Gastric angiogenesis and Helicobacter pylori infection
Angiogénesis gástrica e infección por Helicobacter pylori
I. D. Pousa and J. P. Gisbert
Services of Gastroenterology and Hepatology. Hospital Universitario de La Princesa. Madrid, Spain
ABSTRACT
]]> The formation of new blood vessels seen in conditions commonly associated with Helicobacter pylori (H. pylori) infection, including gastritis, peptic ulcer, and gastric carcinoma, prompts consideration of a potential relationship between mucosal colonization by this organism and the angiogenic process.Key words: Angiogenesis. Endothelial cells. Helicobacter pylori. Vascular endothelium growth factor (VEGF). Gastritis. Peptic ulcer. Gastric cancer.
Introduction
Angiogenesis, that is, the formation of new blood vessels from pre-extant ones, is a concept currently growing in interest both in the clinical medicine and basic science setting. This results from its potential role in the pathogenesis of various cardiovascular conditions (1), respiratory chronic inflammation by a number of organisms (2), rheumatoid arthritis, and diabetic retinopathy (3), in addition to tumor growth and resulting metastatic spread (4).
Under physiologic conditions, the process of angiogenesis plays a role in bone growth and maturation, the menstrual cycle, and injury healing. In order that this process be carried out, endothelial cell (EC) proliferation and survival, or inhibition by apoptosis, is crucial. Major mediators in the adequate development of this process include members of the vascular endothelium growth factor (VEGF) gene class, fibroblastic growth factor, and angiopoietins among others, which play their role following interaction with their corresponding trans-membrane tyrosine-kinase receptors, mainly present on ECs.
Helicobacter pylori (H. pylori) colonizes the gastrointestinal -mainly gastric- epithelium in a non-invasive way (5). This infection is a major cause of chronic gastritis, peptic ulcer, and gastric cancer (6). Given the implication of vessel neoformation in tumor growth and -apparently- the poorer course of various conditions, the relationship between H. pylori infection and angiogenesis has been increasingly studied during the past few years.
This review aims at unifying what to this day is known regarding said relationship between angiogenesis and H. pylori. To that end an Internet search was carried out through October 2005 using the PubMed search engine. The following descriptors or keywords were used (in all search fields): pylori AND (angiogenesis OR microvascular OR "endothelial cell" OR "vascular endothelial growth factor"). Studies assessing the effect of H. pylori on ECs and the formation of new blood vessels were selected, as well as experimental studies measuring the expression of mediators influencing and regulating any biologic mechanism in angiogenesis after bacterial infection, namely EC differentiation, proliferation, survival, migration, invasion, and adhesion.
]]> How does the angiogenesis process occurr?
To understand the potential effect of H. pylori on the formation of new blood vessels following infection, the biologic mechanisms of angiogenesis should be first known. Overall, an angiogenic trigger (hypoxia, acidosis) is presumed to develop first thus inducing a change of mediators in the microenvironment of the organism or involved area, which would result in an irregular expression of both pro- and anti-angiogenic molecules (Table I). These molecules "decide" whether the vessel will expand, remain as it is, or regress (7). There is usually a balance between both mediator groups, but the balance inclines to one side following said angiogenic trigger (Fig. 1).
Angiogenic activation is followed by vasodilation, which allows the extravasation of metalloproteases (MMPs); these in turn degrade the extracellular matrix and endothelial base membrane. ECs differentiate and proliferate under the action of selected growth factors and cytokines, particularly members of the VEGF gene family and angiopoietins. Then, these ECs migrate through the free space resulting protease disgregation and regroup to produce small developing sprouts. Finally the maturation of the vascular network depends on pericytes and various cytokines, including stromal cell-derived factor and its receptor, and platelet-derived growth factor (8) (Table I).
Once the development of the angiogenic process is understood, physiologic and pathologic angiogenesis must be differentiated (Fig. 1). Physiologic angiogenesis is a process that is strictly regulated by a huge variety of cytokines, and occurs in injury repair, bone growth and development, and the menstrual cycle. Once angiogenesis has met its goals, angiogenic factors return to normal, that is, to their usual balanced status.
In a way that remains to be elucidated, these factors on occasion do not return to normal balance, and an excess or deficiency in vessel formation ensues, which may favor the pathogenesis of a various diseases, including rheumatoid arthritis, psoriasis, proliferative retinopathy, and atherosclerosis, among others (1,3,9,10).
A great variety of angiogenic factors exist, which may be classified as follows: a) pro-angiogenic, which induce angiogenesis; and b) anti-angiogenic, which inhibit the formation of new vessels (Table I). Proangiogenic factors include members of the VEGF gene family, fibroblastic growth factor, and angiopoietins, which seem to play a specific, crucial role in the formation of new blood vessels (11).
The gastric mucosa after H. Pylori infection: inflamation and microcirculation (Fig. 2)
It is a well known fact that H. pylori infection is the primary cause of gastritis, peptic ulcer, and gastric cancer, even though the exact mechanism why this bacterial organism contributes to their development in only selected individuals remains to be elucidated.
H. pylori infection is usually associated in genetically predisposed individuals with severe inflammation, possibly as a result of an excessive immune response to bacterial proteins that the host identifies as antigens (Fig. 2). In fact, some in vitro studies show that bacterial surface proteins act as chemotactics for inflammatory cells such neutrophils and monocytes (12).
In the inflammatory process, activated leukocytes are characterized by an increased synthesis of various cytokines and oxygen free radicals. While these mediators -most of them proinflammatory- are initially directed to defend the body against bacteria, such toxic substances may unintentionally damage epithelial cells, thus reducing mucosal resistance to gastric acid (13). Thus, the host's immune response itself, inflammation, and pH changes may as a whole result in gastric disorders, including gastritis, peptic ulcer, and gastric carcinoma.
]]> A major component of gastrointestinal inflammation is the disturbance of vascular structure and function. This statement is supported by endoscopic and histologic findings related to H. pylori infection, including erythema, edema, and vasodilation, as well as inflammatory cell infiltration (14). Several authors reported such disturbances in gastric microcirculation in the presence of H. pylori both in humans (15-17) and rodents in vivo (13,18). The precise cause of said vascular disorders is unknown, but a potential candidate is inflammation itself -as related to this organism's presence.Thus, a question to be asked is the way in which inflammation may affect vascular structure and function. In relatively recent papers, the use of in vivo fluorescence or intravital microscopy has revealed the major function exerted by leukocyte adhesion -associated with the inflammatory process- in microvascular gastric disorders in the presence of H. pylori (19). Also platelets seem to play a major role in inflammation and the subsequent vascular gastric disorders arising after H. pylori infection. Thus, platelets have been suggested to potentially generate -together with bacteria- highly toxic oxygen forms including the superoxide anion and hydroxyl radical; these induce platelet aggregation, which may result in microvascular disorders, even when they were initially directed to defend the host (20). In addition, activated platelets express P-selectin in their surface, which not only facilitates their adhesion to monocytes and neutrophils but also makes these cells ready for the subsequent immune response, thus enhancing inflammation (21).
On the other hand, EC apoptosis has been seen under inflammation or atherosclerosis conditions, which would result in a loss of anticoagulating properties, and in their circulation as coagulating bodies much in the same way as platelets (22).
So, both leukocyte adhesion and platelet aggregation or EC apoptosis may give rise to small vessel-blocking thrombi, which would alter blood flow (19). These changes may favor microvascular gastric disorders following infection by H. pylori.
The gastric mucosa requires an adequate blood flow to maintain tissue viability and to perform its main physiologic activity. A reduction in blood flow to the gastric mucosa would allow intramucosal proton accumulation, which in association with other factors may alter pH and hence result in cell damage (19).
Therefore, it may be said that, following H. pylori infection, a wide variety of microcirculation components become disturbed, including blood flow, vessel diameter, sedimentation rate, leukocyte and platelet activity, and even EC activity (19).
How does H. Pylori infection act upon ecs?
ECs are a potential target for a wide variety of mediators, and a key factor in angiogenesis. This is due to the fact that EC differentiation, proliferation, migration, and invasion represent crucial stages for this process. Thus, the study of ECs in the presence of H. pylori is important, but the literature on this topic is scant.
EC activation may favor chronic inflammation following H. pylori infection, as these cells may increase vascular permeability. The bacterium may in turn change the biologic functions of these cells, be it their proliferation and apoptosis, or their migration and invasion.
]]> Several research teams have focused on the study of epithelial cell proliferation and apoptosis (23-27), but the literature about these biologic mechanisms in ECs is scarce (13,28,29). Various in vitro studies using H. pylori water extracts converge in demonstrating an antiproliferating effect on ECs that is independent of bacterial VacA and cagA genotypes (13,28-31). In the presence of H. pylori S-phase ECs seemingly diminish, which suggests a blockage of the G1-S transition (29). This antiproliferating action on ECs may be reverted by the addition of monoclonal antibodies against tumor necrosis factor alfa (TNF-α), which suggests that this cytokine is involved in H. pylori-induced cytostasis (31). This mitogen is synthesized in the gastric mucosa particularly after H. pylori-related damage, and attenuates EC proliferation at cell cycle level (32).The balance between apoptosis and cell proliferation is relevant for sustained gastric homeostasis, and a loss of balance may lead to the development of gastric tumors, which has been associated with H. pylori infection (33,34).
There is evidence that EC apoptosis follows stimuli such as lipopolysaccharides or TNF-a (13,35). Recent in vitro studies have shown the apoptosis of human umbilical vein ECs (HUVECs) following the addition of H. pylori water extracts to their cultures (28). However, other authors could not confirm these findings (30). This controversy may well result from different magnitudes in the bacterial innoculum added to cell cultures, or the various techniques used to measure apoptosis rates. The first study (28) was based on the research of proteins closely linked to the apoptotic process, namely p21 and p53; the second study (30) quantitized cell death by using a lactate dehydrogenase assay.
Under inflammatory conditions, which are invariably present after H. pylori infection, an increase in the microvascular endothelium's apoptotic rate has been shown to entail increased coagulation and permeability, which may alter blood flow and favor an extravasation of mediators to disturb the host organism. All this may in turn bring about a loss of balance between pro- and anti-angiogenic molecules (17,22,36).
H. pylori, in addition to cytostasis induction and EC apoptosis modulation, may have cytotoxic effects capable of activating leukocytes and other inflammatory cells, thus inducing epithelial damage and ulcer formation (13). On the other hand, no EC chemotaxis or migration has been reported in the presence of this bacterium, which may be surprising when considering that EC migration is a critical step in angiogenesis regarding the formation of a new vessel (29).
Angiogenesis in H. Pylori-associated gastritis
Atrophic gastritis is considered a precursor lesion of intestinal-type gastric cancer, which is associated with hypergastrinemia and the ensuing induction of cyclooxygenase 2 (COX-2), whose products seem to be responsible for delayed apoptosis and angiogenesis in gastric cancer (37). COX-2 is inducible in inflammatory responses, and seems to stimulate NFkB expression, which in turn activates proinflammatory cytokines (IL-8, IL-6, IL-1) and reactive oxygen species (37). COX-2 may play a critical role in a number of gastric conditions related to H. pylori infection, since various studies have shown that bacterial eradication is followed by a decrease in COX-2 gene expression (38,39).
Regarding the angiogenic process, a higher blood vessel density has been reported for gastric mucosa samples from patients with H. pylori-positive gastritis versus patients with H. pylori-negative gastritis (40). These values significantly correlated to the expression of hypoxia-inducible factor 1-alfa (40). Such results are none the least surprising, since the higher the expression of hypoxia-inducible factor 1-alfa, the greater the stimulus for transcription in some angiogenic genes which would translate into angiogenesis-enhancing proteins.
A very recent study has shown a direct relationship between VEGF concentrations and new blood vessel development; gastric mucosal neovascularization was also reported to be significantly higher at the antrum of patients with H. pylori-positive gastritis versus non-infected individuals (41). This neovascularization was seemingly also reported in the gastric body, but with statistically non-significant differences (41). This may result from the fact that G cells, mainly located at the gastric antrum, are responsible for gastrin synthesis and release (41). In turn, gastrin seems to stimulate COX-2 expression (42,43), which may lead to increased VEGF expression (44,45).
]]> Another research team has reported an increased VEGF expression -both the protein and mRNA- in the normal gastric mucosa of patients not infected by H. pylori when compared to infected subjects (41). In contrast, other authors reported no such differences regarding mRNA in patients with gastritis according to their being infected by H. pylori or otherwise (8). Such discrepancies may result from inflammation itself, since one group compared the normal mucosa of patients with and without H. pylori infection (41), and the other group included patients with chronic gastritis (8).VEGF induces most of its angiogenic effects following its interaction with a trans-membrane tyrosin-kinase receptor -VEGFR-2 (46). The expression of this receptor seems to be reduced both in HUVEC cultures in the presence of H. pylori (30) and H. pylori-infected gastric mucosa (8). However, other papers report no such decreased expression (41). Such inconsistencies may result from the methodology used to measure VEGF receptor expression, or from differences in the control population (41).
From the aforementioned papers it may be concluded that angiogenic factors are usually overexpressed in the gastric mucosa of patients with H. pylori infection, and that angiogenesis is probably increased in such individuals.
Angiogenesis in H. Pylori-related peptic ulcer
Once a peptic ulcer has developed, angiogenesis could be logically considered to become activated in order to help in ulcer healing and epithelial repair. This process is essential, as it facilitates oxygen and nutrient supplies to injury sites, as well as the clearance of necrotic tissue, thus facilitating repair mechanisms (29,30,47).
However, a number of experimental studies show delayed ulcer healing in the presence of these bacteria, and usually relate it to a potential inhibition of angiogenesis (30,48-53). On the one hand this delayed healing of ulcers would attenuate tissue repair; on the other hand, the sustained contact with bacterial antigens may increase epithelial damage. Both events may lead to chronic ulcer development, and not only to the appearance of acute lesions in the gastroduodenal mucosa (52,54,55).
Some cytokines, including interleukin 8 (IL-8), IL-6, and TNF-a, are stimulated by H. pylori as a component of the latter's pathologic mechanism, which might inhibit ulcer healing through an angiogenesis attenuating effect (31). While ILs do not seem to affect EC proliferation and apoptosis, TNF-a is indeed involved in H. pylori-induced EC cytostasis (29-31).
The expression of proangiogenic factors such as VEGF, endothelin-1 or nitric oxide has been studied in H. pylori-positive ulcers in various stages: active ulcer, healing ulcer, and healed ulcer (56). A greater expression of these factors in active and healing ulcers seems to predominate versus healed ulcers, which suggests that these factors play a role in angiogenesis, vascular remodeling and mucosal regeneration during ulcer healing (56). On the other hand, subsequent in vitro investigations using molecular biology techniques have suggested that no such changes exist in the production of VEGF and angiopoietins in the presence of H. pylori (30). Regarding the expression of VEGF mRNA, however, no significant differences have been reported between patients with active ulcer, healing ulcer, and healed ulcer (8), and H. pylori seemed to have no influence on their regulation (30). The same was the case with other factors, including angiopoietins, which were also subjected to no bacterial influence (30).
Regarding VEGF receptors, KDR and Flt-1, a significant increase in both mRNAs has been seen in active ulcers versus healing and healed ulcers (8). However, protein and mRNA expression for these VEGF receptors is reduced in infected patients with peptic ulcers (8,30).
]]> Thus, it may be concluded that there possibly exists an activation of the angiogenic process early in ulcer development, and that this process is subsequently inhibited in the presence of this bacterium; so then, new vessel formation is eventually inhibited in infected patients with peptic ulcer.In summary, H. pylori infection seems to induce a deficient angiogenesis in associated ulcers, that is, has an antiangiogenic effect besides its antiproliferating action on ECs in these patients.
Angiogenesis in H. Pylori-related gastric cancer
H. pylori infection represents a highly relevant factor in the pathogenesis of gastric cancer (37). This may be due, at least partly, to the stimulated expression of genes involved in mucosal defense, inflammatory response, angiogenesis modulation, and tumor suppression by H. pylori (57). The two types of histologically distinct gastric cancers -intestinal and diffuse- differ in the combinations of multiple genetic and epigenetic changes involved in the various stages of carcinogenesis in the human stomach (58). Both seem to be associated to H. pylori infection in a similar way (58).
H. pylori infected patients with gastric carcinoma have a higher density of blood vessels when compared to patients with this tumor following H. pylori eradication (59). Therefore, it has been suggested that H. pylori eradication may influence tumor vascularization in gastric carcinoma (59).
The results from some studies suggest that the H. pylori cagA+ strain may play a critical role not only in tissue remodeling, angiogenesis, or injury healing, but also in the process of extracellular matrix degradation, tumor invasion, and metastatic spread (37,60,61). This may result from the fact that cancerigenous gastric cells in the presence of H. pylori cagA+ strains stimulate the expression of urokinase-type plasminogen activator and its receptor (60). This increased expression changes following treatment with a NFkB inhibitor, and these findings thus suggest that cancerigenous cells vary the expression of selected mediators involved in neoangiogenesis through the transcription factor NFkB (60).
Platelet-derived growth factor is proangiogenic and is highly expressed by gastric carcinoma (62), while this expression seems to be independent of H. pylori infection in developed tumors (63). However, this infection results in increased numbers of nonspecific inflammatory cells, which may increase the expression of platelet-derived growth factor in premalignant lesions such as intestinal metaplasia, which may help originate a microenvironment supporting tumor development (63).
Furthermore, it seems that nuclear apoptotic protein p53 is related to gastric carcinoma vasculature, and correlates with COX-2 expression (64,65). In turn, COX-2 is involved in VEGF overexposure in human gastric cancer in the presence of H. pylori (66,67). In vitro cocultures of gastric carcinoma cells and H. pylori induce an increase in mRNA expression for IL-8, VEGF, angiogenin, urokinase-type plasminogen activator, and MMP-9 in said cells (34) (Table I). Some studies suggest that H. pylori may influence the expression of MMP-9 and VEGF, and promote gastric cell invasion via COX-2- and NFkB-mediated pathways (33). Similarly, COX-2 inhibition results in decreased angiogenic factors, and in changes in MMP activity (68).
In summary, COX-2 seems to be inducible in response to cytokines, mitogens, growth factors, and the presence of H. pylori, and may induce carcinogenesis via mechanisms involving apoptosis inhibition, cell proliferation increase, and angiogenesis increase (64).
]]>Conclusions
H. pylori infection seems to have a relevant influence on gastric angiogenesis:
1. It influences the expression of various angiogenic factors (34,69-71), and may directly activate proangiogenic pathways in the gastric mucosa (72).
2. Its colonization of the gastric mucosa results in inflammation, which may induce microvasculature disorders (13,18).
3. The presence of infection is associated with a higher density of blood vessels in clinical conditions such as gastritis and gastric cancer (40,41,59).
4. H. pylori eradication accelerates ulcer healing (73,74). This may suggest an altered expression or regulation of some repair-inhibiting angiogenic mediators in the presence of this bacterium.
The first conclusion that may be drawn from this revision contents is the presence of a stimulating or inhibiting effect on angiogenesis depending upon each H. pylori-associated condition. In this way, conditions such as gastritis and gastric cancer would be associated with a proangiogenic action, whereas such action would be attenuated in peptic ulcer. Thus, this organism seems to inhibit both the angiogenic trigger and vessel maturation in ulcer healing (30); however, blood vessel neoformation is seen in H. pylori-infected patients with gastritis (40,41) or gastric carcinoma (59).
Angiogenesis is activated early in H. pylori-infected patients with peptic ulcer in response to local hypoxia, and becomes progressively attenuated for some still unelucidated reason, although recent studies suggest a disturbance of mediators involved in blood vessel neoformation (30,53).
]]> Acknowledgements
This review was partly supported by a grant from Instituto de Salud Carlos III (C03/02), and a grant from Schering Plough.
References
1. Felmeden DC, Blann AD, Lip GY. Angiogenesis: basic pathophysiology and implications for disease. Eur Heart J 2003; 24: 586-603. [ Links ]
2. McDonald DM. Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med 2001; 164: S39-45. [ Links ]
3. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27-31. [ Links ]
4. Folkman J. Fundamental concepts of the angiogenic process. Curr Mol Med 2003; 3: 643-51. [ Links ]
5. Ricci V, Zarrilli R, Romano M. Voyage of Helicobacter pylori in human stomach: odyssey of a bacterium. Dig Liver Dis 2002; 34: 2-8. [ Links ]
6. Konturek PC, Bielanski W, Konturek SJ, Hahn EG. Helicobacter pylori associated gastric pathology. J Physiol Pharmacol 1999; 50: 695-710. [ Links ]
7. Jiménez B, Volpert OV. Mechanistic insights on the inhibition of tumor angiogenesis. J Mol Med 2001; 78: 663-72. [ Links ]
8. Akimoto M, Hashimoto H, Maeda A, Shigemoto M, Yamashita K. Roles of angiogenic factors and endothelin-1 in gastric ulcer healing. Clin Sci (Lond) 2002; 103 (Supl. 48): 450S-454S. [ Links ]
9. Couffinhal T, Kearney M, Witzenbichler B, Chen D, Murohara T, Losordo DW, et al. Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries. Am J Pathol 1997; 150: 1673-85. [ Links ]
10. Adamis AP, Miller JW, Bernal MT, D'Amico DJ, Folkman J, Yeo TK, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994; 118: 445-50. [ Links ]
11. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407: 242-8. [ Links ]
12. Craig PM, Territo MC, Karnes WE, Walsh JH. Helicobacter pylori secretes a chemotactic factor for monocytes and neutrophils. Gut 1992; 33: 1020-3. [ Links ]
13. Kalia N, Jones C, Bardhan DK, Reed MW, Atherton JC, Brown NJ. Effects of genotypically different strains of Helicobacter pylori on human microvascular endothelial cells in vitro. Dig Dis Sci 2001; 46: 54-61. [ Links ]
14. Wyatt JI. Histopathology of gastroduodenal inflammation: the impact of Helicobacter pylori. Histopathology 1995; 26: 1-15. [ Links ]
15. Taha AS, Huxham IM, Motley P, Morton R, Beattie AD. Reduced gastric mucosal vascularity in patients with chronic gastritis. Eur J Gastroenterol Hepatol 1998; 10: 1001-5. [ Links ]
16. Elizalde JI, Gómez J, Panes J, Lozano M, Casadevall M, Ramírez J, et al. Platelet activation In mice and human Helicobacter pylori infection. J Clin Invest 1997; 100: 996-1005. [ Links ]
17. Kalia N, Jacob S, Brown NJ, Reed MW, Morton D, Bardhan KD. Studies on the gastric mucosal microcirculation. 2. Helicobacter pylori water soluble extracts induce platelet aggregation in the gastric mucosal microcirculation in vivo. Gut 1997; 41: 748-52. [ Links ]
18. Konturek PC, Brzozowski T, Kwiecien S, Drozdowicz D, Harsch IA, Meixner H, et al. Effect of Helicobacter pylori on delay in ulcer healing induced by aspirin in rats. Eur J Pharmacol 2002; 451: 191-202. [ Links ]
19. Kalia N, Bardhan KD. Of blood and guts: association between Helicobacter pylori and the gastric microcirculation. J Gastroenterol Hepatol 2003; 18: 1010-7. [ Links ]
20. Caccese D, Pratico D, Ghiselli A, Natoli S, Pignatelli P, Sanguigni V, et al. Superoxide anion and hydroxyl radical release by collagen-induced platelet aggregation--role of arachidonic acid metabolism. Thromb Haemost 2000; 83: 485-90. [ Links ]
21. Mannaioni PF, Di Bello MG, Masini E. Platelets and inflammation: role of platelet-derived growth factor, adhesion molecules and histamine. Inflamm Res 1997; 46: 4-18. [ Links ]
22. Bombeli T, Karsan A, Tait JF, Harlan JM. Apoptotic vascular endothelial cells become procoagulant. Blood 1997; 89: 2429-42. [ Links ]
23. Olivares D, Gisbert J. Infección por Helicobacter pylori y apoptosis de las células epiteliales de la mucosa gástrica. Rev Esp Enferm Dig 2005; 97: 505-20. [ Links ]
24. Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8: 705-11. [ Links ]
25. Shirin H, Sordillo EM, Oh SH, Yamamoto H, Delohery T, Weinstein IB, et al. Helicobacter pylori inhibits the G1 to S transition in AGS gastric epithelial cells. Cancer Res 1999; 59: 2277-81. [ Links ]
26. Peek RM, Jr., Blaser MJ, Mays DJ, Forsyth MH, Cover TL, Song SY, et al. Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle. Cancer Res 1999; 59: 6124-31. [ Links ]
27. Konturek PC, Pierzchalski P, Konturek SJ, Meixner H, Faller G, Kirchner T, et al. Helicobacter pylori induces apoptosis in gastric mucosa through an upregulation of Bax expression in humans. Scand J Gastroenterol 1999; 34: 375-83. [ Links ]
28. Kurosawa A, Miwa H, Hirose M, Tsune I, Nagahara A, Sato N. Inhibition of cell proliferation and induction of apoptosis by Helicobacter pylori through increased phosphorylated p53, p21 and Bax expression in endothelial cells. J Med Microbiol 2002; 51: 385-91. [ Links ]
29. Pearce HR, Kalia N, Bardhan KD, Atherton JC, Brown NJ. Effects of Helicobacter pylori on endothelial cell proliferation and chemotaxis. Digestion 2004; 69: 201-10. [ Links ]
30. Kim JS, Kim JM, Jung HC, Song IS. Helicobacter pylori down-regulates the receptors of vascular endothelial growth factor and angiopoietin in vascular endothelial cells: implications in the impairment of gastric ulcer healing. Dig Dis Sci 2004; 49: 778-86. [ Links ]
31. Jenkinson L, Bardhan KD, Atherton J, Kalia N. Helicobacter pylori prevents proliferative stage of angiogenesis in vitro: role of cytokines. Dig Dis Sci 2002; 47: 1857-62. [ Links ]
32. Cutry AF, Kinniburgh AJ, Krabak MJ, Hui SW, Wenner CE. Induction of c-fos and c-myc proto-oncogene expression by epidermal growth factor and transforming growth factor alpha is calcium-independent. J Biol Chem 1989; 264: 19700-5. [ Links ]
33. Wu CY, Wang CJ, Tseng CC, Chen HP, Wu MS, Lin JT, et al. Helicobacter pylori promote gastric cancer cells invasion through a NF-kappaB and COX-2-mediated pathway. World J Gastroenterol 2005; 11: 3197-203. [ Links ]
34. Kitadai Y, Sasaki A, Ito M, Tanaka S, Oue N, Yasui W, et al. Helicobacter pylori infection influences expression of genes related to angiogenesis and invasion in human gastric carcinoma cells. Biochem Biophys Res Commun 2003; 311: 809-14. [ Links ]
35. Hansson GK, Chao S, Schwartz SM, Reidy MA. Aortic endothelial cell death and replication in normal and lipopolysaccharide-treated rats. Am J Pathol 1985; 121: 123-7. [ Links ]
36. Elizalde JI, Perez-Pujol S, Heras M, Sionis A, Casanovas N, Martorell T, et al. Effects of Helicobacter pylori eradication on platelet activation and disease recurrence in patients with acute coronary syndromes. Helicobacter 2004; 9: 681-9. [ Links ]
37. Konturek PC, Kania J, Konturek JW, Nikiforuk A, Konturek SJ, Hahn EG. H. pylori infection, atrophic gastritis, cytokines, gastrin, COX-2, PPAR gamma and impaired apoptosis in gastric carcinogenesis. Med Sci Monit 2003; 9: SR53-66. [ Links ]
38. Gisbert JP, Pajares JM. Helicobacter pylori, cyclooxygenase-2 and gastric cancer. Med Clin (Barc) 2003; 120: 189-93. [ Links ]
39. Gisbert JP, Pajares JM. Cyclooxygenase-2 and gastroduodenal lesions. Any relationship with Helicobacter pylori? A systematic review. Med Clin (Barc) 2003; 120: 550-8. [ Links ]
40. Yeo M, Kim DK, Han SU, Lee JE, Kim YB, Cho YK, et al. Novel action of gastric proton pump inhibitor on suppression of Helicobacter pylori-induced angiogenesis. Gut 2006; 55: 26-33. [ Links ]
41. Tuccillo C, Cuomo A, Rocco A, Martinelli E, Staibano S, Mascolo M, et al. Vascular endothelial growth factor and neo-angiogenesis in H. pylori gastritis in humans. J Pathol 2005; 207: 277-84. [ Links ]
42. Konturek PC, Kania J, Kukharsky V, Ocker S, Hahn EG, Konturek SJ. Influence of gastrin on the expression of cyclooxygenase-2, hepatocyte growth factor and apoptosis-related proteins in gastric epithelial cells. J Physiol Pharmacol 2003; 54: 17-32. [ Links ]
43. Abdalla SI, Lao-Sirieix P, Novelli MR, Lovat LB, Sanderson IR, Fitzgerald RC. Gastrin-induced cyclooxygenase-2 expression in Barrett's carcinogenesis. Clin Cancer Res 2004; 10: 4784-92. [ Links ]
44. Caputo R, Tuccillo C, Manzo BA, Zarrilli R, Tortora G, Blanco C del V, et al. Helicobacter pylori VacA toxin up-regulates vascular endothelial growth factor expression in MKN 28 gastric cells through an epidermal growth factor receptor-, cyclooxygenase-2-dependent mechanism. Clin Cancer Res 2003; 9: 2015-21. [ Links ]
45. Huang SP, Wu MS, Shun CT, Wang HP, Hsieh CY, Kuo ML, et al. Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma. J Biomed Sci 2005; 12: 229-41. [ Links ]
46. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-76. [ Links ]
47. Battegay EJ. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 1995; 73: 333-46. [ Links ]
48. Jones MK, Kawanaka H, Baatar D, Szabo IL, Tsugawa K, Pai R, et al. Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1. Gastroenterology 2001; 121: 1040-7. [ Links ]
49. Ernst H, Konturek PC, Hahn EG, Stosiek HP, Brzozowski T, Konturek SJ. Effect of local injection with basic fibroblast growth factor (BFGF) and neutralizing antibody to BFGF on gastric ulcer healing, gastric secretion, angiogenesis and gastric blood flow. J Physiol Pharmacol 2001; 52: 377-90. [ Links ]
50. Szabo S, Khomenko T, Gombos Z, Deng XM, Jadus MR, Yoshida M. Review article: transcription factors and growth factors in ulcer healing. Aliment Pharmacol Ther 2000; 14 (Supl. 1): 33-43. [ Links ]
51. Szabo S, Vincze A. Growth factors in ulcer healing: lessons from recent studies. J Physiol Paris 2000; 94: 77-81. [ Links ]
52. Brzozowski T, Konturek PC, Konturek SJ, Kwiecien S, Pajdo R, Karczewska E, et al. Water extracts of Helicobacter pylori delay healing of chronic gastric ulcers in rats: role of cytokines and gastrin-somatostatin link. Digestion 1999; 60: 22-33. [ Links ]
53. Gunawan E, Tsuji S, Tsujii M, Kimura A, Sun WH, Sawaoka H, et al. Influences of Helicobacter pylori on gastric angiogenesis and ulcer healing in mice. J Gastroenterol Hepatol 2002; 17: 960-5. [ Links ]
54. Brzozowski T, Konturek PC, Konturek SJ, Karczewska E, Pajdo R, Stachura J, et al. Gastric secretion and ulcer healing in mouse stomach infected with cytotoxin expressing strain of Helicobacter pylori. J Physiol Pharmacol 1998; 49: 387-403. [ Links ]
55. Calam J. Clinical science of Helicobacter pylori infection: ulcers and NSAIDs. Br Med Bull 1998; 54: 55-62. [ Links ]
56. Akimoto M, Hashimoto H, Shigemoto M, Yamashita K, Yokoyama I. Changes of nitric oxide and growth factors during gastric ulcer healing. J Cardiovasc Pharmacol 2000; 36: S282-5. [ Links ]
57. Mueller A, Merrell DS, Grimm J, Falkow S. Profiling of microdissected gastric epithelial cells reveals a cell type-specific response to Helicobacter pylori infection. Gastroenterology 2004; 127: 1446-62. [ Links ]
58. Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ 2004: 327-49. [ Links ]
59. Sasaki A, Kitadai Y, Ito M, Sumii M, Tanaka S, Yoshihara M, et al. Helicobacter pylori infection influences tumor growth of human gastric carcinomas. Scand J Gastroenterol 2003; 38: 153-8. [ Links ]
60. Iwamoto J, Mizokami Y, Takahashi K, Nakajima K, Ohtsubo T, Miura S, et al. Expressions of urokinase-type plasminogen activator, its receptor and plasminogen activator inhibitor-1 in gastric cancer cells and effects of Helicobacter pylori. Scand J Gastroenterol 2005; 40: 783-93. [ Links ]
61. Konturek SJ, Starzynska T, Konturek PC, Karczewska E, Marlicz K, Lawniczak M, et al. Helicobacter pylori and CagA status, serum gastrin, interleukin-8 and gastric acid secretion in gastric cancer. Scand J Gastroenterol 2002; 37: 891-8. [ Links ]
62. Katano M, Nakamura M, Fujimoto K, Miyazaki K, Morisaki T. Prognostic value of platelet-derived growth factor-A (PDGF-A) in gastric carcinoma. Ann Surg 1998; 227: 365-71. [ Links ]
63. Franceschi F, Genta RM, Gasbarrini A, Gentiloni Silveri N, Gasbarrini G, Sepulveda AR. Helicobacter pylori infection and expression of the angiogenic factor platelet-derived endothelial cell growth factor by pre-neoplastic gastric mucosal lesions and gastric carcinoma. Dig Liver Dis 2002; 34: 621-5. [ Links ]
64. Shun CT, Wu MS, Huang SP, Wang HP, Chuang SM, Lin JT. Cyclooxygenase-2 expression correlates with nuclear p53 accumulation in gastric carcinoma. Hepatogastroenterology 2003; 50: 988-92. [ Links ]
65. Huang SP, Wu MS, Shun CT, Wang HP, Lin JT. Tumor angiogenesis increases with nuclear p53 accumulation in gastric carcinoma. Hepatogastroenterology 2002; 49: 1453-6. [ Links ]
66. Tian X, Song S, Wu J, Meng L, Dong Z, Shou C. Vascular endothelial growth factor: acting as an autocrine growth factor for human gastric adenocarcinoma cell MGC803. Biochem Biophys Res Commun 2001; 286: 505-12. [ Links ]
67. Yamamoto S, Yasui W, Kitadai Y, Yokozaki H, Haruma K, Kajiyama G, et al. Expression of vascular endothelial growth factor in human gastric carcinomas. Pathol Int 1998; 48: 499-506. [ Links ]
68. Church RD, Fleshman JW, McLeod HL. Cyclo-oxygenase 2 inhibition in colorectal cancer therapy. Br J Surg 2003; 90: 1055-67. [ Links ]
69. Innocenti M, Thoreson AC, Ferrero RL, Stromberg E, Bolin I, Eriksson L, et al. Helicobacter pylori-induced activation of human endothelial cells. Infect Immun 2002; 70: 4581-90. [ Links ]
70. Cox JM, Clayton CL, Tomita T, Wallace DM, Robinson PA, Crabtree JE. cDNA array analysis of cag pathogenicity island-associated Helicobacter pylori epithelial cell response genes. Infect Immun 2001; 69: 6970-80. [ Links ]
71. Ernst P. Review article: the role of inflammation in the pathogenesis of gastric cancer. Aliment Pharmacol Ther 1999; 13 (Supl. 1): 13-8. [ Links ]
72. Strowski MZ, Cramer T, Schafer G, Juttner S, Walduck A, Schipani E, et al. Helicobacter pylori stimulates host vascular endothelial growth factor-A (vegf-A) gene expression via MEK/ERK-dependent activation of Sp1 and Sp3. FASEB J 2004; 18: 218-20. [ Links ]
73. Akimoto M, Hashimoto H, Shigemoto M, Maeda A, Yamashita K. Effects of antisecretory agents on angiogenesis during healing of gastric ulcers. J Gastroenterol 2005; 40: 685-9. [ Links ]
74. Gisbert JP, Pajares JM. Systematic review and meta-analysis: is 1-week proton pump inhibitor-based triple therapy sufficient to heal peptic ulcer? Aliment Pharmacol Ther 2005; 21: 795-804. [ Links ]
]]>
Correspondence: Recibido: 28-11-05
Aceptado: 13-12-05