Affiliations of authors: M. Höckel, Department of Obstetrics and Gynecology, University of Leipzig, Germany; P. Vaupel, Institute of Physiology and Pathophysiology, University of Mainz, Germany.
Correspondence to: Professor Dr. Peter Vaupel, Institute of Physiology and Pathophysiology, University of Mainz, Duesbergweg 6, 55099 Mainz, Germany (e-mail: VAUPEL{at}mail.uni-mainz.de).
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ABSTRACT |
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INTRODUCTION |
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Sustained hypoxia in a growing tumor may cause cellular changes that can result in a more clinically aggressive phenotype (1115). During the process of hypoxia-driven malignant progression, tumors may develop an increased potential for local invasive growth (16,17), perifocal tumor cell spreading (11,18), and regional and distant tumor cell spreading (12,13,1921). Likewise, intrinsic resistance to radiation and other cancer treatments may be enhanced (18,2229).
Hypoxia-induced or hypoxia-mediated changes of 1) the proteome (i.e., the complete set of proteins within a cell at a given time) of the neoplastic and stroma cells and 2) the genome of the genetically unstable neoplastic cells may explain the fact that tumor oxygenation is associated with disease progression, a link that has been demonstrated for a variety of human malignant tumor types (1115). The first goal of this review is to compile current results from experimental and clinical studies, illustrating the interaction between hypoxia and the phenomena of malignant progression and resistance toward oncologic treatment.
In an increasing number of reports on tumor oxygenation, the term "hypoxia" has been used in a somewhat careless manner without due consideration of the clear definitions for certain experimental conditions and scientific questions. Different researchers discussing the problem of tumor hypoxia may use the term "hypoxia" in different ways, thus leading to a "Babylonian confusion." The second goal of this review is, therefore, to shed some light on the pitfalls of the casual use of the term "tumor hypoxia." Because evidence of the fundamental biologic and clinical importance of tumor hypoxia is increasing, molecular biologists, physiologists, and clinicians should take care to communicate on the same "wavelength" and clearly define what they mean when they use the term "tumor hypoxia."
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DEFINITION AND CAUSATIVE MECHANISMS |
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Biochemists usually define hypoxia as O2-limited electron transport (31). Physiologists and clinicians define hypoxia as a state of reduced O2 availability or decreased O2 partial pressures below critical thresholds, thus restricting or even abolishing the function of organs, tissues, or cells (3234). Anoxia describes the state where no O2 is detected in the tissue (O2 partial pressure = 0 mm of mercury [mmHg]).
In solid tumors, oxygen delivery to the respiring neoplastic and stromal cells is frequently reduced or even abolished by a deteriorating diffusion geometry, severe structural abnormalities of tumor microvessels, and disturbed microcirculation (35). In addition, anemia and the formation of methemoglobin or carboxyhemoglobin reduce the blood's capacity to transport O2. As a result, areas with very low (down to zero) oxygen partial pressures exist in solid tumors, occurring either acutely or chronically. These microregions of very low or zero O2 partial pressures are heterogeneously distributed within the tumor mass and may be located adjacent to regions with normal O2 partial pressures. In contrast to normal tissue, neoplastic tissue can no longer fulfill physiologic functions. Thus, tumor hypoxia cannot be defined by functional deficits, although areas of necrosis, which are often found in tumor tissue on microscopic examination, indicate the loss of vital cellular functions.
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METABOLIC HYPOXIA IN SOLID TUMORS |
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In hypoxia, the mitochondrial O2 consumption rate and ATP production are reduced, which hinders inter alia active transport in tumor cells. Specifically, major effects of the reduced production of ATP are 1) collapse of Na+ and K+ gradients, 2) depolarization of membranes, 3) cellular uptake of Cl-, 4) cell swelling, 5) increased cytosolic Ca2+ concentration, and finally, 6) decreased cytosolic pH, resulting in intracellular acidosis in tumor cells.
According to the definition given above, hypoxia is present in tumors when the O2 partial pressure falls below a critical value causing the O2 consumption rate or ATP production rate of a cell or a tissue to decrease progressively. On the basis of experimental results from isolated xenografted human breast cancer tissue (36,37), tumor tissue hypoxia with reduced O2 consumption rates is expected when the O2 partial pressure in the blood at the venous end of the capillaries (end-capillary blood) falls below 4550 mmHg (Table 1). This critical threshold, however, has been validated only under the following boundary conditions: a tumor blood flow rate of 1 mL/g per minute, a hemoglobin concentration of 140 g/L, and an arterial O2 partial pressure of 90100 mmHg. Reducing the perfusion rate to 0.3 mL/g per minute yields an hypoxic tissue fraction of approximately 20% (48). When the hemoglobin concentration falls below 100 g/L or the normal O2 content of arterial blood decreases (hypoxemia), the relative proportion of hypoxic tissue substantially increases in the experimental tumor system described.
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Mitochondrial oxidative phosphorylation is limited at O2 partial pressures of less than approximately 0.5 mmHg [Table 1 and (32,45)]. Above this threshold, mitochondria should function physiologically. Again, this critical threshold depends on the actual substrate supply, on the pH of the suspending medium, and on the technique used to measure O2. Cytochromes aa3 and c in ascites cells require O2 partial pressures of greater than 0.020.07 mmHg [Table 1
and (32,46,47)] to maintain respiration. At O2 partial pressures above this range, cytochromes are fully oxidized. Spectrophotometric measurements on living and rapidly deep-frozen tissues indicate that the same is true in vivo.
From this rather rudimentary summary of critical O2 partial pressures for metabolic hypoxia, there does not appear to be a single hypoxic threshold that is generally applicable. Hypoxic thresholds range from 4550 mmHg in end-capillary blood to 0.02 mmHg in cytochromes (see Fig. 4). Furthermore, such data on hypoxic thresholds in a given tissue do not take into consideration the existence of severe heterogeneities even on a microscopic level related to variable O2 demands and O2 supply.
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METHODS FOR DETECTION OF TUMOR HYPOXIA |
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Assessment of the tumor oxygenation status by invasive and noninvasive procedures has been reviewed [(5154) and Table 2]. Many methods can detect tumor hypoxia. Which method is most appropriate for a particular experimental or clinical need will depend on the feasibility of the approaches available in terms of invasiveness and the degree of resolution required, on whether measurement of a direct or indirect parameter is necessary, and, of course, on financial considerations.
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HYPOXIA-MEDIATED PROTEOME CHANGES AND TUMOR PROPAGATION |
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Binding of the hypoxic marker pimonidazole to suprabasal cells in epithelia supports the hypothesis that hypoxia may act as a morphogen to induce the terminal differentiation of cells (85,100). This observation appears to have a counterpart in well-differentiated squamous cell cancer, where squamous cell differentiation is consistently observed in tumor areas several cell layers away from the nearest blood vessels (Höckel M: unpublished observations). The molecular mechanisms of hypoxia-induced terminal differentiation are largely unknown.
Hypoxia can induce programmed (apoptotic) cell death in normal and neoplastic cells (101). Indeed, oncogenic transformation of cells (e.g., transfection with human papillomavirus E6/E7 genes or c-myc genes) increases their susceptibility to hypoxia-induced apoptosis (23). The level of p53 in cells increases under hypoxic conditions, and the increased level of p53 induces apoptosis by a pathway involving Apaf-1 and caspase-9 as downstream effectors (105). However, hypoxia also initiates p53-independent apoptosis pathways involving hypoxia-inducible factor-1 (HIF-1), genes of the BCL-2 family, and other unidentified genes (106,107). Below a critical energy state, hypoxia/anoxia may result in necrotic cell death, a phenomenon seen in many human tumors and experimental systems. Hypoxia-induced proteome changes, leading to cell cycle arrest, differentiation, apoptosis, and necrosis, may explain delayed recurrences, dormant micrometastases (108,109), and growth retardation in large tumor masses (110).
In contrast, hypoxia-induced proteome changes in tumor and/or stromal cells may promote tumor propagation by enabling the cells to adapt to nutritional deprivation or to escape their hostile environment. Hypoxia stimulates the transcription of glycolytic enzymes, glucose transporters (GLUT1 and GLUT3), angiogenic molecules, survival and growth factors (e.g., vascular endothelial growth factor [VEGF], angiogenin, platelet-derived growth factor-, transforming growth factor-
, and insulin-like growth factor-II), enzymes, proteins involved in tumor invasiveness (e.g., urokinase-type plasminogen activator), chaperones, and other resistance-related proteins (8,17,29,97,106,111119). At the same time, hypoxia-induced inhibition of gene expression has been demonstrated for cell-surface integrins facilitating tumor cell detachment (120).
Many hypoxia-inducible genes are controlled by a common transcription factor, HIF-1, composed of two subunits, HIF-1 and HIF-1
(121). Increased concentrations of HIF-1 in the proteome of a hypoxic cell result from increased transcription of HIF-1
and HIF-1
genes and decreased HIF-1
protein degradation, an example of hypoxia-mediated posttranslational control (122124). Jiang et al. (111) exposed human HeLa cells to concentrations of O2 between 0.125% and 20% (with 5% CO2 added and the remainder N2) and then analyzed HIF-1 expression as a function of intracellular O2 concentration. HIF-1 DNA-binding activity and the concentrations of HIF-1
protein and HIF-1
protein increased exponentially as cells were subjected to decreasing concentrations of O2, with a half-maximal response at about 10 mmHg. Hypoxia-induced HIF-1 activation can also result in an increased production of VEGF. To determine the reduced O2 concentration required to stimulate increased levels of VEGF messenger RNA (mRNA), Chiarotto and Hill (125) determined O2 concentrations in culture medium from cervical cancer cell lines SiHa, ME-180, or HeLa cells, under distinct boundary conditions, and defined the threshold for increasing the level of VEGF mRNA above baseline as O2 pressure of approximately 1 mmHg in the gassing mixture.
Nuclear factor B (NF
B) is another transcriptional factor that can be activated by hypoxia (126). The threshold for activation of NF
B in AG1522 cells occurs after 3 hours at an O2 partial pressure of about 15 mmHg (127). Thus, the critical O2 levels necessary for hypoxia-induced gene expression are probably in the range of 115 mmHg (Table 3
and see Fig. 4
). Below these levels, mRNA levels often rise almost exponentially to a maximum value.
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HYPOXIA-MEDIATED MALIGNANT PROGRESSION |
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In most investigations of hypoxia-induced genomic changes, transformed cells were incubated at almost zero O2 partial pressure and then reoxygenated at atmospheric O2 partial pressure. Rice et al. (29) demonstrated that, after incubating Chinese hamster ovary cells for up to 72 hours in less than 10 parts per million (ppm) of O2, the dihydrofolate reductase gene was amplified, which led to increased methotrexate resistance. By incubating murine cells under similar conditions, Young et al. (19) observed that DNA overreplication transiently enhanced the formation of experimental metastases. To induce the transformation of a benign B16 melanoma cell phenotype to a malignant phenotype, Stackpole et al. (137) incubated monolayers of cells for 48 hours in an O2-depleted medium. After 24 hours, these cultures were severely hypoxic (<50 ppm of O2). Russo and co-workers (134,136) observed DNA breakage resulting from activation of an endogenous endonuclease in immortal rat embryo fibroblasts cultured under anoxic conditions for up to 24 hours. Reynolds et al. (133) used a mouse tumor cell line carrying a chromosomally based phage shuttle vector for reporting mutations. After exposing these cells to an O2 partial pressure of less than 1 mmHg for 4 hours, they detected a mutation rate that was 3.4-fold higher than the rate in similar cells cultured under standard atmospheric conditions. Giaccia and colleagues (22,23,97) used an elegant procedure to select transformed cells with reduced apoptotic potential. Specifically, they cultured transformed mouse embryonic fibroblasts and transformed human cervical epithelial cells under a reduced O2 partial pressure of less than 1 mmHg for 48 hours, followed by up to seven reoxygenation treatments. As a rule, hypoxia-induced genomic changes are detectable at an O2 partial pressure of less than 1 mmHg, which is approximately one order of magnitude lower than the O2 partial pressures associated with proteome changes (Table 3
and Fig. 4
).
Hypoxia-mediated clonal selection of neoplastic cells with persistent genomic changes leading, inter alia, to apoptotic insensitivity and increased angiogenic potential stabilizes and further aggravates tumor hypoxia, which in turn promotes malignant progression. Thus, hypoxia is involved in a vicious circle that is regarded as a fundamental biologic mechanism of the malignant disease, once cellular proliferation has been deregulated [(11,14) and Fig. 3].
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TUMOR HYPOXIA AND TREATMENT RESISTANCE |
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Oxygen dependency has been documented for a number of anticancer agents (e.g., cyclophosphamide, carboplatin, and doxorubicin) under in vitro and in vivo conditions (138,139). However, these investigations have been qualitative, and clear hypoxic thresholds for O2-dependent anticancer agents are still not available, although they presumably exist for each agent. Thus, additional research is necessary to provide quantitative data on hypoxia-induced chemoresistance, although this information may be difficult to obtain under in vivo conditions. Multiple mechanisms are probably also involved in the hypoxia-induced resistance to chemotherapeutic agents, including an inhibition of cell proliferation (140), a hypoxia-induced decreased cytotoxicity of some agents (98,138,141), and tissue acidosis, which is often observed in hypoxic tumors with a high glycolytic rate (142). Furthermore, hypoxic stress proteins and the loss of apoptotic potential can impart resistance to certain chemotherapeutic drugs (2629,112,114,143).
Photodynamic therapy-mediated cell death requires the presence of oxygen, a photosensitizing drug, and light of the appropriate wavelength, both in vitro and in vivo [for a review, see (144)]. Reports (129,145), however, vary greatly on the extent to which photodynamic therapy with hematoporphyrin derivatives is dependent on oxygen. Cells were not killed under anoxic conditions. The critical threshold below which progressively reduced cell death was observed varied from 15 to 35 mmHg (129131), probably because of the reduced production of singlet oxygen (1O2) species and different sensitivities to the treatment in different cell lines (Table 3 and Fig. 4
). Considering the reduced effectiveness of photodynamic agents at lower O2 partial pressures, the rapid induction of tumor hypoxia by photodynamic therapy itselfeither as a consequence of a photodynamic therapy-induced decrease in blood flow or as a result of oxygen consumption by the photodynamic therapy process itselfhas to be considered under in vivo conditions, since it may mean that this therapy is self-limiting (129,132,146). Photodynamic therapy involving prodrugs, such as aminolevulinic acid, may be further limited because conversion of the prodrug to the active photosensitizer appears to be less effective under hypoxic conditions.
Studies of cells in vitro have identified several factors that can influence the effect of hyperthermia on cell survival. Cell lines can vary substantially in their intrinsic heat sensitivity. In addition, cell cycle position, intracellular pH, nutrient deprivation, and ATP depletion can affect cell survival after a heat treatment (147,148). At 43 °C hyperthermia, hypoxia per se may not cause cell death as long as concomitant changes in the nutritional and/or bioenergetic status of the cells do not occur (149).
Finally, tumor hypoxia can dramatically alter the potency of cytokines (interferon gamma and tumor necrosis factor-) and alter interleukin 2-induced activation of lymphokine-activated killer cells [reviewed in (128)]. The potency of treatment started to decrease at O2 partial pressures of less than approximately 35 mmHg (Table 3
and Fig. 4
).
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TUMOR HYPOXIA AS AN ADVERSE PROGNOSTIC FACTOR |
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In local recurrences of cervical cancer, oxygenation levels of the recurrent tumor were generally lower than levels in the primary tumors of comparable mass. In the cohort of patients with recurrent tumors, oxygenation measurements provided additional prognostic information. Patients with tumors that had a median O2 partial pressure of less than 4 mmHg had a statistically significantly shorter median survival time than those with median O2 partial pressure of 4 mmHg or more [Table 4 and (14)].
The pretreatment tumor oxygenation status was also assessed in patients with soft-tissue sarcomas (12,153,155,159,160). In these patients, the more hypoxic tumors were associated with a poorer survival when compared with normoxic tumors resulting from local treatment failure or distant metastases (Table 4).
In a study on the association between the tissue oxygenation status and the radiation response in lymph node metastases of squamous cell carcinomas of the head and neck, Nordsmark et al. (156) showed that the most hypoxic tumors had statistically significantly lower locoregional tumor control than well-oxygenated tumors. Cox multiple regression analysis found that an O2 partial pressure of 2.5 mmHg or less was the strongest independent variable for prediction of a response to radiation therapy, when the end point was tumor control at the site where the O2 partial pressure was measured. Brizel et al. (20,155) also showed that tumor hypoxia appears to adversely affect the prognosis of patients with primary and metastatic squamous cell carcinomas of the head and neck (Table 4).
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HOW CAN THE TERM "TUMOR HYPOXIA" BE USED APPROPRIATELY? |
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We, therefore, recommend that only data describing defined functions or activities of tumor cells or characteristics of tumors be compared. Because critical O2 levels of different parameters or reactions can vary substantially, we recommend that only results from assays describing the same biologic parameter (e.g., radiation sensitivity) be tested for correlation. Otherwise, pseudocorrelations may be misinterpreted as real biologic interrelationships.
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NOTES |
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We thank Dr. Debra Kelleher for her valuable input during manuscript preparation.
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Manuscript received May 10, 2000; revised November 1, 2000; accepted November 30, 2000.
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