Hypoxia-Inducible Factor 1α Expression in Renal Cell Carcinoma Analyzed by Tissue Microarray

Lidgren, Anders; Hedberg, Ylva; Grankvist, Kjell; Rasmuson, Torgny; Bergh, Anders; Ljungberg, Börje

doi:10.1016/j.eururo.2006.05.043

Cited by 68 publications

(43 citation statements)

References 21 publications

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“…Based on the HIF-1α mRNA positive cell number (the cytoplasm or nucleus of the cells appeared brown in color), the criteria were set as follows [10] : negative (-): less than 1% positive cells or without positive staining; (+): 1%-10% positive cells; (++): 11%-50% positive cells; and (+++): more than 50% positive cells. Based on the VEGF-positive cell number (the cytoplasm or membrane of the cell appeared brown in color), the criteria were [7] : negative (-): no positive staining; (+): less than 25% positive cells; (++): 26%-50% positive cells; and (+++): more than 50% positive cells. The MVD in the carcinoma tissue was calculated as previously described [11] .…”

Section: Results Evaluationmentioning

confidence: 99%

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Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Zhang²,

Ru³

et al. 2007

WJG

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of HIF-1α and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm 2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value < 41.5/0.72 mm 2 . CONCLUSION:Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice. INTRODUCTIONAngiogenesis plays an important role in tumor growth and metastasis [1,2] . The formation of tumor microvessels is stimulated by angiogenic factors, especially vascular endothelial growth factor (VEGF) [3][4][5] . Hypoxia is related to tumor cell growth, differentiation, invasion and metastasis activity. In recent years, studies showed that hypoxia inducible factor-1 (HIF-1) played an important role in oxygen balance and tumor angiogenesis [6] . HIF-1 consists of α and β subunits, and HIF-1α is a key subunit of HIF activity regulated by hypoxia [1] . HIF-1 mRNA and protein overexpression was found in a variety of tumors, including breast cancer, prostate cancer, kidney cancer, rectal adenocarcinoma, etc [2,4,[7][8][9] . However, research on HIF-1α in gastric cancer was rarely reported. In the present study, BASIC RESEARCHUpregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma Abstract AIM:To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS:In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS:The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF-1α was positively correlated with VEGF protein. There were positive correlations between MVD and expression

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Section: Results Evaluationmentioning

confidence: 99%

“…HIF-1 consists of α and β subunits, and HIF-1α is a key subunit of HIF activity regulated by hypoxia [1] . HIF-1 mRNA and protein overexpression was found in a variety of tumors, including breast cancer, prostate cancer, kidney cancer, rectal adenocarcinoma, etc [2,4,[7][8][9] . However, research on HIF-1α in gastric cancer was rarely reported.…”

mentioning

confidence: 99%

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Zhang²,

Ru³

et al. 2007

WJG

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“…In a subsequent analysis of the clear cell group among patients with metastatic disease, a high HIF-1␣ expression level (Ͼ35%) was independently associated with shorter survival than a low expression level (Յ35%; median survival time, 13.5 months versus 24.4 months, respectively; p ϭ .005). Other groups have demonstrated mixed results when evaluating cytoplasmic HIF staining [52,53]. Ku et al [54] assessed HIF-1␣ and HIF-2␣ expression within individual tumor epithelial and sarcomatoid regions; they observed predominantly cytoplasmic HIF staining, with expression in both epithelial and sarcomatoid components (epithelial Ͼ sarcomatoid).…”

Section: Prognostication/predicting Response To Therapymentioning

confidence: 99%

Tumor Biology and Prognostic Factors in Renal Cell Carcinoma

2011

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In the past 15 years, there has been an increased understanding of the tumor biology of renal cell carcinoma (RCC). The identification of vascular endothelial growth factor (VEGF), its related receptor (VEGFR), and the mammalian target of rapamycin as dysregulated signaling pathways in the development and progression of RCC has resulted in the rational development of pharmaceutical agents capable of specifically targeting key steps in these pathways. Clinical trials have demonstrated survival benefit with these agents, particularly in clear cell RCC patients. However, metastatic RCC will progress in all patients, resulting in a critical need to determine patient risk and optimize treatment. The goal of this article is to highlight the significant breakthroughs made in understanding the critical genetic alterations and signaling pathways underlying the pathogenesis of RCC. The discovery of prognostic factors and development of comprehensive nomograms to stratify patient risk and predictive biomarkers to facilitate individualized treatment selection and predict patient response to therapy also are reviewed. The Oncologist 2011;16(suppl 2):4 -13

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“…In a recent Western blot -driven study among 66 patients with clear cell RCC, high HIF-1a expression was paradoxically found to be a favorable prognostic factor (13). However, in a separate study, the same group evaluated 176 tumor specimens using immunohistochemistry, and found that the survival difference between low and high HIF-1a expressors did not reach statistical significance (14). The prognostic role of HIF-1a in clear cell RCC therefore remains unclear.…”

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confidence: 99%

Hypoxia-Inducible Factor 1α in Clear Cell Renal Cell Carcinoma

Klatte

Seligson²,

Riggs³

et al. 2007

Clinical Cancer Research

177

124

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Purpose: Hypoxia-inducible factor-1a (HIF-1a) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1ain renal cell carcinoma (RCC). Experimental Design: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival. Results: HIF-1aexpression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1a was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1a was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1aexpression predicted outcome in metastatic patients: patients with high HIF-1a expression (>35%) had significantly worse survival than patients with low expression (V35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1aand CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC. Conclusions: HIF-1ais an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1aand CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.

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Hypoxia-Inducible Factor 1α Expression in Renal Cell Carcinoma Analyzed by Tissue Microarray

Cited by 68 publications

References 21 publications

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Tumor Biology and Prognostic Factors in Renal Cell Carcinoma

Hypoxia-Inducible Factor 1α in Clear Cell Renal Cell Carcinoma

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