Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy

Gatenby, Robert A.; Kessler, Howard; J, Rosenblum; Coia, Lawrence R.; Moldofsky, Philip J.; Hartz, William H.; Broder, George

doi:10.1016/0360-3016(88)90002-8

Cited by 743 publications

(311 citation statements)

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“…Cells found 100-200 µm away from blood vessels are already hypoxic (Gatenby et al, 1988), which suggests that hypoxic conditions will have been established in a cluster of cells of about 0.5 mm diameter. Activation of the HIF1 pathway may therefore be expected to occur at a very early step of tumour progression.…”

Section: Discussionmentioning

confidence: 99%

Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival

et al. 2001

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Summary Hypoxia inducible factors HIF1α and HIF2α are important proteins involved in the regulation of the transcription of a variety of genes related to erythropoiesis, glycolysis and angiogenesis. Hypoxic stimulation results in rapid increase of the HIF1α and 2α protein levels, as a consequence of a redox-sensitive stabilization. The HIFαs enter the nucleus, heterodimerize with the HIF1β protein, and bind to DNA at the hypoxia response elements (HREs) of target genes. In this study we evaluated the immunohistochemical expression of these proteins in 108 tissue samples from non-small-cell lung cancer (NSCLC) and in normal lung tissues. Both proteins showed a mixed cytoplasmic/nuclear pattern of expression in cancer cells, tumoural vessels and tumour-infiltrating macrophages, as well as in areas of metaplasia, while normal lung components showed negative or very weak cytoplasmic staining. Positive HIF1α and HIF2α expression was noted in 68/108 (62%) and in 54/108 (50%) of cases respectively. Correlation analysis of HIF2α expression with HIF1α expression showed a significant association (P < 0.0001, r = 0.44). A strong association of the expression of both proteins with the angiogenic factors VEGF (P < 0.004), PD-ECGF (P < 0.003) and bFGF (P < 0.04) was noted. HIF1α correlated with the expression of bek-bFGF receptor expression (P = 0.01), while HIF2α was associated with intense VEGF/KDR-activated vascularization (P = 0.002). HIF2α protein was less frequently expressed in cases with a medium microvessel density (MVD); a high rate of expression was noted in cases with both low and high MVD (P = 0.006). Analysis of overall survival showed that HIF2α expression was related to poor outcome (P = 0.008), even in the group of patients with low MVD (P = 0.009). HIF1α expression was marginally associated with poor prognosis (P = 0.08). In multivariate analysis HIF2α expression was an independent prognostic indicator (P = 0.006, t-ratio 2.7). We conclude that HIF1α and HIF2α overexpression is a common event in NSCLC, which is related to the up-regulation of various angiogenic factors and with poor prognosis. Targeting 881-890 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2018, available online at http://www.idealibrary.com on http://www.bjcancer.comIn the present study we examined the expression patterns of HIF1α and of HIF2α in normal lung and in a series of non-smallcell lung carcinomas. The expression of HIFs was analysed in comparison with the microvessel density, with the expression of multiple angiogenic factors and receptors as well as with the expression of onco-proteins, previously shown to have a role in lung cancer. The prognostic role of HIF expression was also studied. MATERIALS AND METHODSWe examined 108 tumour samples from patients with early operable (T1,2-N0,1-M0 staged) non-small-cell lung cancer (72 squamous and 36 adenocarcinomas). 12 samples from normal lung obtained during thoracic surgery for reasons other than lung cancer were also examined. Histological diagnosis, grading and Nstage w...

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Section: Discussionmentioning

confidence: 99%

Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival

et al. 2001

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“…This level of sensitivity is likely to be of clinical relevance; for example, the radiocurability of human tumours is reduced with the presence of . 26% of tumour cells with pO2< 8 mmHg (Gatenby et al, 1988). As part of the present study, it was necessary to investigate the effect of anaesthesia on pO, as this form of restraint may be required in experimental studies with SR-4554.…”

Section: Resultsmentioning

confidence: 99%

“…Such measurements have been used clinically to investigate the effect of tumour oxygenation on the radiocurability of human tumours (Kolstad 1968;Gatenby et al, 1988;Okunieff et al, 1993). In addition, a good correlation between the radiobiological hypoxic fraction and oxygen electrode measurements has been reported in various mouse tumour models to date (Horsman et al, 1994;Nordsmark et al, 1995).…”

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confidence: 99%

The relationship between tumour oxygenation determined by oxygen electrode measurements and magnetic resonance spectroscopy of the fluorinated 2-nitroimidazole SR-4554

Aboagye¹,

Maxwell²,

Horsman³

et al. 1998

Br J Cancer

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Summary The relationship between two methods of assessing tumour oxygenation in vivo, namely oxygen electrode measurement and magnetic resonance spectroscopy (MRS) of the fluorinated 2-nitroimidazole SR-4554, was investigated. Using three tumour models (two sites), no linear correlation was observed between 19F retention index and P02 parameters (r < 0.3). Substantial retention of SR-4554 (19F retention index > 0.5) was, however, associated with low tumour P02 (% P02 < 5 mmHg = 60%). Depending on the P02 parameters used, SR-4554 administration was shown to produce either a significant or a non-significant increase in tumour oxygenation. We conclude that measurement of SR-4554-related compound(s) by 19F-MRS has the potential to detect clinically relevant levels of tumour hypoxia.

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“…A number of reports have demonstrated that the probability of distant metastases correlates with oxygen pressure in the tumour tissues (Gatenby et al, 1988;Brizel et al, 1996;Hockel et al, 1998;Rofstad, 2000), suggesting that hypoxia may promote metastatic potential. However, it remains poorly understood how hypoxia promotes the metastatic potential of tumour cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although a variety of factors have been documented to play important roles in the metastatic steps (Poste and Fidler, 1980;Liotta, 1986Liotta, , 1988Nicolson, 1988), many factors are yet to be elucidated. Several clinical investigations demonstrated that patients with hypoxic tumours had poor prognoses and that the incidence of distant metastases was higher in the tumours with low oxygen pressure than in those with high oxygen pressure (Gatenby et al, 1988;Brizel et al, 1996;Hockel et al, 1998;Rofstad, 2000). These studies suggest that the tumour cells exposed to hypoxia at the primary tumour sites acquire aggressive properties including metastatic potential more than the welloxygenated tumour cells do.…”

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confidence: 99%

Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells

et al. 2002

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The incidence of distant metastases is higher in the tumours with low oxygen pressure than in those with high oxygen pressure. It is well known that hypoxia induces the transcription of various genes involved in angiogenesis and anaerobic metabolism necessary for the growth of tumour cells in vivo, suggesting that hypoxia may also induce the transcription of metastasis-associated genes. We sought to identify the metastasis-associated genes differentially expressed in tumour cells under hypoxic conditions with the use of a DNA microarray system. We found that hypoxia enhanced the expression of autocrine motility factor mRNA in various cancer cells and also enhanced the random motility of pancreatic cancer cells. Autocrine motility factor inhibitors abrogated the increase of motility under hypoxic conditions. In order to explore the roles of hypoxia-inducible factor-1a, we established hypoxia-inducible factor-1a-transfectants and dominant negative hypoxiainducible factor-1a-transfectants. Transfection with hypoxia-inducible factor-1a and dominant-negative hypoxia-inducible factor-1a enhanced and suppressed the expression of autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA and the random motility, respectively. These results suggest that hypoxia may promote the metastatic potential of cancer cells through the enhanced autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA expression and that the disruption of the hypoxia-inducible factor-1 pathway may be an effective treatment for metastasis. As metastasis is the major cause of death in cancer patients, control of metastasis is most important in the therapies for cancer patients. In order to control metastasis, we need to understand the details of metastatic process that is now thought to take multiple steps. Although a variety of factors have been documented to play important roles in the metastatic steps (Poste and Fidler, 1980;Liotta, 1986Liotta, , 1988Nicolson, 1988), many factors are yet to be elucidated. Several clinical investigations demonstrated that patients with hypoxic tumours had poor prognoses and that the incidence of distant metastases was higher in the tumours with low oxygen pressure than in those with high oxygen pressure (Gatenby et al, 1988;Brizel et al, 1996;Hockel et al, 1998;Rofstad, 2000). These studies suggest that the tumour cells exposed to hypoxia at the primary tumour sites acquire aggressive properties including metastatic potential more than the welloxygenated tumour cells do. In fact, recent reports have demonstrated that hypoxia enhances the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in tumour cells, resulting in an increase of metastatic potential (Claffey and Robinson, 1996;Shi et al, 1999;Biroccio et al, 2000). However, it remains poorly understood how hypoxia promotes tumour cells' metastatic potential.When tumour cells are exposed to hypoxia, hypoxia-inducible factor-1 (HIF-1), which is a transcription factor composed of HIF-1a and HIF-1b subunits (Wang et al,...

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Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy

Cited by 743 publications

References 16 publications

Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival

Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival

The relationship between tumour oxygenation determined by oxygen electrode measurements and magnetic resonance spectroscopy of the fluorinated 2-nitroimidazole SR-4554

Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells

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