
  9. Tafani, M.; Sansone, L.; Limana, F.; Arcangeli, T.; De Santis, E.; Polese, M.; Fini, M.; Russo, M.A. The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression. Oxid. Med. Cell. Longev. 2016, 2016, 3907147. [Google Scholar] [CrossRef] [Green Version]
  10. Liou, G.-Y.; Storz, P. Reactive Oxygen Species in Cancer. Free Radic. Res. 2010, 44, 479–496. [Google Scholar] [CrossRef] [Green Version]
  11. Biagioni, A.; Skalamera, I.; Peri, S.; Schiavone, N.; Cianchi, F.; Giommoni, E.; Magnelli, L.; Papucci, L. Update on Gastric Cancer Treatments and Gene Therapies. Cancer Metastasis Rev. 2019, 38, 537–548. [Google Scholar] [CrossRef] [PubMed]
  12. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  13. Necchi, V.; Candusso, M.E.; Tava, F.; Luinetti, O.; Ventura, U.; Fiocca, R.; Ricci, V.; Solcia, E. Intracellular, Intercellular, and Stromal Invasion of Gastric Mucosa, Preneoplastic Lesions, and Cancer by Helicobacter Pylori. Gastroenterology 2007, 132, 1009–1023. [Google Scholar] [CrossRef] [PubMed]
  14. Sasaki, A.; Kitadai, Y.; Ito, M.; Sumii, M.; Tanaka, S.; Yoshihara, M.; Haruma, K.; Chayama, K. Helicobacter Pylori Infection Influences Tumor Growth of Human Gastric Carcinomas. Scand. J. Gastroenterol. 2003, 38, 153–158. [Google Scholar] [CrossRef] [PubMed]
  15. Liu, Y.; Zhu, J.; Liu, J.; Ma, X.; Zhao, J.; Su, Z. Knockdown of Gastrin Promotes Apoptosis of Gastric Cancer Cells by Decreasing ROS Generation. BioMed Res. Int. 2021, 2021, 5590037. [Google Scholar] [CrossRef]
  16. Koukourakis, M.I.; Giatromanolaki, A.; Sivridis, E.; Fezoulidis, I. Cancer Vascularization: Implications in Radiotherapy? Int. J. Radiat. Oncol. Biol. Phys. 2000, 48, 545–553. [Google Scholar] [CrossRef]
  17. Carmeliet, P.; Jain, R.K. Angiogenesis in Cancer and Other Diseases. Nature 2000, 407, 249–257. [Google Scholar] [CrossRef]
  18. Hellström, M.; Phng, L.-K.; Hofmann, J.J.; Wallgard, E.; Coultas, L.; Lindblom, P.; Alva, J.; Nilsson, A.-K.; Karlsson, L.; Gaiano, N.; et al. Dll4 Signalling through Notch1 Regulates Formation of Tip Cells during Angiogenesis. Nature 2007, 445, 776–780. [Google Scholar] [CrossRef]
  19. Mailhos, C.; Modlich, U.; Lewis, J.; Harris, A.; Bicknell, R.; Ish-Horowicz, D. Delta4, an Endothelial Specific Notch Ligand Expressed at Sites of Physiological and Tumor Angiogenesis. Differ. Res. Biol. Divers. 2001, 69, 135–144. [Google Scholar] [CrossRef]
  20. Chen, W.; Xia, P.; Wang, H.; Tu, J.; Liang, X.; Zhang, X.; Li, L. The Endothelial Tip-Stalk Cell Selection and Shuffling during Angiogenesis. J. Cell Commun. Signal. 2019, 13, 291–301. [Google Scholar] [CrossRef]
  21. Ohtsu, A.; Shah, M.A.; Van Cutsem, E.; Rha, S.Y.; Sawaki, A.; Park, S.R.; Lim, H.Y.; Yamada, Y.; Wu, J.; Langer, B.; et al. Bevacizumab in Combination with Chemotherapy as First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2011, 29, 3968–3976. [Google Scholar] [CrossRef] [PubMed]
  22. Shen, L.; Li, J.; Xu, J.; Pan, H.; Dai, G.; Qin, S.; Wang, L.; Wang, J.; Yang, Z.; Shu, Y.; et al. Bevacizumab plus Capecitabine and Cisplatin in Chinese Patients with Inoperable Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer: Randomized, Double-Blind, Phase III Study (AVATAR Study). Gastric Cancer Off. J. Int. Gastric Cancer Assoc. Jpn. Gastric Cancer Assoc. 2015, 18, 168–176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Li, H.; Wang, C.; Wei, Z.; Chen, W.; Guo, Z.; He, Y.; Zhang, C. Differences in the Prognosis of Gastric Cancer Patients of Different Sexes and Races and the Molecular Mechanisms Involved. Int. J. Oncol. 2019, 55, 1049–1068. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Fuchs, C.S.; Tomasek, J.; Yong, C.J.; Dumitru, F.; Passalacqua, R.; Goswami, C.; Safran, H.; dos Santos, L.V.; Aprile, G.; Ferry, D.R.; et al. Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma (REGARD): An International, Randomised, Multicentre, Placebo-Controlled, Phase 3 Trial. Lancet 2014, 383, 31–39. [Google Scholar] [CrossRef]
  25. Wilke, H.; Muro, K.; Van Cutsem, E.; Oh, S.-C.; Bodoky, G.; Shimada, Y.; Hironaka, S.; Sugimoto, N.; Lipatov, O.; Kim, T.-Y.; et al. Ramucirumab plus Paclitaxel versus Placebo plus Paclitaxel in Patients with Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma (RAINBOW): A Double-Blind, Randomised Phase 3 Trial. Lancet Oncol. 2014, 15, 1224–1235. [Google Scholar] [CrossRef]
  26. Shan, F.; Miao, R.; Xue, K.; Li, Z.; Li, Z.; Bu, Z.; Wu, A.; Zhang, L.; Wu, X.; Zong, X.; et al. Controlling Angiogenesis in Gastric Cancer: A Systematic Review of Anti-Angiogenic Trials. Cancer Lett. 2016, 380, 598–607. [Google Scholar] [CrossRef]
  27. Mendel, D.B.; Laird, A.D.; Xin, X.; Louie, S.G.; Christensen, J.G.; Li, G.; Schreck, R.E.; Abrams, T.J.; Ngai, T.J.; Lee, L.B.; et al. In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor Receptors: Determination of a Pharmacokinetic/Pharmacodynamic Relationship. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2003, 9, 327–337. [Google Scholar]
  28. Kappers, M.H.W.; de Beer, V.J.; Zhou, Z.; Danser, A.H.J.; Sleijfer, S.; Duncker, D.J.; van den Meiracker, A.H.; Merkus, D. Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress. Hypertens. Dallas Tex 1979 2012, 59, 151–157. [Google Scholar] [CrossRef] [Green Version]
  29. Bergers, G.; Hanahan, D. Modes of Resistance to Anti-Angiogenic Therapy. Nat. Rev. Cancer 2008, 8, 592–603. [Google Scholar] [CrossRef] [Green Version]
  30. Maniotis, A.J.; Folberg, R.; Hess, A.; Seftor, E.A.; Gardner, L.M.G.; Pe’er, J.; Trent, J.M.; Meltzer, P.S.; Hendrix, M.J.C. Vascular Channel Formation by Human Melanoma Cells in Vivo and in Vitro: Vasculogenic Mimicry. Am. J. Pathol. 1999, 155, 739–752. [Google Scholar] [CrossRef] [Green Version]
  31. Chang, Y.S.; di Tomaso, E.; McDonald, D.M.; Jones, R.; Jain, R.K.; Munn, L.L. Mosaic Blood Vessels in Tumors: Frequency of Cancer Cells in Contact with Flowing Blood. Proc. Natl. Acad. Sci. USA 2000, 97, 14608–14613. [Google Scholar] [CrossRef] [Green Version]
  32. Lv, J.; Sun, B.; Sun, H.; Zhang, Y.; Sun, J.; Zhao, X.; Gu, Q.; Dong, X.; Che, N. Significance of Vasculogenic Mimicry Formation in Gastric Carcinoma. Oncol. Res. Treat. 2017, 40, 35–41. [Google Scholar] [CrossRef]
  33. Kirschmann, D.A.; Seftor, E.A.; Hardy, K.M.; Seftor, R.E.B.; Hendrix, M.J.C. Molecular Pathways: Vasculogenic Mimicry in Tumor Cells: Diagnostic and Therapeutic Implications. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2012, 18, 2726–2732. [Google Scholar] [CrossRef] [Green Version]
  34. Kim, H.S.; Won, Y.J.; Shim, J.H.; Kim, H.J.; Kim, J.; Hong, H.N.; Kim, B.S. Morphological Characteristics of Vasculogenic Mimicry and Its Correlation with EphA2 Expression in Gastric Adenocarcinoma. Sci. Rep. 2019, 9, 3414. [Google Scholar] [CrossRef] [Green Version]
  35. Sun, B.; Qie, S.; Zhang, S.; Sun, T.; Zhao, X.; Gao, S.; Ni, C.; Wang, X.; Liu, Y.; Zhang, L. Role and Mechanism of Vasculogenic Mimicry in Gastrointestinal Stromal Tumors. Hum. Pathol. 2008, 39, 444–451. [Google Scholar] [CrossRef]
  36. Guo, Q.; Yuan, Y.; Jin, Z.; Xu, T.; Gao, Y.; Wei, H.; Li, C.; Hou, W.; Hua, B. Association between Tumor Vasculogenic Mimicry and the Poor Prognosis of Gastric Cancer in China: An Updated Systematic Review and Meta-Analysis. BioMed Res. Int. 2016, 2016, 2408645. [Google Scholar] [CrossRef] [Green Version]
  37. Li, W.; Zong, S.; Shi, Q.; Li, H.; Xu, J.; Hou, F. Hypoxia-Induced Vasculogenic Mimicry Formation in Human Colorectal Cancer Cells: Involvement of HIF-1a, Claudin-4, and E-Cadherin and Vimentin. Sci. Rep. 2016, 6, 37534. [Google Scholar] [CrossRef]
  38. Sun, T.; Zhao, N.; Zhao, X.-L.; Gu, Q.; Zhang, S.-W.; Che, N.; Wang, X.-H.; Du, J.; Liu, Y.-X.; Sun, B.-C. Expression and Functional Significance of Twist1 in Hepatocellular Carcinoma: Its Role in Vasculogenic Mimicry. Hepatology 2010, 51, 545–556. [Google Scholar] [CrossRef]
  39. Zhang, D.; Sun, B.; Zhao, X.; Ma, Y.; Ji, R.; Gu, Q.; Dong, X.; Li, J.; Liu, F.; Jia, X.; et al. Twist1 Expression Induced by Sunitinib Accelerates Tumor Cell Vasculogenic Mimicry by Increasing the Population of CD133+ Cells in Triple-Negative Breast Cancer. Mol. Cancer 2014, 13, 207. [Google Scholar] [CrossRef] [Green Version]
  40. Hess, A.R.; Margaryan, N.V.; Seftor, E.A.; Hendrix, M.J.C. Deciphering the Signaling Events That Promote Melanoma Tumor Cell Vasculogenic Mimicry and Their Link to Embryonic Vasculogenesis: Role of the Eph Receptors. Dev. Dyn. Off. Publ. Am. Assoc. Anat. 2007, 236, 3283–3296. [Google Scholar] [CrossRef]
  41. Hardy, K.M.; Kirschmann, D.A.; Seftor, E.A.; Margaryan, N.V.; Postovit, L.-M.; Strizzi, L.; Hendrix, M.J.C. Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype. Cancer Res. 2010, 70, 10340–10350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Peri, S.; Biagioni, A.; Versienti, G.; Andreucci, E.; Staderini, F.; Barbato, G.; Giovannelli, L.; Coratti, F.; Schiavone, N.; Cianchi, F.; et al. Enhanced Vasculogenic Capacity Induced by 5-Fluorouracil Chemoresistance in a Gastric Cancer Cell Line. Int. J. Mol. Sci. 2021, 22, 7698. [Google Scholar] [CrossRef]
  43. Meng, J.; Sun, B.; Zhao, X.; Zhang, D.; Zhao, X.; Gu, Q.; Dong, X.; Zhao, N.; Liu, P.; Liu, Y. Doxycycline as an Inhibitor of the Epithelial-to-Mesenchymal Transition and Vasculogenic Mimicry in Hepatocellular Carcinoma. Mol. Cancer Ther. 2014, 13, 3107–3122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Wang, R.; Chadalavada, K.; Wilshire, J.; Kowalik, U.; Hovinga, K.E.; Geber, A.; Fligelman, B.; Leversha, M.; Brennan, C.; Tabar, V. Glioblastoma Stem-like Cells Give Rise to Tumour Endothelium. Nature 2010, 468, 829–833. [Google Scholar] [CrossRef] [PubMed]
  45. Huang, M.; Ke, Y.; Sun, X.; Yu, L.; Yang, Z.; Zhang, Y.; Du, M.; Wang, J.; Liu, X.; Huang, S. Mammalian Target of Rapamycin Signaling Is Involved in the Vasculogenic Mimicry of Glioma via Hypoxia-Inducible Factor-1α. Oncol. Rep. 2014, 32, 1973–1980. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Xue, Q.; Nagy, J.A.; Manseau, E.J.; Phung, T.L.; Dvorak, H.F.; Benjamin, L.E. Rapamycin Inhibition of the Akt/MTOR Pathway Blocks Select Stages of VEGF-A 164 –Driven Angiogenesis, in Part by Blocking S6Kinase. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 1172–1178. [Google Scholar] [CrossRef] [Green Version]
  47. Teppo, H.-R.; Soini, Y.; Karihtala, P. Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy. Oxid. Med. Cell. Longev. 2017, 2017, 1485283. [Google Scholar] [CrossRef]
  48. Chen, W.; Zou, P.; Zhao, Z.; Chen, X.; Fan, X.; Vinothkumar, R.; Cui, R.; Wu, F.; Zhang, Q.; Liang, G.; et al. Synergistic Antitumor Activity of Rapamycin and EF24 via Increasing ROS for the Treatment of Gastric Cancer. Redox Biol. 2016, 10, 78–89. [Google Scholar] [CrossRef] [Green Version]
  49. Chen, X.; Dai, X.; Zou, P.; Chen, W.; Rajamanickam, V.; Feng, C.; Zhuge, W.; Qiu, C.; Ye, Q.; Zhang, X.; et al. Curcuminoid EF24 Enhances the Anti-Tumour Activity of Akt Inhibitor MK-2206 through ROS-Mediated Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Gastric Cancer. Br. J. Pharmacol. 2017, 174, 1131–1146. [Google Scholar] [CrossRef] [Green Version]
  50. Chen, X.; Chen, X.; Zhang, X.; Wang, L.; Cao, P.; Rajamanickam, V.; Wu, C.; Zhou, H.; Cai, Y.; Liang, G.; et al. Curcuminoid B63 Induces ROS-Mediated Paraptosis-like Cell Death by Targeting TrxR1 in Gastric Cells. Redox Biol. 2019, 21, 101061. [Google Scholar] [CrossRef]
  51. Zhou, H.-B.; Chen, J.-J.; Wang, W.-X.; Cai, J.-T.; Du, Q. Apoptosis of Human Primary Gastric Carcinoma Cells Induced by Genistein. World J. Gastroenterol. 2004, 10, 1822–1825. [Google Scholar] [CrossRef] [PubMed]
  52. Kiriakidis, S.; Högemeier, O.; Starcke, S.; Dombrowski, F.; Hahne, J.C.; Pepper, M.; Jha, H.C.; Wernert, N. Novel Tempeh (Fermented Soyabean) Isoflavones Inhibit in Vivo Angiogenesis in the Chicken Chorioallantoic Membrane Assay. Br. J. Nutr. 2005, 93, 317–323. [Google Scholar] [CrossRef] [Green Version]
  53. Spagnuolo, C.; Russo, G.L.; Orhan, I.E.; Habtemariam, S.; Daglia, M.; Sureda, A.; Nabavi, S.F.; Devi, K.P.; Loizzo, M.R.; Tundis, R.; et al. Genistein and Cancer: Current Status, Challenges, and Future Directions. Adv. Nutr. 2015, 6, 408–419. [Google Scholar] [CrossRef] [Green Version]
  54. Huang, W.; Wan, C.; Luo, Q.; Huang, Z.; Luo, Q. Genistein-Inhibited Cancer Stem Cell-Like Properties and Reduced Chemoresistance of Gastric Cancer. Int. J. Mol. Sci. 2014, 15, 3432–3443. [Google Scholar] [CrossRef] [Green Version]
  55. Yu, D.; Shin, H.-S.; Lee, Y.S.; Lee, D.; Kim, S.; Lee, Y.C. Genistein Attenuates Cancer Stem Cell Characteristics in Gastric Cancer through the Downregulation of Gli1. Oncol. Rep. 2014, 31, 673–678. [Google Scholar] [CrossRef] [Green Version]
  56. Kita, T.; Takahashi, H.; Hashimoto, Y. Thymidine Phosphorylase Inhibitors with a Homophthalimide Skeleton. Biol. Pharm. Bull. 2001, 24, 860–862. [Google Scholar] [CrossRef] [Green Version]
  57. Fischbach, W. Gastric MALT Lymphoma—Update on Diagnosis and Treatment. Best Pract. Res. Clin. Gastroenterol. 2014, 28, 1069–1077. [Google Scholar] [CrossRef]
  58. Zhang, Y.; Wei, Z.; Li, J.; Liu, P. Molecular Pathogenesis of Lymphomas of Mucosa-Associated Lymphoid Tissue—From (Auto)Antigen Driven Selection to the Activation of NF-ΚB Signaling. Sci. China Life Sci. 2015, 58, 1246–1255. [Google Scholar] [CrossRef] [Green Version]
  59. Ishikawa, E.; Nakamura, M.; Satou, A.; Shimada, K.; Nakamura, S. Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era. Cancers 2022, 14, 446. [Google Scholar] [CrossRef]
  60. Coussens, L.M.; Werb, Z. Inflammation and Cancer. Nature 2002, 420, 860–867. [Google Scholar] [CrossRef]
  61. Broccoli, A.; Zinzani, P.L. How Do We Sequence Therapy for Marginal Zone Lymphomas? Hematology 2020, 2020, 295–305. [Google Scholar] [CrossRef] [PubMed]
  62. Nakamura, M.; Takahashi, T.; Matsui, H.; Takahashi, S.; Murayama, S.Y.; Suzuki, H.; Tsuchimoto, K. New Pharmaceutical Treatment of Gastric MALT Lymphoma: Anti-Angiogenesis Treatment Using VEGF Receptor Antibodies and Celecoxib. Curr. Pharm. Des. 2014, 20, 1097–1103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Søreide, K.; Sandvik, O.M.; Søreide, J.A.; Giljaca, V.; Jureckova, A.; Bulusu, V.R. Global Epidemiology of Gastrointestinal Stromal Tumours (GIST): A Systematic Review of Population-Based Cohort Studies. Cancer Epidemiol. 2016, 40, 39–46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Corless, C.L.; Barnett, C.M.; Heinrich, M.C. Gastrointestinal Stromal Tumours: Origin and Molecular Oncology. Nat. Rev. Cancer 2011, 11, 865–878. [Google Scholar] [CrossRef]
  65. Ricci, R.; Giustiniani, M.C.; Gessi, M.; Lanza, P.; Castri, F.; Biondi, A.; Persiani, R.; Vecchio, F.M.; Risio, M. Telocytes Are the Physiological Counterpart of Inflammatory Fibroid Polyps and PDGFRA-Mutant GISTs. J. Cell. Mol. Med. 2018, 22, 4856–4862. [Google Scholar] [CrossRef] [Green Version]
  66. Kondo, J.; Huh, W.J.; Franklin, J.L.; Heinrich, M.C.; Rubin, B.P.; Coffey, R.J. A Smooth Muscle-Derived, Braf-Driven Mouse Model of Gastrointestinal Stromal Tumor (GIST): Evidence for an Alternative GIST Cell-of-Origin. J. Pathol. 2020, 252, 441–450. [Google Scholar] [CrossRef]
  67. Unk, M.; Jezeršek Novaković, B.; Novaković, S. Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision. Cancers 2023, 15, 1498. [Google Scholar] [CrossRef]
  68. Joensuu, H.; Eriksson, M.; Sundby Hall, K.; Reichardt, A.; Hermes, B.; Schütte, J.; Cameron, S.; Hohenberger, P.; Jost, P.J.; Al-Batran, S.-E.; et al. Survival Outcomes Associated With 3 Years vs 1 Year of Adjuvant Imatinib for Patients With High-Risk Gastrointestinal Stromal Tumors: An Analysis of a Randomized Clinical Trial After 10-Year Follow-Up. JAMA Oncol. 2020, 6, 1241–1246. [Google Scholar] [CrossRef]
  69. Xu, K.; He, Z.; Chen, M.; Wang, N.; Zhang, D.; Yang, L.; Xu, Z.; Xu, H. HIF-1α Regulates Cellular Metabolism, and Imatinib Resistance by Targeting Phosphogluconate Dehydrogenase in Gastrointestinal Stromal Tumors. Cell Death Dis. 2020, 11, 586. [Google Scholar] [CrossRef]
  70. Papadakos, S.P.; Tsagkaris, C.; Papadakis, M.; Papazoglou, A.S.; Moysidis, D.V.; Zografos, C.G.; Theocharis, S. Angiogenesis in Gastrointestinal Stromal Tumors: From Bench to Bedside. World J. Gastrointest. Oncol. 2022, 14, 1469–1477. [Google Scholar] [CrossRef]
  71. Mu, J.; Sun, P.; Ma, Z.; Sun, P. BRD4 Promotes Tumor Progression and NF-ΚB/CCL2-Dependent Tumor-Associated Macrophage Recruitment in GIST. Cell Death Dis. 2019, 10, 935. [Google Scholar] [CrossRef] [Green Version]
  72. Xie, J.; Yoon, J.; Yang, S.-S.; Lin, S.-H.; Huang, C.-L. WNK1 Protein Kinase Regulates Embryonic Cardiovascular Development through the OSR1 Signaling Cascade. J. Biol. Chem. 2013, 288, 8566–8574. [Google Scholar] [CrossRef] [Green Version]
  73. Lai, J.-G.; Tsai, S.-M.; Tu, H.-C.; Chen, W.-C.; Kou, F.-J.; Lu, J.-W.; Wang, H.-D.; Huang, C.-L.; Yuh, C.-H. Zebrafish WNK Lysine Deficient Protein Kinase 1 (Wnk1) Affects Angiogenesis Associated with VEGF Signaling. PLoS ONE 2014, 9, e106129. [Google Scholar] [CrossRef]
  74. Hu, F.; Li, H.; Liu, L.; Xu, F.; Lai, S.; Luo, X.; Hu, J.; Yang, X. Histone Demethylase KDM4D Promotes Gastrointestinal Stromal Tumor Progression through HIF1β/VEGFA Signalling. Mol. Cancer 2018, 17, 107. [Google Scholar] [CrossRef]
  75. Gebreyohannes, Y.K.; Schöffski, P.; Van Looy, T.; Wellens, J.; Vreys, L.; Cornillie, J.; Vanleeuw, U.; Aftab, D.T.; Debiec-Rychter, M.; Sciot, R.; et al. Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations. Mol. Cancer Ther. 2016, 15, 2845–2852. [Google Scholar] [CrossRef] [Green Version]
  76. Huynh, H.; Lee, J.W.J.; Chow, P.K.H.; Ngo, V.C.; Lew, G.B.; Lam, I.W.L.; Ong, H.S.; Chung, A.; Soo, K.C. Sorafenib Induces Growth Suppression in Mouse Models of Gastrointestinal Stromal Tumor. Mol. Cancer Ther. 2009, 8, 152–159. [Google Scholar] [CrossRef] [Green Version]
  77. Kondoh, M.; Ohga, N.; Akiyama, K.; Hida, Y.; Maishi, N.; Towfik, A.M.; Inoue, N.; Shindoh, M.; Hida, K. Hypoxia-Induced Reactive Oxygen Species Cause Chromosomal Abnormalities in Endothelial Cells in the Tumor Microenvironment. PLoS ONE 2013, 8, e80349. [Google Scholar] [CrossRef]
  78. Pham-Huy, L.A.; He, H.; Pham-Huy, C. Free Radicals, Antioxidants in Disease and Health. Int. J. Biomed. Sci. IJBS 2008, 4, 89–96. [Google Scholar]
  79. Branca, J.J.V.; Pacini, A.; Gulisano, M.; Taddei, N.; Fiorillo, C.; Becatti, M. Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain. Front. Cell Dev. Biol. 2020, 8, 604377. [Google Scholar] [CrossRef]
  80. Di Meo, S.; Reed, T.T.; Venditti, P.; Victor, V.M. Role of ROS and RNS Sources in Physiological and Pathological Conditions. Oxid. Med. Cell. Longev. 2016, 2016, 1245049. [Google Scholar] [CrossRef]
  81. Pensalfini, A.; Cecchi, C.; Zampagni, M.; Becatti, M.; Favilli, F.; Paoli, P.; Catarzi, S.; Bagnoli, S.; Nacmias, B.; Sorbi, S.; et al. Protective Effect of New S-Acylglutathione Derivatives against Amyloid-Induced Oxidative Stress. Free Radic. Biol. Med. 2008, 44, 1624–1636. [Google Scholar] [CrossRef] [PubMed]
  82. Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules 2019, 24, 1583. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Fiorillo, C.; Becatti, M.; Attanasio, M.; Lucarini, L.; Nassi, N.; Evangelisti, L.; Porciani, M.C.; Nassi, P.; Gensini, G.F.; Abbate, R.; et al. Evidence for Oxidative Stress in Plasma of Patients with Marfan Syndrome. Int. J. Cardiol. 2010, 145, 544–546. [Google Scholar] [CrossRef] [Green Version]
  84. Becatti, M.; Marcucci, R.; Bruschi, G.; Taddei, N.; Bani, D.; Gori, A.M.; Giusti, B.; Gensini, G.F.; Abbate, R.; Fiorillo, C. Oxidative Modification of Fibrinogen Is Associated with Altered Function and Structure in the Subacute Phase of Myocardial Infarction. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 1355–1361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Xu, T.; Ding, W.; Ji, X.; Ao, X.; Liu, Y.; Yu, W.; Wang, J. Oxidative Stress in Cell Death and Cardiovascular Diseases. Oxid. Med. Cell. Longev. 2019, 2019, 9030563. [Google Scholar] [CrossRef] [Green Version]
  86. Bisht, S.; Faiq, M.; Tolahunase, M.; Dada, R. Oxidative Stress and Male Infertility. Nat. Rev. Urol. 2017, 14, 470–485. [Google Scholar] [CrossRef]
  87. Cito, G.; Becatti, M.; Natali, A.; Fucci, R.; Picone, R.; Cocci, A.; Falcone, P.; Criscuoli, L.; Mannucci, A.; Argento, F.R.; et al. Redox Status Assessment in Infertile Patients with Non-Obstructive Azoospermia Undergoing Testicular Sperm Extraction: A Prospective Study. Andrology 2020, 8, 364–371. [Google Scholar] [CrossRef]
  88. El Assar, M.; Angulo, J.; Rodríguez-Mañas, L. Oxidative Stress and Vascular Inflammation in Aging. Free Radic. Biol. Med. 2013, 65, 380–401. [Google Scholar] [CrossRef]
  89. Zhang, H.; Davies, K.J.A.; Forman, H.J. Oxidative Stress Response and Nrf2 Signaling in Aging. Free Radic. Biol. Med. 2015, 88, 314–336. [Google Scholar] [CrossRef] [Green Version]
  90. Klaunig, J.E. Oxidative Stress and Cancer. Curr. Pharm. Des. 2018, 24, 4771–4778. [Google Scholar] [CrossRef]
  91. Aggarwal, V.; Tuli, H.; Varol, A.; Thakral, F.; Yerer, M.; Sak, K.; Varol, M.; Jain, A.; Khan, M.; Sethi, G. Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements. Biomolecules 2019, 9, 735. [Google Scholar] [CrossRef] [Green Version]
  92. Deng, R.; Mo, F.; Chang, B.; Zhang, Q.; Ran, H.; Yang, S.; Zhu, Z.; Hu, L.; Su, Q. Glucose-Derived AGEs Enhance Human Gastric Cancer Metastasis through RAGE/ERK/Sp1/MMP2 Cascade. Oncotarget 2017, 8, 104216–104226. [Google Scholar] [CrossRef] [Green Version]
  93. Kanner, J.; Selhub, J.; Shpaizer, A.; Rabkin, B.; Shacham, I.; Tirosh, O. Redox Homeostasis in Stomach Medium by Foods: The Postprandial Oxidative Stress Index (POSI) for Balancing Nutrition and Human Health. Redox Biol. 2017, 12, 929–936. [Google Scholar] [CrossRef]
  94. Lee, D.Y.; Jung, D.E.; Yu, S.S.; Lee, Y.S.; Choi, B.K.; Lee, Y.C. Regulation of SIRT3 Signal Related Metabolic Reprogramming in Gastric Cancer by Helicobacter Pylori Oncoprotein CagA. Oncotarget 2017, 8, 78365–78378. [Google Scholar] [CrossRef] [Green Version]
  95. Rey, S.; Schito, L.; Koritzinsky, M.; Wouters, B.G. Molecular Targeting of Hypoxia in Radiotherapy. Adv. Drug Deliv. Rev. 2017, 109, 45–62. [Google Scholar] [CrossRef]
  96. Park, J.-H.; Kim, T.-Y.; Jong, H.-S.; Kim, T.Y.; Chun, Y.-S.; Park, J.-W.; Lee, C.-T.; Jung, H.C.; Kim, N.K.; Bang, Y.-J. Gastric Epithelial Reactive Oxygen Species Prevent Normoxic Degradation of Hypoxia-Inducible Factor-1alpha in Gastric Cancer Cells. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2003, 9, 433–440. [Google Scholar]
  97. Naito, Y.; Yoshikawa, T. Molecular and Cellular Mechanisms Involved in Helicobacter Pylori-Induced Inflammation and Oxidative Stress. Free Radic. Biol. Med. 2002, 33, 323–336. [Google Scholar] [CrossRef]
  98. Fu, S.; Ramanujam, K.S.; Wong, A.; Fantry, G.T.; Drachenberg, C.B.; James, S.P.; Meltzer, S.J.; Wilson, K.T. Increased Expression and Cellular Localization of Inducible Nitric Oxide Synthase and Cyclooxygenase 2 in Helicobacter Pylori Gastritis. Gastroenterology 1999, 116, 1319–1329. [Google Scholar] [CrossRef]
  99. Handa, O.; Naito, Y.; Yoshikawa, T. CagA Protein of Helicobacter Pylori: A Hijacker of Gastric Epithelial Cell Signaling. Biochem. Pharmacol. 2007, 73, 1697–1702. [Google Scholar] [CrossRef]
  100. Handa, O.; Naito, Y.; Yoshikawa, T. Redox Biology and Gastric Carcinogenesis: The Role of Helicobacter pylori. Redox Rep. 2011, 16, 1–7. [Google Scholar] [CrossRef] [Green Version]
  101. Wada, Y.; Takemura, K.; Tummala, P.; Uchida, K.; Kitagaki, K.; Furukawa, A.; Ishige, Y.; Ito, T.; Hara, Y.; Suzuki, T.; et al. Helicobacter pylori Induces Somatic Mutations in TP 53 via Overexpression of CHAC 1 in Infected Gastric Epithelial Cells. FEBS Open Bio 2018, 8, 671–679. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Magnelli, L.; Schiavone, N.; Staderini, F.; Biagioni, A.; Papucci, L. MAP Kinases Pathways in Gastric Cancer. Int. J. Mol. Sci. 2020, 21, 2893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Huang, X.-W.; Luo, R.-H.; Zhao, Q.; Shen, Z.-Z.; Huang, L.-L.; An, X.-Y.; Zhao, L.-J.; Wang, J.; Huang, Y.-Z. Helicobacter Pylori Induces Mitochondrial DNA Mutation and Reactive Oxygen Species Level in AGS Cells. Int. J. Med. Sci. 2011, 8, 56–67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Tsugawa, H.; Suzuki, H.; Saya, H.; Hatakeyama, M.; Hirayama, T.; Hirata, K.; Nagano, O.; Matsuzaki, J.; Hibi, T. Reactive Oxygen Species-Induced Autophagic Degradation of Helicobacter Pylori CagA Is Specifically Suppressed in Cancer Stem-like Cells. Cell Host Microbe 2012, 12, 764–777. [Google Scholar] [CrossRef] [Green Version]
  105. Yuan, J.; Li, P.; Tao, J.; Shi, X.; Hu, B.; Chen, H.; Guo, X.H. Pylori Escape Host Immunoreaction Through Inhibiting ILK Expression by VacA. Cell. Mol. Immunol. 2009, 6, 191–197. [Google Scholar] [CrossRef] [Green Version]
  106. Suzuki, H.; Miyazawa, M.; Nagahashi, S.; Sato, M.; Bessho, M.; Nagata, H.; Miura, S.; Ishii, H. Rabeprazole Treatment Attenuated Helicobacter Pylori-Associated Gastric Mucosal Lesion Formation in Mongolian Gerbils. J. Gastroenterol. Hepatol. 2003, 18, 787–795. [Google Scholar] [CrossRef]
  107. Handa, O.; Yoshida, N.; Fujita, N.; Tanaka, Y.; Ueda, M.; Takagi, T.; Kokura, S.; Naito, Y.; Okanoue, T.; Yoshikawa, T. Molecular Mechanisms Involved in Anti-Inflammatory Effects of Proton Pump Inhibitors. Inflamm. Res. 2006, 55, 476–480. [Google Scholar] [CrossRef]
  108. Lian, S.; Li, S.; Zhu, J.; Xia, Y.; Do Jung, Y. Nicotine Stimulates IL-8 Expression via ROS/NF-ΚB and ROS/MAPK/AP-1 Axis in Human Gastric Cancer Cells. Toxicology 2022, 466, 153062. [Google Scholar] [CrossRef]
  109. Toyokuni, S.; Okamoto, K.; Yodoi, J.; Hiai, H. Persistent Oxidative Stress in Cancer. FEBS Lett. 1995, 358, 1–3. [Google Scholar] [CrossRef] [Green Version]
  110. Li, Z.; Xu, X.; Leng, X.; He, M.; Wang, J.; Cheng, S.; Wu, H. Roles of Reactive Oxygen Species in Cell Signaling Pathways and Immune Responses to Viral Infections. Arch. Virol. 2017, 162, 603–610. [Google Scholar] [CrossRef]
  111. Qin, W.; Li, C.; Zheng, W.; Guo, Q.; Zhang, Y.; Kang, M.; Zhang, B.; Yang, B.; Li, B.; Yang, H.; et al. Inhibition of Autophagy Promotes Metastasis and Glycolysis by Inducing ROS in Gastric Cancer Cells. Oncotarget 2015, 6, 39839–39854. [Google Scholar] [CrossRef] [Green Version]
  112. Liu, T.-I.; Lu, T.-Y.; Yang, Y.-C.; Chang, S.-H.; Chen, H.-H.; Lu, I.-L.; Sabu, A.; Chiu, H.-C. New Combination Treatment from ROS-Induced Sensitized Radiotherapy with Nanophototherapeutics to Fully Eradicate Orthotopic Breast Cancer and Inhibit Metastasis. Biomaterials 2020, 257, 120229. [Google Scholar] [CrossRef]
  113. Itoh, T.; Terazawa, R.; Kojima, K.; Nakane, K.; Deguchi, T.; Ando, M.; Tsukamasa, Y.; Ito, M.; Nozawa, Y. Cisplatin Induces Production of Reactive Oxygen Species via NADPH Oxidase Activation in Human Prostate Cancer Cells. Free Radic. Res. 2011, 45, 1033–1039. [Google Scholar] [CrossRef]
  114. Santoro, V.; Jia, R.; Thompson, H.; Nijhuis, A.; Jeffery, R.; Kiakos, K.; Silver, A.R.; Hartley, J.A.; Hochhauser, D. Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer. J. Natl. Cancer Inst. 2015, 108, djv394. [Google Scholar] [CrossRef] [Green Version]
  115. Peri, S.; Ruzzolini, J.; Urciuoli, S.; Versienti, G.; Biagioni, A.; Andreucci, E.; Peppicelli, S.; Bianchini, F.; Bottari, A.; Calorini, L.; et al. An Oleocanthal-Enriched EVO Oil Extract Induces the ROS Production in Gastric Cancer Cells and Potentiates the Effect of Chemotherapy. Antioxidants 2022, 11, 1762. [Google Scholar] [CrossRef]
  116. Barker, H.E.; Paget, J.T.E.; Khan, A.A.; Harrington, K.J. The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence. Nat. Rev. Cancer 2015, 15, 409–425. [Google Scholar] [CrossRef] [Green Version]
  117. Triner, D.; Shah, Y.M. Hypoxia-Inducible Factors: A Central Link between Inflammation and Cancer. J. Clin. Investig. 2016, 126, 3689–3698. [Google Scholar] [CrossRef] [Green Version]
  118. Klug, F.; Prakash, H.; Huber, P.E.; Seibel, T.; Bender, N.; Halama, N.; Pfirschke, C.; Voss, R.H.; Timke, C.; Umansky, L.; et al. Low-Dose Irradiation Programs Macrophage Differentiation to an INOS+/M1 Phenotype That Orchestrates Effective T Cell Immunotherapy. Cancer Cell 2013, 24, 589–602. [Google Scholar] [CrossRef] [Green Version]
  119. Prasad, S.; Gupta, S.C.; Tyagi, A.K. Reactive Oxygen Species (ROS) and Cancer: Role of Antioxidative Nutraceuticals. Cancer Lett. 2017, 387, 95–105. [Google Scholar] [CrossRef]
  120. Blaser, H.; Dostert, C.; Mak, T.W.; Brenner, D. TNF and ROS Crosstalk in Inflammation. Trends Cell Biol. 2016, 26, 249–261. [Google Scholar] [CrossRef]
  121. Negre-Salvayre, A.; Guerby, P.; Gayral, S.; Laffargue, M.; Salvayre, R. Role of Reactive Oxygen Species in Atherosclerosis: Lessons from Murine Genetic Models. Free Radic. Biol. Med. 2020, 149, 8–22. [Google Scholar] [CrossRef] [PubMed]
  122. Xia, C.; Meng, Q.; Liu, L.-Z.; Rojanasakul, Y.; Wang, X.-R.; Jiang, B.-H. Reactive Oxygen Species Regulate Angiogenesis and Tumor Growth through Vascular Endothelial Growth Factor. Cancer Res. 2007, 67, 10823–10830. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Griess, B.; Tom, E.; Domann, F.; Teoh-Fitzgerald, M. Extracellular Superoxide Dismutase and Its Role in Cancer. Free Radic. Biol. Med. 2017, 112, 464–479. [Google Scholar] [CrossRef] [PubMed]
  124. Weydert, C.J.; Cullen, J.J. Measurement of Superoxide Dismutase, Catalase and Glutathione Peroxidase in Cultured Cells and Tissue. Nat. Protoc. 2010, 5, 51–66. [Google Scholar] [CrossRef] [Green Version]
  125. Subbannayya, Y.; Mir, S.A.; Renuse, S.; Manda, S.S.; Pinto, S.M.; Puttamallesh, V.N.; Solanki, H.S.; Manju, H.C.; Syed, N.; Sharma, R.; et al. Identification of Differentially Expressed Serum Proteins in Gastric Adenocarcinoma. J. Proteom. 2015, 127, 80–88. [Google Scholar] [CrossRef] [Green Version]
  126. Yang, J.; Zhang, C.; Zhang, W.; Shi, R.; Zhang, Z. Extracellular Superoxide Dismutase, a Potential Extracellular Biomarker Candidate for Prolactinoma. West Indian Med. J. 2012, 61, 665–669. [Google Scholar]
  127. Liu, J.; Hinkhouse, M.M.; Sun, W.; Weydert, C.J.; Ritchie, J.M.; Oberley, L.W.; Cullen, J.J. Redox Regulation of Pancreatic Cancer Cell Growth: Role of Glutathione Peroxidase in the Suppression of the Malignant Phenotype. Hum. Gene Ther. 2004, 15, 239–250. [Google Scholar] [CrossRef]
  128. Coso, S.; Harrison, I.; Harrison, C.B.; Vinh, A.; Sobey, C.G.; Drummond, G.R.; Williams, E.D.; Selemidis, S. NADPH Oxidases as Regulators of Tumor Angiogenesis: Current and Emerging Concepts. Antioxid. Redox Signal. 2012, 16, 1229–1247. [Google Scholar] [CrossRef] [Green Version]
  129. Garrido-Urbani, S.; Jemelin, S.; Deffert, C.; Carnesecchi, S.; Basset, O.; Szyndralewiez, C.; Heitz, F.; Page, P.; Montet, X.; Michalik, L.; et al. Targeting Vascular NADPH Oxidase 1 Blocks Tumor Angiogenesis through a PPARα Mediated Mechanism. PLoS ONE 2011, 6, e14665. [Google Scholar] [CrossRef]
  130. Violi, F.; Sanguigni, V.; Carnevale, R.; Plebani, A.; Rossi, P.; Finocchi, A.; Pignata, C.; De Mattia, D.; Martire, B.; Pietrogrande, M.C.; et al. Hereditary Deficiency of Gp91 phox Is Associated With Enhanced Arterial Dilatation: Results of a Multicenter Study. Circulation 2009, 120, 1616–1622. [Google Scholar] [CrossRef] [Green Version]
  131. Belaiba, R.; Djordjevic, T.; Petry, A.; Diemer, K.; Bonello, S.; Banfi, B.; Hess, J.; Pogrebniak, A.; Bickel, C.; Gorlach, A. NOX5 Variants Are Functionally Active in Endothelial Cells. Free Radic. Biol. Med. 2007, 42, 446–459. [Google Scholar] [CrossRef]
  132. You, X.; Ma, M.; Hou, G.; Hu, Y.; Shi, X. Gene Expression and Prognosis of NOX Family Members in Gastric Cancer. OncoTargets Ther. 2018, 11, 3065–3074. [Google Scholar] [CrossRef] [Green Version]
  133. Qiao, L.; Xie, N.; Bai, Y.; Qin, B.; Zou, B.; Shi, Y. The Expression and Prognostic Value of NOX4 in Gastric Cancer. Clin. Oncol. 2018, 3, 1505. [Google Scholar]
  134. Echizen, K.; Horiuchi, K.; Aoki, Y.; Yamada, Y.; Minamoto, T.; Oshima, H.; Oshima, M. NF-ΚB-Induced NOX1 Activation Promotes Gastric Tumorigenesis through the Expansion of SOX2-Positive Epithelial Cells. Oncogene 2019, 38, 4250–4263. [Google Scholar] [CrossRef] [Green Version]
  135. Tominaga, K.; Kawahara, T.; Sano, T.; Toida, K.; Kuwano, Y.; Sasaki, H.; Kawai, T.; Teshima-Kondo, S.; Rokutan, K. Evidence for Cancer-Associated Expression of NADPH Oxidase 1 (NOX1)-Based Oxidase System in the Human Stomach. Free Radic. Biol. Med. 2007, 43, 1627–1638. [Google Scholar] [CrossRef]
  136. Zorov, D.B.; Filburn, C.R.; Klotz, L.O.; Zweier, J.L.; Sollott, S.J. Reactive Oxygen Species (ROS)-Induced ROS Release: A New Phenomenon Accompanying Induction of the Mitochondrial Permeability Transition in Cardiac Myocytes. J. Exp. Med. 2000, 192, 1001–1014. [Google Scholar] [CrossRef] [Green Version]
  137. Graham, N.A.; Tahmasian, M.; Kohli, B.; Komisopoulou, E.; Zhu, M.; Vivanco, I.; Teitell, M.A.; Wu, H.; Ribas, A.; Lo, R.S.; et al. Glucose Deprivation Activates a Metabolic and Signaling Amplification Loop Leading to Cell Death. Mol. Syst. Biol. 2012, 8, 589. [Google Scholar] [CrossRef]
  138. Kim, Y.-M.; Kim, S.-J.; Tatsunami, R.; Yamamura, H.; Fukai, T.; Ushio-Fukai, M. ROS-Induced ROS Release Orchestrated by NOX4, NOX2, and Mitochondria in VEGF Signaling and Angiogenesis. Am. J. Physiol. Cell Physiol. 2017, 312, C749–C764. [Google Scholar] [CrossRef] [Green Version]
  139. Brower, V. Apatinib in Treatment of Refractory Gastric Cancer. Lancet Oncol. 2016, 17, e137. [Google Scholar] [CrossRef]
  140. Zhao, L.; Peng, Y.; He, S.; Li, R.; Wang, Z.; Huang, J.; Lei, X.; Li, G.; Ma, Q. Apatinib Induced Ferroptosis by Lipid Peroxidation in Gastric Cancer. Gastric Cancer 2021, 24, 642–654. [Google Scholar] [CrossRef]
Figure 1. A schematic representation of the NOX and DUOX-mediated ROS generation, their interaction with HIF-1α and HIF-2α, and the ROS scavenging system in GC cells.
Figure 1. A schematic representation of the NOX and DUOX-mediated ROS generation, their interaction with HIF-1α and HIF-2α, and the ROS scavenging system in GC cells.
Biomolecules 13 00886 g001
Table 1. Chemotherapies aimed to control tumor-induced vascularization.
Table 1. Chemotherapies aimed to control tumor-induced vascularization.
TreatmentTargetInhibited PhenomenonReference
Anti-Notch4 AntibodiesNotch4Angiogenesis/EET[43]
Dual Antiplatelet TherapyDll4-Notch axisAngiogenesis/EET[44]
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Biagioni, A.; Peri, S.; Versienti, G.; Fiorillo, C.; Becatti, M.; Magnelli, L.; Papucci, L. Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species. Biomolecules 2023, 13, 886.

AMA Style

Biagioni A, Peri S, Versienti G, Fiorillo C, Becatti M, Magnelli L, Papucci L. Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species. Biomolecules. 2023; 13(6):886.

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Biagioni, Alessio, Sara Peri, Giampaolo Versienti, Claudia Fiorillo, Matteo Becatti, Lucia Magnelli, and Laura Papucci. 2023. "Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species" Biomolecules 13, no. 6: 886.

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