Phosphorylated KDR expression in endometrial cancer cells relates to HIF1α/VEGF pathway and unfavourable prognosis

Giatromanolaki, Alexandra; Koukourakis, Michael I.; Turley, Helen; Sivridis, Efthimios; Harris, Adrian L.; Gatter, Kevin C.

doi:10.1038/modpathol.3800579

Cited by 37 publications

(33 citation statements)

References 30 publications

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“…In a recent study on 70 stage 1 endometrioid adenocarcinomas, phosphorylated KDR expression was directly related to the HIF-1a/VEGF pathway and to unfavorable prognosis. 25 In the present study, high expression of Ki-67 was significantly different in the type I compared to type …”

Section: Discussionsupporting

confidence: 40%

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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Section: Discussionsupporting

confidence: 40%

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

et al. 2007

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“…Complete suppression of tumour growth has been demonstrated using dominant-negative VEGF receptors (Zhang et al, 1995;Millauer et al, 1996;Goldman et al, 1998) and blocking antibodies (Kim et al, 1993;Asano et al, 1995;Warren et al, 1995;Melnyk et al, 1996;Yuan et al, 1996;Borgstrom et al, 1998) as well as small-molecule inhibitors of VEGFR-2 kinase (Wood et al, 2000;Wedge et al, 2002) as single-agent therapies in model systems. Overexpression of VEGF is common in solid tumours and associated with poorer prognosis (Dosquet et al, 1997;Raben and Helfrich, 2004;Giatromanolaki et al, 2006).…”

mentioning

confidence: 99%

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Strumberg¹,

Schultheis²,

Adamietz

et al. 2008

Br J Cancer

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Telatinib is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor b tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t max of 3 hours or less. Geometric mean C max and AUC 0À12 increased in a less than doseproportional manner and plateaued in the 900 -1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC 0À12 of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.

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“…> 6 cm, those with poor histologic differentiation and high CEF1 (the nineteen complex, a non-snRNA containing protein complex, involved in splicing of nuclear RNAs via the spliceosome alpha expression). Increased VEGFR-2 expression also correlated with high VEGF and HIF expression (Giatromanolaki et al 2007). In addition to chronic inflammatory states obesity can also predispose patients to the development of colon cancer.…”

Section: Colon Cancermentioning

confidence: 99%

“…VEGFR-2 was found weakly expressed in normal tissues or cells, but VEGFR-2 overexpression was reported in various cancers including lung, colon, uterus, ovarian cancer, as well as breast cancers (Giatromanolaki et al 2007). The overexpression of VEGFR-2 not only occurs in cancer, but also the expression of VEGFR-2 relates to the disease stage, recurrence and worse outcome.…”

Section: Expression Of Vegfr-2 In Human Cancermentioning

confidence: 99%

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Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

Guo¹,

Colbert²,

McGlothen³

et al. 2012

Tumor Angiogenesis

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Phosphorylated KDR expression in endometrial cancer cells relates to HIF1α/VEGF pathway and unfavourable prognosis

Cited by 37 publications

References 30 publications

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

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

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

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