Tumour BiologyHypoxia-induced tumor angiogenic pathway in head and neck cancer: an in vivo study
Introduction
Tumor angiogenesis is a fundamental event for the local growth, and metastatic spread of solid neoplasms [1], and vascular endothelial growth factor (VEGF) is undoubtedly the key stimulator of this procedure [2], [3]. Increased VEGF production by tumor cells was associated with poor prognosis and low survival in various malignancies [4], [5] and in head and neck cancer [6], [7]. VEGF exhibits its effect in the vasculature in a paracrine fashion, by inducing the proliferation, differentiation, and migration of vascular endothelial cells [3], by increasing the permeability of the capillaries [3], [8], and also by the prevention of the apoptosis of endothelial cells [3], [9]. Furthermore, autocrine action for this molecule has been proposed [10], [11], indicating a pleiotropic functional profile for this protein in human tumorigenesis.
VEGF expression in producing cells is regulated by a plethora of mechanisms, including alterations in tissue microenvironment physiological conditions (such as hypoxia and hypoglycemia) [12], up-regulation of the expression of a variety of growth factors, cytokines, enzymes and other extracellular molecules, and inactivation of tumor suppressor genes [12].
Numerous in vitro studies indicate the importance of hypoxia-induced pathway in the stimulation of VEGF expression, in which the transcription factor hypoxia-inducible factor 1 (HIF-1) plays a major role. This factor is a heterodimeric basic helix–loop–helix protein composed of HIF-1a and HIF-1β subunits [13]. Under normoxic conditions, the HIF-1a subunit is subjected to ubiquitination and proteosomal degradation; whiles in hypoxia, its degradation is inhibited, and it's expression is rapidly accumulated [14], [15]. HIF-1a binds to a DNA recognition sequence in the promoter of target genes, including VEGF gene [15]. Thus, under hypoxic conditions, VEGF transcription is up-regulated by HIF, and additionally hypoxia promotes the stabilization of VEGF mRNA by proteins that bind to sequences in the 3′ untranslated region (UTR) of the mRNA [16]. Furthermore, hypoxia influences VEGF activity by post-transcriptional regulation of VEGFR-2 (also known as Flk-1/KDR), by hypoxia-inducible expression of VEGFR-1 (also known as flt-1), and by involvement in VEGF-soluble flt-1 interaction, which inhibits VEGF activity [15].
HIF-1a expression in head and neck cancer was addressed in vivo by a small number of studies [17], [18], [19], [20], that enrolled limited number of patients, and only one report [20] has examined the relation between HIF-1a expression and VEGF in tissue samples obtained from patients with head and neck cancer. Given the multiplicity of mechanisms enabling the HIF system in cancer, the many HIF target genes, among with the plethora of VEGF up-regulating pathways, more in vivo studies are required in order to confirm in vitro observations, and address the importance of these pathways in tumor aggressiveness and prognosis.
In the present study, we performed immunohistochemical evaluation of HIF-1a and VEGF expression in 81 primary tumor samples from patients with head and neck squamous cell carcinoma. Our aim was to investigate the presence of any association between the expression of these two proteins, and examine possible correlations between HIF-1a and VEGF expression with clinicopathologic parameters and overall survival in this cohort of patients.
Section snippets
Tissues and clinical parameters
A total of 81 paraffin-embedded archival tissue blocks from patients with head and neck squamous cell carcinoma specimens were obtained from the Department of Pathology of the General University Hospital of Ioannina. Fifty of these samples were also included in our previous study [21]. Specimens consisted of surgical material, obtained from the primary tumor. These patients with head and neck squamous cell carcinoma were treated in the Ear Nose Throat (ENT) Department (Director: Prof. A.
Clinicopathologic data
A total of 81 patients with head and neck squamous carcinoma were included in this retrospective study. The median age of the patients was 65 (range 33–98). Sixty-three of the patients (78%) were male and 18 (22%) were female. Fifty of the tumors were located in the lower lip, 22 in the oral cavity and 9 in larynx. Twenty-one patients (26%) presented with lymph node metastases at the time of diagnosis. Fifty-six of the patients (69%) had cancer classified as lower (I and II) clinical stage, and
Discussion
Previous studies examining the importance of HIF-1a expression in head and neck squamous cell carcinoma suggest an association of higher immunohistochemical staining for this factor with poor response to radiotherapy, and with adverse prognosis [18], [19], [20], [24]. It is generally accepted that tumor hypoxia thwarts the therapeutic effect of ionizing radiation, and this aspect offers convincing explanation for the observed radioresistence of tumors with high HIF-1a immunostaining [25].
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