Significant correlation of hypoxia-inducible factor-1α with treatment outcome in cervical cancer treated with radical radiotherapy

Burri, Philipp; Djonov, Valentin; Aebersold, Daniel M.; Lindel, Katja; Studer, Urs; Altermatt, H. J.; Mazzucchelli, Luca; Greiner, Richard; Gruber, G.

doi:10.1016/s0360-3016(02)04579-0

Cited by 117 publications

(74 citation statements)

References 33 publications

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“…Indeed, the significance of this factor was higher than for other prognostic parameters. Lymphnode metastasis, a very potent parameter in the univariate analysis, failed to attain significance for LPFS in Cox's regression model, which is contrary to previous findings of our group (Burri et al, 2003). There exist some differences in patient number and in the follow-up time, but these factors alone cannot account for the present results.…”

Section: Discussioncontrasting

confidence: 99%

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

et al. 2004

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Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, b3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of b3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell or adenocarcinomas of the uterine cervix who had undergone external-beam radiotherapy with or without brachytherapy. These tissue samples were analysed immunohistochemically for the expression of b3-integrin. The impact of immunoreactivity for b3-integrin on survival end points was assessed by univariate and multivariate analyses, and its correlation with clinicopathological characteristics evaluated by crosstabulations. b3-integrin was expressed in 61% (50 of 82) of the patients. KaplanMeier curves revealed local progression-free survival, distant metastasis-free survival and cause-specific survival to be significantly shorter (P-values according to the log-rank test: 0.002, 0.04 and 0.01, respectively) in patients with b3-integrin expression. The prognostic impact of this parameter was even higher than for other well-known prognostic parameters and remained statistically significant in the multivariate analyses. b3-integrin, which is expressed in the majority of patients with advanced cervical cancer, has a significant prognostic impact on outcome according to univariate and multivariate analyses.

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Section: Discussioncontrasting

confidence: 99%

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

et al. 2004

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“…High expression of HIF-1a was also associated with resistance to radiotherapy treatment of oropharyngeal and cervical carcinomas. [4][5][6][7]21 In the current study, we found expression of HIF-1a protein was correlated with aggressive tumor characteristics (higher grade of tumor, depth of tumor invasion and adnexal invasion) in type I endometrial adenocarcinoma, but failed to show similar correlation in type II endometrial adenocarcinoma. This may be due to the different biologic nature of these two types and the inherent high-grade property of type II endometrial adenocarcinoma.…”

Section: Myometrial Invasionmentioning

confidence: 66%

“…[5][6][7] Significant correlation of HIF-1a was also noted with radiotherapy treatment of oropharyngeal and cervical carcinomas. [5][6][7][8]21 Overexpression of HIF-1a has also been described in endometrial carcinomas. 11 Sivridis et al found HIF-1a overexpression in 49% of 81 low-stage endometrioid adenocarcinomas (type I endometrial adenocarcinoma).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

et al. 2007

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Hypoxia-inducible factor 1a (HIF-1a) is a nuclear protein that is upregulated in many tumors and triggers biologic events intimately associated with aggressive tumor behavior. The aim of this study was to analyze the expression of HIF-1a, vascular endothelial growth factor (VEGF), Ki-67 and p53 in type I and type II endometrial adenocarcinoma. In total, 149 patients diagnosed with endometrial adenocarcinoma in our institute from 1995 to 2001 were included in this study, of which 108 were type I and 41 were type II endometrial adenocarcinoma. Patient demographics, clinical and pathological data were reviewed. Tissue microarrays were prepared from the paraffin blocks and immunohistochemistry was performed for antibodies against HIF-1a, VEGF, Ki-67 and p53. High expression of HIF-1a, VEGF, Ki-67 and p53 were significantly more frequent in type II than type I endometrial adenocarcinoma (Po0.001). HIF-1a expression was highly correlated with VEGF expression in the tumor cells (P ¼ 0.001). In type I endometrial adenocarcinoma, high expression of HIF-1a showed a significant correlation with higher grade of the tumor, depth of myometrial invasion, adnexal invasion and clinical stage. A similar correlation was not observed in type II endometrial adenocarcinoma. Surgical stage was the only independent prognostic marker for survival. In conclusion, high expression of HIF-1a is more frequent in type II than in type I endometrial adenocarcinoma. In type I endometrial adenocarcinoma, HIF-1a expression correlates with morphologic features of aggressiveness. In type II endometrial adenocarcinoma, there is no correlation between HIF-1a expression and these features. Thus, HIF-1a may play an important role in endometrial adenocarcinoma progression, particularly in type I endometrial adenocarcinoma. Additional investigations of HIF-1a as a biomarker of aggressive potential and as a novel target for therapeutics in endometrial adenocarcinoma are warranted. Hypoxia-inducible factor 1 (HIF-1) is a nuclear protein that activates gene transcription specifically in response to reduced cellular oxygen concentration and therefore acts as a marker for hypoxia. It is a dimeric protein with two subunits, a and b. HIF-1a is the specific hypoxia-regulated subunit. 2 Hypoxia results in stabilization of HIF-1a, facilitating nuclear HIF-1a binding and restoration of oxygen homeostasis by inducing glycolysis and angiogenesis through upregulation of vascular endothelial growth

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“…20,24 In addition, in patients with esophageal, nasopharyngeal, and cervical tumors who received treatment with a variety of modalities, HIF-1a expression has been correlated with a poor outcome. 19,30,34 Although HIF-2a expression has been used as a marker of tumor hypoxia, there is equivocal evidence linking its expression with clinical outcome. Whereas it has been shown to be an independent indicator of survival in patients with HNSCC 20 and patients with early-stage nonsmall cell lung cancers 35 , other studies in patients with HNSCC and nasopharyngeal cancers have found that HIF-2a does not correlate with outcome.…”

Section: Discussionmentioning

confidence: 99%

“…17 Furthermore, in patients with endometrial cancer, no association was found between Hb and levels of HIF-1a, HIF-2a, or VEGF, 43 although HIF-1a was correlated with Hb in cervical cancers. 34 This finding has implications for the therapeutic approach of correcting anemia to alter tumor oxygenation and suggests that altering Hb levels may not modify the molecular response to hypoxia. However, it is possible that hypoxic protein expression reflects the response of a molecular pathway that can be modified by other signaling pathways or that anemia may be interacting with other pathways that obscure its independent assessment.…”

Section: Discussionmentioning

confidence: 99%

The relation between hypoxia‐inducible factor (HIF)‐1α and HIF‐2α expression with anemia and outcome in surgically treated head and neck cancer

Winter

Shah

Han

et al. 2006

Cancer

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BACKGROUND.Hypoxia promotes tumorigenesis through the hypoxia‐inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF‐1α and HIF‐2α, which have different effects in genetic knock‐out experiments. Anemia may contribute to hypoxia by reducing oxygen delivery, but it is not known whether this influences HIF‐α expression in tumors.METHODS.The expression of HIF‐1α, HIF‐2α, carbonic anhydrase‐9 (CA‐9), and peripheral hemoglobin (Hb) levels in 151 patients who underwent surgery for head and neck squamous cell carcinoma (HNSCC) were analyzed and related to outcome.RESULTS.High HIF‐1α was expressed in 45 of 140 tumors (30%), HIF‐2α was expressed in 21 of 139 tumors (14%), and CA‐9 was expressed in 56 of 149 tumors (62%). There was a positive correlation between HIF‐1α expression and HIF‐2α expression (P = .0001). HIF‐1α alone was associated with a worse disease‐specific survival (DSS) (P = .05) and disease‐free survival (DFS) (P = .03) in multivariate analyses. Nine percent of tumors expressed both high HIF‐1α and high HIF‐2α. High HIF‐1α/high HIF‐2α expression was an independent prognostic factors in DSS (P = .04) and DFS (P = .005) in multivariate analyses. There was no correlation noted between Hb and HIF‐1α, HIF‐2α, or CA‐9.CONCLUSIONS.HIF‐1α alone was correlated with DSS and DFS. The additive effect of HIF‐2α on poor prognosis suggested that different pathways may be regulated by HIF‐2α. Anemia that was not related to HIF‐α expression suggests that tumor intrinsic factors regulate HIF‐α; therefore, anemia may be a surrogate marker for other factors that affect outcome. Cancer 2006. © 2006 American Cancer Society.

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Significant correlation of hypoxia-inducible factor-1α with treatment outcome in cervical cancer treated with radical radiotherapy

Cited by 117 publications

References 33 publications

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

The relation between hypoxia‐inducible factor (HIF)‐1α and HIF‐2α expression with anemia and outcome in surgically treated head and neck cancer

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