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

BACKGROUND: Hypoxia promotes tumorigenesis through the hypoxia-inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF-1alpha and HIF-2alpha, 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-alpha expression in tumors. METHODS: The expression of HIF-1alpha, HIF-2alpha, 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-1alpha was expressed in 45 of 140 tumors (30%), HIF-2alpha 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-1alpha expression and HIF-2alpha expression (P =.0001). HIF-1alpha 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-1alpha and high HIF-2alpha. High HIF-1alpha/high HIF-2alpha 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-1alpha, HIF-2alpha, or CA-9. CONCLUSIONS: HIF-1alpha alone was correlated with DSS and DFS. The additive effect of HIF-2alpha on poor prognosis suggested that different pathways may be regulated by HIF-2alph. Anemia that was not related to HIF-alpha expression suggests that tumor intrinsic factors regulate HIF-alpha therefore, anemia may be a surrogate marker for other factors that affect outcome.     

Ibuprofen-mediated reduction of hypoxia-inducible factors HIF-1alpha and HIF-2alpha in prostate cancer cells.

PURPOSE: Hypoxia-inducible factors HIF-1alpha and HIF-2alpha are considered to be potential targets for antineoplastic therapy because they regulate the expression of genes that contribute to tumor cell survival, aggressiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs (NSAIDs) have gained considerable interest as anticancer agents because of their cytotoxic and antiangiogenic properties. The aim of this study was to investigate whether NSAIDs inhibit HIFs and HIF-regulated gene expression in prostate cancer cells. Experimental Design: PC3 and DU-145 cells were treated with ibuprofen (Ibu) and other NSAIDs under normoxic and hypoxic (95% N(2), 5% CO(2); <10 ppm O(2)) conditions. The effect of NSAIDs on HIF proteins was analyzed by Western blot analysis. HIF-regulated proteins, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1), were analyzed by ELISA and Western blot analysis, respectively. RESULTS: Exposure of PC3 and DU-145 cells to hypoxic condition up-regulated HIF-1alpha and HIF-2alpha proteins. Treatment with Ibu under normoxic and hypoxic conditions reduced the level of HIF-1alpha and HIF-2alpha. Ibu-mediated down-regulation of HIFs was associated with down-regulation of HIF-regulated proteins VEGF and Glut-1 in cells exposed to hypoxia. Other nonspecific NSAIDs, diclofenac and ketorolac, also inhibited HIF-1alpha and HIF-2alpha. The reduction in HIFs was observed in PC3 cells that expressed cyclooxygenase-2 (COX-2) protein as well as in DU-145 cells, which did not express COX-2 protein. COX-2-specific inhibitor NS-398 did not inhibit HIF-1alpha or VEGF and GLUT-1. CONCLUSIONS: These data indicate that one of the effects of NSAIDs is to reduce HIF protein levels. The inhibition of HIFs by NSAIDs was COX-2 independent.     

Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer

Endogenous hypoxia markers have been studied as prognostic indicators because they appear to be associated with tumor aggressiveness. This study was undertaken to compare the expression of two endogenous hypoxia markers, Hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX), with regard to their prognostic significance. We also compared spatial distribution of HIF-1alpha and CA IX and examined their relationship with expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9, which may be regulated by hypoxia. We studied 74 resected stage I/II non-small cell lung cancers (NSCLCs) for expression of HIF-1alpha, CA IX, VEGF, and MMP-9 by immunohistochemistry, and the extent of tumor necrosis. Univariate and multivariate analyses were performed to assess prognostic implications of these markers for disease free survival. HIF-1alpha expression was strongly correlated with CA IX (r=0.667, p<0.001) and was co-localized with CA IX in corresponding areas. HIF-1alpha and CA IX expression were higher in areas with moderate to severe tumor necrosis relative to areas with minimal necrosis, suggesting their relationship with hypoxia. VEGF expression also showed a modest relationship with HIF-1alpha (p=0.07); however, there was no relationship between HIF-1alpha and MMP-9 expression (p>0.99). Expression of HIF-1alpha and CA IX above the median value was significantly associated with shorter disease free survival in univariate analysis (p<0.05). However, only high CA IX expression and pathologic stage were independent prognostic indicators in a multivariate analysis. Of the markers considered in this study, CA IX expression status was the most reliable hypoxia marker for predicting tumor aggressiveness.     

Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer

Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation treatment. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. This study correlated the exogenous 2-nitroimidazole hypoxia marker 1-[(2-hydroxy-3-piperidinyl)propyl]-2-nitroimidazole hydrochloride (pimonidazole) with the endogenous hypoxia-related marker carbonic anhydrase 9 (CA9) and with vascular parameters using immunohistochemical techniques and a computerized image analysis system. Tumor biopsies were obtained from patients with head and neck carcinomas that were potential candidates for a Phase II trial with accelerated radiotherapy combined with carbogen and nicotinamide (ARCON). If, after completion of the diagnostic workup, the eligibility criteria were met and informed consent was obtained, patients were treated with ARCON. Those patients that were not eligible or refused ARCON were treated with radiotherapy, surgery, or a combined modality. Forty-three biopsies were analyzed, and the results were related with treatment outcome. The distribution patterns of pimonidazole and CA9 were similar, although the CA9 signal was generally observed already at shorter distances from blood vessels. There was a weak but significant correlation between the relative tumor areas positive for pimonidazole binding and areas with CA9 expression. Locoregional tumor control was significantly lower for patients who had hypoxic tumors or tumors with low vascular density. The 2-year control rates were 48 versus 87% for tumors with high and low pimonidazole binding levels (stratified by median, P = 0.01) and 48 and 88% for tumors with low and high vascular density (stratified by median, P = 0.01). These associations disappeared in the subgroup of patients treated with ARCON. There was no relationship between the level of CA9 expression and treatment outcome. It is concluded that pimonidazole binding and vascular density can predict treatment outcome in head and neck cancer and may be useful as selection tools for hypoxia-modifying treatments. Pimonidazole and CA9 demonstrate concordant staining patterns, but the latter is a less specific marker for hypoxia.     

Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients

BackgroundHuman prominin-1 (CD133) is a novel pentaspan membrane protein which was originally classified as a marker of primitive haematopoietic and neural stem cells. Cancer stem cells have been isolated and expanded from leukaemia and several solid tumours, and have been associated with metastasis, chemoresistance and relapse. CD133 is recognised as a stem cell marker and is capable of identifying a tumour-initiating subpopulation in brain, colon, melanoma and other solid tumours.MethodsWe assessed CD133 mRNA expression levels by RT-QPCR in tumour and matched normal tissue from 64 stages I–III colorectal cancer (CRC) patients and correlated tumour CD133 levels with clinicopathological characteristics and clinical outcome.ResultsIn four patients, CD133 mRNA was not expressed in tumour or in normal tissue. In the remaining 60 patients, expression levels were higher in tumour than in normal tissue (p = 0.001). Higher levels of CD133 expression were associated with shorter relapse-free interval (RFI) (p = 0.004) and overall survival (OS) (p < 0.0001). In the multivariate analyses, CD133 levels emerged as a prognostic marker for RFI and OS.ConclusionsWe have observed longer RFI and OS in patients with lower levels of CD133, regardless of adjuvant treatment and other clinical characteristics. If these findings are confirmed in larger prospective studies, CD133 assessment may prove useful for new diagnostic and therapeutic procedures for CRC patients.     

Patterns of recurrence and outcome in patients with surgically resected small cell lung cancer

Background

Although prophylactic cranial irradiation (PCI) in limited-stage (LS) small cell lung cancer (SCLC) patients who are surgically resected and treated with adjuvant chemotherapy is considered to be a reasonable treatment option, the efficacy of PCI for those patients remains unclear.

Methods

The records of 28 patients with SCLC undergoing curative surgery at the Aichi Cancer Center Hospital between 1995 and March 2008 were retrospectively reviewed to assess patterns of relapse and overall survival.

Results

The patients were 27 men and 1 woman. Eight patients underwent induction chemotherapy. Fourteen patients (50%) had pathologic stage (p-stage) I disease, 7 patients (25%) had p-stage II, and 7 patients (25%) had p-stage III. Nineteen patients underwent adjuvant chemotherapy and one patient received adjuvant chemoradiotherapy. There were a total of 13 deaths and 8 were disease-related. Most patients developed hematogenous distant metastases before their death. The 5-year overall probability of survival was 47%. Ten (36%) of the 28 patients had a relapse. Two had a local relapse alone, one patient had combined local and distant relapses, and seven patients had distant metastases alone as their first site of failure. Four patients with p-stage II/III disease developed brain metastases with a cumulative incidence at 1 and 2?years of 25 and 36%, respectively.

Conclusions

Our retrospective study suggested that PCI might have a role in surgically resected patients with p-stage II/III SCLC because of their relatively high frequency of brain metastasis.     

Compliance to radiation therapy of head and neck cancer patients and impact on treatment outcome

Aims

The aims of the study were to evaluate head and neck cancer (HNC) patient’s compliance to the planned radiation therapy (RT) using the department policy established in 2005 at IPOCFG and to estimate the impact on treatment outcome due to failure in receiving RT as prescribed.

Materials and methods

359 HNC patients irradiated from 2007 to 2013 were included in this study. Patient cohort was divided into Group 1: patients receiving RT as prescribed and Group 2: patients that interrupted or suspended RT. Group Tox is the subgroup of patients that interrupted RT due to toxicity or intercurrent disease. Number and causes for treatment interruptions were assessed. The cumulative incidence of locoregional control (LRC), disease-free survival (DFS) and overall survival for Groups 1 and 2 was determined. Cox regression was performed to investigate potential hazard factors and logistic regression was made to determine risk factors related to treatment interruptions.

Results

Major causes for treatment interruptions were toxicity plus intercurrent disease (41.7 %) and public holidays (30.1 %). 10.3 % of the patients interrupted 3–9 days. Significant differences in survival distributions of the LRC between Groups 1 and 2, of up to 19 %, were found in the subgroup of patients with N2–3 tumours, for post-operative RT and for concomitant RT. Treatment breaks larger than two days had an almost fourfold increased risk of poorer LRC and DFS.

Conclusions

Twin accelerators and treating on public holidays are effective measures minimizing RT breaks. For HNC, patient compliance is mostly limited by RT side-effects. Efforts to maintain RT biological effective dose in HNC must be always undertaken.

     

The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma

Two hundred seventy (270) consecutive surgical patients treated at Roswell Park Memorial Institute for carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx between 1977 and 1982 were reviewed to determine the relationship between pathological findings at the surgical margins of the primary tumor and the incidence of local recurrence and clinical outcome. The estimated 5-year disease-free survival rate was 39% for patients with free surgical margins (10%--hypopharynx, 30%--oropharynx, 40%--oral cavity, and 53%--larynx) and 7% for not-free surgical margins. Patients with free surgical margins and with well-differentiated squamous cell carcinoma had better prognosis than those patients with moderately- and poorly-differentiated carcinomas. The local recurrence rate for Stage T1 and T2 lesions with free surgical margins was 17%, compared with 27% for Stages T3 and T4. The results of this study indicate that pathological evidence of complete excision of the primary tumor is important and attempts should be made to obtain pathological clearance. The local recurrence rate for Stage T3 and T4 lesions is high. Adjuvant therapy is indicated and post-operative radiotherapy is recommended.     

Molecular biology in head and neck cancer

Major changes in the treatment of head and neck cancer are possible today because of the knowledge that we have on the molecular biology of these tumors. Different pathways are active in the development of this cancer and field cancerization is a major problem for the cure in early stage disease. Epidermal growth factor signal transduction pathway is now the principal target for this disease. New therapeutic strategies such as monoclonal antibodies and small molecules have appeared, however no more than 20% of the patients have objective responses with these therapies. Consequently, new alternatives of treatment in the basis of the understanding of molecular biology are necessary to increase the number of patients that can be cured in the future. Supported by an unrestricted educational grant by Bristol-Myers Squibb.     

Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia.

PURPOSE: Erythropoietin, an oxygen-regulated glycoprotein hormone, is a hematopoietic cytokine that stimulates erythropoiesis by binding to its cellular receptor [erythropoietin receptor (EPOR)]. The recombinant form of human erythropoietin is used to prevent or treat anemia in cancer patients. However, in a recent randomized, placebo-controlled trial involving patients receiving curative radiotherapy for squamous cell carcinoma of the head and neck, erythropoietin treatment was associated with poorer locoregional progression-free survival. The purpose of our study was to determine whether EPOR and its ligand erythropoietin are expressed in primary head and neck cancer. We also investigated the hypothesis that erythropoietin expression in malignant cells may be associated with the presence of tumor hypoxia, an important factor involved in resistance to radiation treatment, tumor aggressiveness, and poor prognosis. EXPERIMENTAL DESIGN: Twenty-one patients received an i.v. infusion of the hypoxia marker pimonidazole hydrochloride before multiple tumor biopsies. Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for EPOR and erythropoietin expression and pimonidazole binding. RESULTS: EPOR expression was present in tumor cells in 97% of the biopsies. Coexpression of erythropoietin was observed in 90% of biopsies. Erythropoietin and pimonidazole adduct staining did not always colocalize within tumors, but there was a significant positive correlation between levels of microregional erythropoietin expression and pimonidazole binding. CONCLUSIONS: The coexpression of erythropoietin and EPOR in tumor cells suggests that erythropoietin may potentially function as an autocrine or paracrine factor in head and neck cancer. The expression of the hypoxia-inducible protein erythropoietin in tumor cells correlates with levels of tumor hypoxia.     

肺癌组织中缺氧诱导因子-1α的表达及其与凋亡和增殖的关系

背景与目的：缺氧诱导因子－1（Hypoxia inducible factor-1,HIF-1）是调节肿瘤细胞适应缺氧的核转录因子。大量研究证实HIF－1在维持肿瘤细胞的能量代谢、新血管形成及转移起重要作用。但关于HIF－1与肿瘤细胞凋亡、增殖的关系鲜见报道,且结论存在较大差异。本研究旨在探讨缺氧诱导因子－1α（HIF-1α)在肺癌组织中的表达及其与bcl-2、Bax及PCNA的关系。方法：采用免疫组化SP法检测60例肺癌组织中HIF－1、bcl-2、Bax蛋白及PCNA的表达。结果：60例肺癌组织中HIF－1α阳性表达率为28．3％。其中小细胞肺癌（SCLC）阳性率为66．7％显著高于非小细胞肺癌（NSCLC）的21．5％（P＜0．01）。HIF－1α表达水平随临床分期的增高而增加（P＜0．01）。bcl-2 Bax,PCNA蛋白阳性率分别为31．7％（19／60）,40．0％（24／60）,76．7％（46／60）;bcl-2的表达与肿瘤细胞的分化程度显著相关（P＜0．01）。HIF－1α蛋白表达与bcl-2呈负相关（P＜0．01）,与Bax蛋白之间显著正相关（P＜0．01）,但与PCNA无相关性（P＞0．05）。结论：HIF－1α与肿瘤细胞凋亡密切相关,但与肿瘤细胞增殖无关。     

Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype

In neuroblastoma specimens, HIF-2alpha but not HIF-1alpha is strongly expressed in well-vascularized areas. In vitro, HIF-2alpha protein was stabilized at 5% O2 (resembling end capillary oxygen conditions) and, in contrast to the low HIF-1alpha activity at this oxygen level, actively transcribed genes like VEGF. Under hypoxia (1% O2), HIF-1alpha was transiently stabilized and primarily mediated acute responses, whereas HIF-2alpha protein gradually accumulated and governed prolonged hypoxic gene activation. Knockdown of HIF-2alpha reduced growth of neuroblastoma tumors in athymic mice. Furthermore, high HIF-2alpha protein levels were correlated with advanced clinical stage and high VEGF expression and predicted poor prognosis in a clinical neuroblastoma material. Our results demonstrate the relevance of HIF-2alpha in neuroblastoma progression and have general tumor biological implications.     

Health outcome priorities in older patients with head and neck cancer

ObjectivesOlder patients with head and neck cancer often have comorbidity, have reduced life-expectancy and await intensive treatment. For the decision-making process, knowledge of a patient's health outcome prioritization is of paramount importance. We aim to study the health outcome priorities of older patients with head and neck cancer, and to evaluate whether general health, markers of physical, cognitive, and social functioning, and quality of life are associated with health outcome prioritization.Materials and MethodsPatients aged ≥70 years with head and neck cancer received a Comprehensive Geriatric Assessment and their priorities were assessed using the Outcome Prioritization Tool (OPT). Distribution of first priority, and associations with general health, markers of physical, cognitive, and social functioning, and quality of life were evaluated using ANOVA or chi-square.ResultsOf the 201 included patients, the OPT was available in 170 patients. The majority prioritized maintaining independence (n = 91, 53.3%), followed by extending life (n = 58, 34.1%), reducing pain (n = 14, 8.2%), and reducing other symptoms (n = 7, 4.1%). Housing situation, Body Mass Index, presence of musculoskeletal diseases, and quality of life were significantly related to prioritization of health outcomes. Reducing pain or other symptoms was more often prioritized by patients who lived alone, had a history of musculoskeletal problems, or had poor perceived quality of life. Age, sex, comorbidity, and markers of physical and cognitive functioning were not associated with health prioritization.ConclusionMaintaining independence is most often prioritized by older patients with head and neck cancer. In addition, we found that health outcome priorities of older patients are only limited based on general and specific health characteristics. We suggest to systematically discuss patients' priorities in order to facilitate complex treatment decisions in older patients with cancer.     

Influence of p53 and bcl-2 on proliferative activity and treatment outcome in head and neck cancer patients

Knowledge about the influence of biomarkers on cell proliferative activity might explain differences in radiosensitivity between head and neck tumors and might improve patient selection for the most optimal treatment strategy. p53 and bcl-2 protein expression were determined immunohistochemically in 56 head and neck cancer patients, treated by surgery only in five cases and by radiotherapy, with or without surgery, in 51 cases. Relationships with various cell proliferation markers, determined by flow-cytometry (G1-phase fraction, S-phase fraction, BrdUrd-labeling index, duration of S-phase and potential doubling time) were investigated. Associations between these cell proliferation parameters, on the one hand, and both p53 and bcl-2, on the other, were not found. Furthermore, p53 and bcl-2 expression were both not related to clinicopathological parameters (T- and N-stage, site, grade) and did not affect loco-regional recurrence-free survival and/or disease-free survival. We could not find a prognostic value for both p53 and bcl-2 protein expression to differentiate radiosensitive from radioresistant head and neck tumors.     

HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome

Hypoxia stabilizes HIF-1alpha (Hypoxia Inducible Factor-1alpha), which then triggers the expression of several genes involved in many aspects of cancer progression, including metabolic adaptation, cell survival and angiogenesis. The aim of our study was to evaluate the impact of HIF-1alpha and CA IX (carbonic anhydrase IX) (one of its target genes) expression on prognosis and treatment outcome of patients with breast cancer. Because of the extreme O2-dependent instability of the protein, we first validated HIF-1alpha staining using xenograft tumours that were subjected to experimental conditions mimicking surgical clamping or sitting at room temperature under normoxic conditions after surgical excision but before fixation. Afterwards, the immunohistochemical staining of HIF-1alpha and CA IX was evaluated in 132 invasive breast carcinomas with a 10-year follow-up, and correlated to classical clinicopathological parameters and response to adjuvant therapy. No significant correlation was found between tumour size or nodal status and the expression of HIF-1alpha or CA IX. Statistically significant association was found between HIF-1alpha or CA IX staining and the grade, hormonal receptors loss and the presence of carcinoma in situ. Overexpression of HIF-1alpha and CA IX correlates with a poor prognosis in breast cancer. We show that HIF-1alpha is an independent prognostic factor for distant metastasis-free survival and disease-free survival in multivariate analysis. Furthermore, overexpression of HIF-1alpha or CA IX correlates with a poor outcome after conventional adjuvant therapy. CA IX is, however, a weaker prognostic and predictive factor than HIF-1alpha, and its association with HIF-1alpha does not modify the survival curve neither response to therapy, compared to HIF-1alpha alone.     

The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial

The effect of an adjuvant mistletoe extract treatment was tested in a prospective, randomised controlled clinical trial involving 477 patients with head and neck squamous cell carcinoma. The patients were stratified into two treatment groups that underwent surgery or surgery followed by radiotherapy and both groups were randomised for additional treatment with mistletoe extract. Patients treated with a mistletoe lectin-1 (ML-1) standardised mistletoe preparation had no lower risk of local/locoregional recurrences, distant metastases or second primaries. In the main analysis based on 202 patients treated with surgery and 275 patients treated with surgery and radiotherapy the adjusted hazard ratio for the disease-free survival (DFS) was 0.959 (95% confidence interval (CI) 0.725-1.268). The 5-year survival rates of patients from the mistletoe group were no better than the survival rates of patients from the control group. Furthermore, no significant changes in the cellular immune reaction or in quality of life could be detected. We conclude that the used mistletoe preparation has no indication in the adjuvant treatment of patients with head and neck cancer.     

Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.

PURPOSE: Angiogenesis plays an important role in a multitude of biological processes including those of tumorigenesis and cancer progression. Hypoxia is the prime driving factor for tumor angiogenesis and the family of hypoxia-inducible factors (HIFs) plays a pivotal role in this process. The role of HIF in tumor angiogenesis has been underscored in different carcinomas but yet to be reported for colorectal carcinomas. EXPERIMENTAL DESIGN: In this study, we examined HIF [HIF-1alpha (HIF1) and HIF-2alpha (HIF2)] expression in 87 curatively resected colorectal carcinoma samples, and the results were correlated with clinicopathological factors, microvessel density, cyclooxygenase 2 expression, and patient prognosis. RESULTS: HIF1 (44.8%) was more frequently expressed than HIF2 (29.9%). Most of the clinicopathological factors representing the tumor aggressiveness were significantly correlated with overexpression of HIF2 but not with HIF1 expression. HIF2 expression had direct correlation with microvessel density and cyclooxygenase 2 expression. and, in contrast, HIF1 expression had a weak but significant inverse correlation in T1 and T2 tumors only. HIF2 expression alone and the combined expression of HIF1 and HIF2 had significant impact on patient survival. In the multivariate analysis, however, only the combined expression of HIF1 and HIF2 remained independently significant. CONCLUSIONS: Taken together, our results suggest that HIF2 expression may play an important role in angiogenesis and that the combined expression of HIF1 and HIF2 may play an important role in tumor progression and prognosis of colorectal carcinomas. Therefore, HIF expression could be a useful target for therapeutic intervention.