Hypoxia,hypoxia-inducible factor-1α and vascular endothelial growth factor in a murine model of Schistosoma mansoni infection

Schistosomiasis mansoni is a chronic parasitic disease where much of the symptomatology is attributed to granuloma formation, an immunopathological reaction against Schistosoma eggs. To more clearly understand the immunopathology of schistosomiasis, the tissue microenvironment generated by S. mansoni infected mice was investigated. Using the hypoxia marker pimonidazole, we provide immunohistochemical evidence that hypoxia occurred in inflammatory cells infiltrated around the eggs and cells surrounding granulomas in the liver, intestine, spleen and lungs of infected mice. Hypoxia-inducible factor-1α (HIF-1α) was mainly expressed in inflammatory cells surrounding the eggs and in hepatocytes surrounding cellular and fibrocellular granulomas in infected mouse liver. HIF-1α expression was also verified in granulomas in the other tissues tested (intestine, spleen and lungs). Vascular endothelial growth factor (VEGF) expression was observed in the extracellular space surrounding inflammatory cells in liver granuloma. The VEGF expression pattern verified in infected mouse liver was very similar to that observed in the other tissues tested. A strong positive correlation occurred between pimonidazole binding and HIF-1α and VEGF expression in the tissues tested, except for lung. This work is the first evidence that infection by a helminth parasite, S. mansoni, produces a hypoxic tissue microenvironment and induces HIF-1α and VEGF expression.     

The role of tumour necrosis factor-α and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity

Chronic inflammatory diseases are characterised by systemically elevated levels of tumour necrosis factor (TNF)-α, a proinflammatory cytokine with pleiotropic downstream effects. We have previously demonstrated increased genotoxicity in peripheral leukocytes and various tissues in models of intestinal inflammation. In the present study, we asked whether TNF-α is sufficient to induce DNA damage systemically, as observed in intestinal inflammation, and whether tumour necrosis factor receptor (TNFR) signalling would be necessary for the resultant genotoxicity. In the wild-type mice, 500 ng per mouse of TNF-α was sufficient to induce DNA damage to multiple cell types and organs 1-h post-administration. Primary splenic T cells manifested TNF-α-induced DNA damage in the absence of other cell types. Furthermore, TNFR1(-/-)TNFR2(-/-) mice demonstrated decreased systemic DNA damage in a model of intestinal inflammation and after TNF-α injection versus wild-type mice, indicating the necessity of TNFR signalling. Nuclear factor (NF)-κB inhibitors were also able to decrease damage induced by TNF-α injection in wild-type mice. When TNF-α administration was combined with interleukin (IL)-1β, another proinflammatory cytokine, DNA damage persisted for up to 24 h. When combined with IL-10, an anti-inflammatory cytokine, decreased genotoxicity was observed in vivo and in vitro. TNF-α/TNFR-mediated signalling is therefore sufficient and plays a large role in mediating DNA damage to various cell types, subject to modulation by other cytokines and their mediators.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Levels and patterns of expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, glucose transporter-1 and CD105 in adenoid cystic carcinomas with high-grade transformation

Costa A F, Tasso M G, Mariano F V, Soares A B, Chone C T, Crespo A N, Fresno M F, Llorente J L, Suárez C, de Araújo V C, Hermsen M & Altemani A
(2012) Histopathology  60, 816–837 Levels and patterns of expression of hypoxia‐inducible factor‐1α, vascular endothelial growth factor, glucose transporter‐1 and CD105 in adenoid cystic carcinomas with high‐grade transformation Aims: To compare the expression of proteins regulated by hypoxia between adenoid cystic carcinoma (ACC) with and without high‐grade transformation (HGT). Methods and results: In eight ACC–HGT and 18 ACC without HGT, expression of hypoxia‐inducible factor‐1 (HIF‐1α), vascular endothelial growth factor (VEGF), glucose transporter‐1 (GLUT‐1) and microvascular density (MVD) by CD105 (a hypoxia‐inducible protein expressed in angiogenic endothelial cells) was determined. Expression levels of HIF‐1α and VEGF as well as CD105‐MVD did not differ significantly between: (i) transformed and conventional areas (TA and CA, respectively) of ACC–HGT, (ii) CA and ordinary ACC. HIF‐1α was detected in 100% of cases and presented a diffuse expression pattern. No significant association was found between levels of HIF‐1α expression and tumour size, metastasis and recurrence. GLUT‐1 showed a prostromal expression pattern and was observed exclusively in TA (three of six cases) and in only three of 14 ACC. Conclusions: Both the absence of significant alterations in levels of expression of HIF‐1α, VEGF and CD105 and the patterns of expression of HIF‐1α and GLUT‐1 suggest that hypoxia may not play a key role in the process of high‐grade transformation of ACC. Although HIF‐1α expression is a common finding in ACC, it cannot be used as a marker of tumour aggressiveness.     

Vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1ɑ) in lacrimal gland Adenoid cystic carcinoma: Correlation with clinical outcome

PurposeVEGF and HIF-1α are important regulators of angiogenesis, overexpressed in various tumors. Lacrimal gland Adenoid cystic carcinoma (ACC) is a malignant tumor whose angiogenic properties remain unexplored. This study was designed to evaluate the expression of HIF-1α and VEGF in lacrimal gland ACC.MethodsVEGF and HIF-1α immunoexpression was undertaken in 30 lacrimal gland ACC cases. mRNA expression of VEGF and HIF-1α was analysed in 17 cases by quantitative real time PCR. The results obtained were correlated with clinicopathological features and survival of the patients to determine the prognostic significance.ResultsImmunoexpression of HIF-1α and VEGF was seen in 36.6% and 46.6% ACC cases. HIF-1α expression showed significant association with advanced T-stage (P = 0.001) and VEGF with intracranial extension (P = 0.014) and solid histological pattern (P = 0.045). HIF-1α mRNA expression was seen in 29.4% cases and showed significant association with perineural invasion (P = 0.027). Recurrence occurred in 60%, distant metastasis in 20% and death in 20% cases. Survival analysis revealed that patients with HIF-1α, VEGF immunoexpression, solid histological pattern, perineural invasion, bone erosion, intracranial extension, metastasis, advanced T-stage, and exenteration had poor survival. On multivariate analysis VEGF immunoexpression (hazard ratio, 16.785; 95% confidence interval, 1.872–150.495; P = 0.012) was the most significant poor prognostic factor.ConclusionsThis study demonstrates that VEGF is a potential predictor for poor clinical outcome in lacrimal gland Adenoid cystic carcinoma.