p53, vessel count,and vascular endothelial growth factor expression in human colon cancer

We previously demonstrated an association between vascular endothelial growth factor (VEGF), vessel counts and metastasis in human colon cancer specimens. Mutant p53 has been implicated in the regulation of angiogenesis. Immuno-histochemical detection of p53 protein has been associated with p53 gene mutations. We sought to determine a correlation between p53 protein detection (i.e., mutant p53), VEGF expression and vessel counts in human colon cancer. Surgical specimens from 93 patients with colon cancer were stained immuno-histochemically for p53, VEGF and factor VIII. Vessel counts were greater in metastatic tumors than in non-metastatic tumors and adenomas, and greater in non-metastatic tumors than in adenomas. Vessel counts were highest in tumors with the highest VEGF expression. Vessel counts and VEGF expression were greater in p53-positive tumors than in p53-negative tumors. p53 expression correlated with both VEGF expression and vessel count. The association of p53 expression with VEGF and vessel count suggests that the poor prognosis associated with p53 mutations may be due, in part, to the role of mutant p53 in promoting angiogenesis. Int. J. Cancer (Pred. Oncol.) 79:34–38, 1998. © 1998 Wiley-Liss, Inc.     

Expression of vascular endothelial growth factor in renal cell carcinoma and the relation to angiogenesis and p53 protein expression

BACKGROUND AND OBJECTIVES: Vascular endothelial growth factor (VEGF) seems to play an important role in tumor angiogenesis. The tumor-suppressor gene p53 has been thought to regulate VEGF expression. We investigated the effect of VEGF expression on renal cell carcinoma (RCC) and the correlation between the expression of VEGF and tumor angiogenesis and p53 protein expression. METHODS: Sixty-two RCCs were examined by immunohistochemical studies with anti-VEGF, anti-p53, and anti-CD34 antibodies. RESULTS: Forty tumors (80.6%) were classified as VEGF positive, and 28 tumors (45.2%) were positive for p53 protein. The microvessel density was 75.3 +/- 33.5. A significant correlation was found between VEGF expression and both the nuclear grade (P < 0.05) and the TNM stage (P < 0.05). The tumors with VEGF expression had a significantly higher microvessel density than those without VEGF expression (P < 0.01). There was no statistically significant correlation between p53 protein and VEGF expression. No statistically significant differences in survival were found to be associated with microvessel density, VEGF expression or p53 protein expression. By using multivariate survival analyses, nuclear grade (P < 0.05) and TNM stage (P < 0.05) were the only independent prognostic factors. CONCLUSIONS: Our data do not show a direct regulation of VEGF expression by p53. We suggest that VEGF expression plays a role in the promotion of angiogenesis in RCC.     

Expression of inducible nitric oxide synthase is significantly correlated with expression of vascular endothelial growth factor and dendritic cell infiltration in patients with advanced gastric carcinoma

OBJECTIVE: Nitric oxide (NO) is a product of L-arginine to L-citrulline conversion by nitric oxide synthase (NOS). The inducible form of NOS (iNOS) is one of three classes of NOS and the strongest producer of NO. It has been reported that NO correlates with angiogenesis and immune responses in some types of cancer, however, the correlations between iNOS expression, angiogenesis, and immune responses are still unclear in gastric carcinoma. METHODS: iNOS expression was determined in 135 gastric cancer patients by immunohistochemical procedures and compared with the expression of vascular endothelial growth factor (VEGF), microvessel (MV) density, and dendritic cell (DC) infiltration to evaluate the effect of iNOS on angiogenesis and immune responses in gastric carcinoma. RESULTS: iNOS expression was detected in 106 (78.5%) of 135 cases. There was a close correlation between iNOS expression and VEGF expression, a correlation with MV density and an inverse correlation with DC infiltration. There was no correlation between iNOS and p53 expression. The prognoses of patients whose tumors expressed iNOS were significantly worse than those of patients whose tumors did not express iNOS. Multivariate analysis indicated iNOS expression was an independent prognostic factor. CONCLUSION: iNOS might be associated with tumor progression by stimulating angiogenesis and suppressing immune responses in gastric carcinoma.     

Ras homolog gene family, member A promotes p53 degradation and vascular endothelial growth factor-dependent angiogenesis through an interaction with murine double minute 2 under hypoxic conditions

BACKGROUND:

Tumor neovascularization (TNV) is a common pathologic basis for malignant growth and metastasis. However, the mechanism of TNV pathogenesis is not fully understood. Ras homolog gene family, member A (RhoA), a Rho guanosine triphosphatase (GTPase) family member, may be involved in a hypoxia‐induced vascular endothelial growth factor (VEGF) pathway that regulates TNV angiogenesis through an unclear mechanism.

METHODS:

The regulation of RhoA on p53, the p53 binding protein homolog murine double minute 2 (MDM2), and VEGF was analyzed in hypoxic MCF‐7 cells using Western blot analysis, real‐time polymerase chain reaction (PCR) analysis, coimmunoprecipitation, and immunofluorescence staining assays. Changes in proliferation, invasion, migration, stress fiber formation, and tube formation were detected in an MCF‐7 human umbilical vein endothelial cell (HUVEC) coculture system. Correlations of RhoA expression with MDM2, wild‐type p53 (wt‐p53), and VEGF expression in breast cancer tissues and relations between RhoA and breast cancer clinical features were analyzed by immunohistochemistry.

RESULTS:

Activated RhoA down‐regulated p53 protein, which increased VEGF expression in hypoxic MCF‐7 cells; whereas p53 messenger RNA levels were not altered. In addition, the ubiquitin‐mediated degradation of p53 was enhanced by active RhoA. RhoA and MDM2 colocalized in the cytoplasm of hypoxic MCF‐7 cells and interacted with each other physically. Furthermore, nutlin‐3, a specific MDM2 inhibitor, was capable of reducing activated RhoA‐induced p53 protein stability and attenuating VEGF accumulation. In an MCF‐7‐HUVEC coculture system, nutlin‐3 effectively inhibited HUVEC proliferation, invasion, migration, stress fiber formation, and tube formation mediated by activated RhoA under hypoxic conditions. Data from 129 clinical breast cancer specimens with wt‐p53 revealed that high RhoA expression was correlated with high MDM2 expression, low wt‐p53 expression, and high VEGF expression.

CONCLUSIONS:

The current data suggested that activated RhoA promotes VEGF expression and hypoxia‐induced angiogenesis through the up‐regulation of MDM2 to decrease p53 stability. Cancer 2012. © 2012 American Cancer Society.     

乳腺癌组织中p53和VEGF及NOS的表达及临床意义

目的探讨p53、VEGF（血管生成因子）及NOS（一氧化氮合酶）的表达与乳腺癌内血管生成和预后的关系。方法应用免疫组化SP法检测49例乳腺癌的p53、iNOS、eNOS及VEGF,并与临床病例及预后进行分析,同时进行随访。结果乳腺癌组织中p53、iNOS、eNOS及VEGF阳性率分别为59.2%、71.4%、57.1%和49.0%。p53、NOS及VEGF均与乳腺癌临床分期、术后生存时间有密切关系（P〈0.05）,但与组织学类型无关（P〉0.05）;iNOS与乳腺癌病理分级有密切关系;p53、NOS与VEGF的表达呈正相关（P〈0.05）。结论 p53、iNOS及VEGF的表达水平与乳腺癌的进展、术后生存时间有密切关系,提示p53、NOS及VEGF可作为患者预后评估的重要指标。     

Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications

Background  

Hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) are frequently overexpressed in numerous types of cancers and are known to be important regulators of angiogenesis. Until now, few studies have been carried out to investigate the prognostic role of these factors in solid tumors, especially in colorectal cancer (CRC). The purpose of this study was to evaluate the expression of HIF-1α and VEGF in CRC tissues, and to analyze the association of these two factors with several clinical and pathological characteristics, and patients' survival.     

The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers

Tumor angiogenesis is an essential step for tumor cell growth, progression and metastasis. Vascular endothelial growth factor (VEGF) is mitogen specific for endothelial cells, and therefore is believed to play a key role in tumor angiogenesis. However, the mechanisms underlying the regulation of VEGF expression remain virtually unknown and the only major regulator of VEGF expression has been reported to be hypoxia. Recently, it was reported that a mutant p53 in#duced the expression of VEGF mRNA, and that wild-type p53 down-regulated endogenous VEGF mRNA levels. In contrast, it has also been reported that mutant ras oncogenes were associated with the marked up-regulation of VEGF in transformed epithelial cells. Based on these results, we performed a retrospective study of the p53 and K-ras genes status and VEGF gene expression in the tumor tissues from 181 patients with non-small cell lung cancer using SSCP, sequencing, RT-PCR and immunohistochemical techniques. Forty-six carcinomas (25.4%) were evaluated as having high VEGF expression, and 135 tumors (74.6%) had low VEGF expression. Of the 181 primary NSCLC studied, 63 carcinomas (34.8%) contained mutations of p53, whereas only 14 carcinomas (7.7%) had mutations of K-ras. There were no significant relationships between VEGF expression and p53 status or each mutant exon of p53. In contrast, a significant difference was found between VEGF expression and K-ras status. Of the 14 tumors with mutant K-ras genes, 7 cases (50.0%) had high VEGF expression whereas only 39 of the 167 tumors with wild-type K-ras (23.4%) had high VEGF expression (p=0.0278). The mean VEGF conservation rate for the 14 tumors with mutant K-ras genes was 0.77+/-0.58 and the rate of the 167 tumors with wild-type K-ras genes was 0.49+/-0.46 (p=0. 0350). Moreover, the overall survival rate of patients with high VEGF expression was lower than patients with low VEGF expression (45.7% vs 60.7%, p=0.0419). On the other hand, there was no significant difference in the overall survival rate between patients with a mutant p53 and those with a wild-type p53; there was also no difference in the overall survival between patients with a mutant K-ras and those with a wild-type K-ras. The Cox regression model analysis indicated that three variables, VEGF status, K-ras status and nodal status, were found to be significant indicators for prognosis (p=0.0236, p=0.0172 and p<0.0001, respectively). Our data suggest that a high expression of VEGF in lung cancer may be associated with a poor prognosis. This may be a clue to improving lung cancer diagnoses and therapies aimed at inhibiting tumor angiogenesis due to VEGF.     

Insulin-like growth factor-I receptor blockade reduces tumor angiogenesis and enhances the effects of bevacizumab for a human gastric cancer cell line, MKN45

BACKGROUND:

Insulin‐like growth factor (IGF)‐I receptor (IGF‐IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal cancers. The authors previously reported the success of therapy for gastrointestinal cancers using adenoviruses that expressed dominant‐negative IGF‐IR (IGF‐IR/dn). In addition, it has been demonstrated that IGF‐IR signaling affects vascular endothelial growth factor (VEGF) expression in some other types of tumors. The objective of the current study was to evaluate this interaction by studying the roles of IGF‐IR in tumor angiogenesis and lymphangiogenesis and their implications for targeted therapy in gastric cancer.

METHODS:

The impact of IGF signals on the expression of VEGF‐A and VEGF‐C in a human gastric cancer cell, MKN45, and vascular formation were assessed. The effects of IGF‐IR/dn with or without bevacizumab on angiogenesis, lymphangiogenesis, and tumor suppression in mouse xenografts were assessed.

RESULTS:

IGFs induced the expression of VEGF ligands and up‐regulated in vitro vascular vessel formation. IGF‐IR/dn reduced VEGF expression, reduced the activation of both protein kinase B (Akt) and mitogen‐activated protein kinase (MAPK), and reduced vascular formation, indicating that IGF‐IR/dn inhibited tumor growth in mice by inhibiting both angiogenesis and lymphangiogenesis. However, IGF‐IR/dn did not affect either blood sugar or body weight in these mice. The combination of IGF‐IR/dn and bevacizumab was highly effective against these xenograft tumors, and only this combination resulted in the complete regression of 43% of tumors, reduced the expression of VEGF, and induced apoptosis.

CONCLUSIONS:

The current results indicated that IGF‐IR is involved in angiogenesis and lymphangiogenesis through the modulation of VEGF ligand expression in the gastric cancer cell line MKN45. Targeting IGF‐IR in combination with agents that block the VEGF pathway may have therapeutic utility for gastric cancer therapy. Cancer 2011. © 2011 American Cancer Society.     

TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients

Background  

Angiogenesis appears to play an important role in ovarian cancer. Vascular endothelial growth factor (VEGF) has recently been implicated as a therapeutic target in ovarian cancer. The tissue inhibitor of metalloproteinase 1 (TIMP-1) is involved in tissue invasion and angiogenesis. The application of serum TIMP-1 and VEGF to monitor primary therapy and predict clinical outcome of patients with ovarian cancer is unclear.     

The role of tumour-derived iNOS in tumour progression and angiogenesis

Background:

Progressive tumour growth is dependent on the development of a functional tumour vasculature and highly regulated by growth factors and cytokines. Nitric oxide (NO) is a free radical, produced both by tumour and host cells, and functions as a signalling molecule downstream of several angiogenic factors. Both pro- and antitumourigenic properties have been attributed to NO.

Methods:

The expression of the inducible isoform of NO synthase (iNOS) was knocked down in the C6 glioma cell line using constitutive expression of antisense RNA, and the effect of tumour-derived NO on tumour progression and angiogenesis was investigated.

Results:

Tumours in which iNOS expression was decreased displayed significantly reduced growth rates compared with tumours derived from parental C6 cells. Quantitative non-invasive magnetic resonance imaging and fluorescence microscopy of tumour uptake of Hoechst 33342, and haematoxylin and eosin staining, revealed significantly impaired vascular development and function in antisense iNOS tumours compared with control in vivo, primarily associated with the more necrotic tumour core. Decreased iNOS expression had no effect on tumour VEGF expression.

Conclusion:

Nitric oxide derived from tumour iNOS is an important modulator of tumour progression and angiogenesis in C6 gliomas and further supports the therapeutic strategy of inhibiting iNOS for the treatment of cancer.     

Expression of vascular endothelial growth factor,mitogen-activated protein kinase and p53 in human colorectal cancer

BACKGROUND: VEGF is a growth factor involved in the regulation of angiogenesis, a process that plays a central role in tumor growth. It has been suggested that mutations of p53 and activation of the Ras/MAPK pathway may contribute to the up-regulation of VEGF expression and induction of angiogenesis. PATIENTS AND METHODS: We explored the expression of p53 and VEGF and p44MAPK phosphorylation in 43 human colorectal carcinomas, as well as in peritumoral mucosas, and in normal mucosas in order to establish a correlation between VEGF expression and either mutations of p53 or phosphorylation of p44MAPK. Overexpression of p53 in tumor tissues was interpreted as evidence of mutations. RESULTS: p53 was overexpressed in 22 out of 43 tumors; MAPK was phosphorylated in 25 out of 43 cases whereas only 4 out of 22 peritumoral mucosas showed a moderate phosphorylation of p44MAPK VEGF was up-regulated in 22 out of 43 tumors, moderately expressed in 4 out of 22 peritumoral mucosas and not detectable in normal mucosa. Immunohistochemical analysis showed the presence of a phosphorylated form of p44 MAPK only in neoplastic cells. Statistical analysis demonstrated a significant correlation between p53 and VEGF expression (p<0.03) as well as between VEGF expression and p44 MAPK phosphorylation (p<0.002). CONCLUSION: These data suggest that mutations of p53 and activation of the Ras/MAPK pathway may play a role in the induction of VEGF expression in human colorectal cancer.     

诱导型一氧化氮合酶在反应性及肿瘤性星形胶质细胞中的表达

目的:探讨诱导型一氧化氮合酶(iNOS)、突变型p53及VEGF在反应性及肿瘤性星形胶质细胞中的表达及其在星形胶质细胞瘤发生发展、血管形成中的作用。方法:应用组织芯片及免疫组织化学技术检测12例正常脑组织、49例星形细胞反应性增生、49例低级别(I-II级)及50例高级别(III-IV级)星形胶质细胞瘤中iNOS、突变型p53、VEGF表达情况。结果:在正常脑组织中三者均为阴性表达;从星形细胞反应性增生组到高级别星形细胞瘤组,三者的阳性表达率均呈升高趋势,分别为:iNOS:28.89%(13/45),57.75%(27/47),81.63%(40/49);p53:23.81%(10/42),53.66%(22/41),79.55%(35/44);VEGF:22.73%(10/44),44.19%(19/43),69.77%(30/43),并且三者在星形细胞反应性增生组及低级别星形胶质细胞瘤组中的表达差异显著(P<0.05);各实验组中iNOS与p53表达水平一致性较好,具有明显的相关性(P<0.05);而iNOS与VEGF在低级别及高级别星形胶质细胞瘤组中表达水平具有较好的一致性及明显的相关性(P<0.05),在反应性增生组表达无相关性(P>0.05)。结论:iNOS、突变型p53及VEGF的过表达是胶质瘤发生的早期分子生物学事件,三者相互作用共同促进星形胶质细胞瘤的发生发展及血管的形成;单一或联合检测可能有助于星形细胞反应性增生及低级别星形细胞瘤的鉴别诊断。     

Effects of COX-2 inhibition on expression of vascular endothelial growth factor and interleukin-8 in lung cancer cells

Background  

Cyclooxygenase (COX)-2 has been implicated in tumour progression, angiogenesis and metastasis in non-small cell lung cancer (NSCLC). We speculated that inhibition of COX-2 activity might reduce expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in lung cancer cells.     

Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways

Purpose

We previously reported that barbigerone (BA), an isoflavone isolated from Suberect Spatholobus, exhibited inhibitory effects on proliferation of many cancer cell lines in vitro. The objective of this study was to explore whether BA could effectively suppress tumor angiogenesis and tumor growth.

Methods

Zebrafish model and Matrigel assay were performed to access the anti-angiogenesis effects of BA. A549 and SPC-A1 tumor xenografts in mice models were used to examine the antitumor activity of BA. The anti-angiogenic effects and underlying mechanisms were also investigated using human umbilical vein endothelial cells (HUVECs) and A549 cells.

Results

In zebrafish model, 2.5???mol/L of BA significantly inhibited angiogenesis. Intravenous administration of BA effectively inhibited the tumor growth of A549 and SPC-A1 xenograft models in mice. The anti-angiogenic effect was indicated by CD31 immunohistochemical staining, Matrigel plug assay, and mouse aortic ring assay. BA could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tuber formation of HUVECs in a dose-dependent manner, suggesting that BA inhibited tumorigenesis by targeting angiogenesis. Western blots revealed that BA directly inhibited the phosphorylation of VEGFR2, followed by inhibiting the activations of its downstream protein kinases, including ERK, p38, FAK, AKT, and expression of iNOS, but had no effect on COX2. Additionally, BA could also down-regulate VEGF secretion in A549 cancer cells, which may correlate with the suppression of ERK, AKT activation, indicating that BA inhibits tumor angiogenesis and tumor growth through VEGFR2 signaling pathways.

Conclusions

These findings suggest that BA may be a novel candidate in inhibiting tumor angiogenesis and NSCLC tumor growth.     

<Emphasis Type="Italic">In vivo</Emphasis> measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients

Background  

Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue.     

乳腺肿瘤癌变过程中血管生成与VEGF表达相关性研究

Objective  

The aim of the study was to detect the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in breast benign tissues and malignant tumors to clarify the relationship between VEGF expression, angiogenesis and breast carcinoma occurrence.     

Analysis of p53 and vascular endothelial growth factor and its receptor Flk-1 expression in human gallbladder carcinoma for determination of tumor vascularity

Objective： More and more studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. There is some evidence that p53 mutations cause overexpression of vascular endothelial growth factor （VEGF）, a major inducer of angiogenesis. In addition, there is now growing evidence that several malignancies express receptors for VEGF, especially receptor-2 （Flk-1/KDR）, raising the possibility that the VEGF/VEGF receptor axis may serve as an autocrine pathway in some tumors. We examined the expression of p53 and VEGF and its receptor FlK-1, together with microvessel count （MVC） to investigate the role of VEGF as an angiogenic marker, the presence of VEGF/Flk-1 axis, and the possible role of p53 in the regulation of angiogenesis in human gallbladder carcinoma. Methods： Surgically resected specimens of 49 gallbladder carcinomas were studied by immunohistochemical staining for p53 protein, VEGF, Flk-1 and factor VIII-related antigen. VEGF expression and mutant p53 expression were then correlated with Nevin stage, differentiation grade, MVC, and lymph nodes metastasis. Results： VEGF, Flk-1 expression and positive p53 protein accumulation and BEGF expression was found in 63.3%, 67.3% and 61.2% of tumors, respectively. The expression of Flk-1 was markedly correlated with VEGF （P〈0.05）. The percentage of the patients with both positive VEGF and Flk-1 expressions was 49.0% （24/49）, and their MVC value was markedly higher than that of the others. P53 and VEGF staining status were identical in 55.1% of tumors. The Nevin staging of p53-or VEGF-positive tumors was significantly later than negative tumors. The MVC in p53-or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-negative tumors was significantly lower than that in the other subgroups. Conclusion： The findings suggest the VEGF/F1 k- 1 axis and p53-VEGF pathway tumor angiogenesis in human gallbladder carcinoma. Combined analysis of p53 and VEGF expression, plus Flk-1 and VEGF expression might be useful for predicting the tumor vacularity and biologic behaviors of gallbladder cancer.     

Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer

Objective

EphA2 overexpression predicts poor prognosis in endometrial cancer. To explore mechanisms for this association and assess its potential as therapeutic target, the relationship of EphA2 expression to markers of angiogenesis was examined using patient samples and an orthotopic mouse model of uterine cancer.

Results

Of 85 EE C samples, EphA2 was overexpressed in 47% of tumors and was significantly associated with high VEGF expression (p = 0.001) and high MVD counts (p = 0.02). High EphA2 expression, high VEGF expression and high MVD counts were significantly associated with shorter disease-specific survival. EA5 led to decrease in EphA2 expression and phosphorylation in vitro. In the murine model, while EA5 (33–88%) and docetaxel (23–55%) individually led to tumor inhibition over controls, combination therapy had the greatest efficacy (78–92%, p < 0.001). In treated tumors, combination therapy resulted in significant reduction in MVD counts, percent proliferation and apoptosis over controls.

Experimental Design

Expression of EphA2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, vascular endothelial growth factor (VEGF) and microvessel density (MVD) was evaluated using immunohistochemistry in 85 endometrioid endometrial adenocarcinomas (EEC) by two independent investigators. Results were correlated with clinicopathological characteristics. The effect of EphA2-agonist monoclonal antibody EA5, alone or in combination with docetaxel was studied in vitro and in vivo. Samples were analyzed for markers of angiogenesis, proliferation and apoptosis.

Conclusions

EphA2 overexpression is associated with markers of angiogenesis and is predictive of poor clinical outcome. EphA2 targeted therapy reduces angiogenesis and tumor growth in orthotopic uterine cancer models and should be considered for future clinical trials.Key words: endometrial cancer, EphA2, VEGF, microvessel density, angiogenesis     

PTEN and rapamycin inhibiting the growth of K562 cells through regulating mTOR signaling pathway

Background

Clear cell renal cell carcinoma (ccRCC) is the most frequently encountered tumor in the adult kidney. Many factors are known to take part in the development and progression of this tumor. Nuclear factor kappa B (NF-κB) is a family of the genes that includes five members acting in events such as inflammation and apoptosis. In this study, the role of NF-κB (p50 subunit) in ccRCC and its relation to angiogenesis and apoptosis were investigated.

Methods

Formalin-fixed and paraffin embedded tissue blocks from 40 patients with ccRCC were studied. Expressions of NF-κB (p50), VEGF, EGFR, bc1-2 and p53 were detected immunohistochemically. The relationship of NF-κB with these markers and clinicopathological findings were evaluated.

Results

The expression of NF-κB was detected in 35 (85%), VEGF in 37 (92.5%), EGFR in 38 (95%), bc1-2 in 33 (82.5%) and p53 in 13 (32.5%) of 40 ccRCC patients. Statistical analyses revealed a significant relation between NF-κB expression and VEGF (p = 0.001), EGFR (p = 0.004), bc1-2 (p = 0.010) and p53 (p = 0.037). There was no significant correlation between NF-κB and such parameters as tumor grade, stage, age and sex.

Conclusion

The results of this study indicated that in ccRCC cases NF-κB was associated with markers of angiogenesis and apoptosis such as VEGF, EGFR, bc1-2 and p53. In addition, the results did not only suggest a close relationship between NF-κB and VEGF, EGFR, bc1-2 and p53 in ccRCC, but also indicate that NF-κB was a potential therapeutic target in the treatment of ccRCC resistant to chemotherapy.