Journal Article•
Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma.
TL;DR: The 18-month actuarial disease-free survival was 70% for patients with tumor median oxygen pressure (pO2) values of >10 mm Hg but only 35% for those with median pO2 values of <10mm Hg (P=0.01); potential mechanisms and implications for clinical trial design are discussed.
Abstract: This study was performed to explore the relationship between tumor oxygenation and treatment outcome in human soft tissue sarcoma. Twenty-two patients with nonmestastatic, high-grade, soft tissue sarcomas underwent preoperative irradiation and hyperthermia and pretreatment measurement of tumor oxygenation. The 18-month actuarial disease-free survival was 70% for patients with tumor median oxygen pressure (pO2) values of >10 mm Hg but only 35% for those with median pO2 values of <10 mm Hg (P=0.01). There were eight treatment failures; the first site of recurrence was lung in all patients. Median pO2 was 7.5 mm Hg for metastasizing tumors versus 20 mm Hg for nonmetastasizing tumors (P=0.03). Potential mechanisms and implications for clinical trial design are discussed.
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TL;DR: Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumor patients.
Abstract: Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.
2,539 citations
TL;DR: Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis, which provides an opportunity for tumour-selective therapy, including prodrugs activated by Hypoxia, hypoxia-specific gene therapy, targeting the hypoxIA-inducible factor 1 transcription factor, and recombinant anaerobic bacteria.
Abstract: Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis. The cells in these hypoxic regions are resistant to both radiotherapy and chemotherapy. However, the existence of hypoxia and necrosis also provides an opportunity for tumour-selective therapy, including prodrugs activated by hypoxia, hypoxia-specific gene therapy, targeting the hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria. These strategies could turn what is now an impediment into a significant advantage for cancer therapy.
2,428 citations
Journal Article•
TL;DR: The first clinical data indicating that HIF-1alpha may play an important role in human cancer progression are provided, indicating adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality.
Abstract: Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1α subunit. In this study, HIF-1α expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1α was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1α expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1α, whereas benign tumors in breast and uterus did not. HIF-1α overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1α immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1α may play an important role in human cancer progression.
2,338 citations
Cites background from "Tumor oxygenation predicts for the ..."
...In many cancers, the degree of vascularization is inversely correlated with patient survival (5); ( c) the probability of invasion, metastasis, and death are positively correlated with the degree of intratumoral hypoxia (6, 7), which is caused by an architecturally defective microcirculation such that even cells adjacent to neovessels may be hypoxic (8)....
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TL;DR: It is shown by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.
1,960 citations
Additional excerpts
...(Brizel et al., 1996; Cairns and Hill, 2004; Hockel et al., 1996; Nordsmark and Overgaard, 2004)....
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TL;DR: HIF-1 appears to function as a master regulator of O2 homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.
Abstract: Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS transcription factor consisting of HIF-1 alpha and HIF-1 beta subunits. HIF-1 alpha expression and HIF-1 transcriptional activity increase exponentially as cellular O2 concentration is decreased. Several dozen target genes that are transactivated by HIF-1 have been identified, including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The products of these genes either increase O2 delivery or allow metabolic adaptation to reduced O2 availability. HIF-1 is required for cardiac and vascular development and embryonic survival. In fetal and postnatal life, HIF-1 is required for a variety of physiological responses to chronic hypoxia. HIF-1 expression is increased in tumor cells by multiple mechanisms and may mediate adaptation to hypoxia that is critical for tumor progression. HIF-1 thus appears to function as a master regulator of O2 homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.
1,912 citations
References
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TL;DR: In this article, the product-limit (PL) estimator was proposed to estimate the proportion of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t).
Abstract: In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed. For random samples of size N the product-limit (PL) estimate can be defined as follows: L...
52,450 citations
"Tumor oxygenation predicts for the ..." refers methods in this paper
...DFS was measured by the Kaplan-Meier prod uct limit method (10)....
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TL;DR: The number of microvessels per 200x field in the areas of most intensive neovascularization in an invasive breast carcinoma may be an independent predictor of metastatic disease either in axillary lymph nodes or at distant sites (or both).
Abstract: Background. Experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis, which may also permit metastasis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, we counted microvessels (capillaries and venules) and graded the density of microvessels within the initial invasive carcinomas of 49 patients (30 with metastases and 19 without). Methods. Using light microscopy, we highlighted the vessels by staining their endothelial cells immunocyto-chemically for factor VIII. The microvessels were carefully counted (per 200×field), and their density was graded (1 to 4+), in the most active areas of neovascularization, without knowledge of the outcome in the patient, the presence or absence of metastases, or any other pertinent variable. Results. Both microvessel counts and density grades correlated with metastatic disease. The mean (±SD) count and grade in the patients with metastases were 101±49.3 and 2.95±1.00 vessels, respect...
5,699 citations
TL;DR: It is proposed that hypoxia provides a physiological selective pressure in tumours for the expansion of variants that have lost their apoptotic potential, and in particular for cells acquiring p53mutations.
Abstract: Apoptosis is a genetically encoded programme of cell death that can be activated under physiological conditions and may be an important safeguard against tumour development. Regions of low oxygen (hypoxia) and necrosis are common features of solid tumours. Here we report that hypoxia induces apoptosis in oncogenically transformed cells and that further genetic alterations, such as loss of the p53 tumour-suppressor gene or overexpression of the apoptosis-inhibitor protein Bcl-2, substantially reduce hypoxia-induced cell death. Hypoxia also selects for cells with defects in apoptosis, because small numbers of transformed cells lacking p53 overtake similar cells expressing wild-type p53 when treated with hypoxia. Furthermore, highly apoptotic regions strongly correlate with hypoxic regions in transplanted tumours expressing wild-type p53, whereas little apoptosis occurs in hypoxic regions of p53-deficient tumours. We propose that hypoxia provides a physiological selective pressure in tumours for the expansion of variants that have lost their apoptotic potential, and in particular for cells acquiring p53 mutations.
2,266 citations
TL;DR: Consideration is given to the supply of oxygen to tissues as a factor in radiotherapy, and it is concluded that in certain circumstances the effectiveness of X-ray treatment might be increased if the patient were breathing oxygen at the time of irradiation.
Abstract: The sensitivity of tumour cells to X rays has been shown to be about three times as great when irradiated in a well-oxygenated medium as under anoxic conditions. The manner in which sensitivity depends on oxygen tension closely resembles that found by other workers for plant and insect tissues. The sensitivity of the tumour cells to fast neutron radiation is only slightly affected by oxygen tension. Consideration is given to the supply of oxygen to tissues as a factor in radiotherapy, and it is concluded on the basis of existing knowledge that in certain circumstances the effectiveness of X-ray treatment might be increased if the patient were breathing oxygen at the time of irradiation. The Ehrlich ascites tumour cells used in the in vitro experiments were grown as a solid tumour and exposed to X rays while the mice were inhaling various mixtures of oxygen and nitrogen at 1 atmosphere pressure and above. In all cases, except when the tumour was very large at the time of irradiation, the regression produce...
2,041 citations
"Tumor oxygenation predicts for the ..." refers background in this paper
...(1) postulated that tumor hypoxia played a significant role in detennining the radiocurability of many cancers because of the well established role that oxygen has in modifying radiation damage....
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Journal Article•
TL;DR: Assay of microvessel density within invasive tumors may prove valuable in selecting patients for aggressive adjuvant therapies in early prostate carcinoma, and was present predominantly in the poorly differentiated tumors.
Abstract: Tumor growth and metastasis require angiogenesis; and microvessel density, a measure of tumor angiogenesis, correlates with metastasis in breast and lung carcinoma To determine how microvessel density correlated with metastasis in prostate carcinoma, we counted microvessels within the initial invasive carcinomas of 74 patients (29 with metastasis, 45 without) Microvessels were highlighted by immunostaining endothelial cells for factor VIII-related antigen Without knowledge of the patient's cancer stage, microvessels were counted in a 200 field (0739 mm2) in the most active areas of neovascularization The mean microvessel count in tumors from patients with metastases was 768 microvessels per 200 field (median, 66; standard deviation, 446) The counts within carcinomas from patients without metastasis were significantly lower, 392 (median, 36; standard deviation, 186) (P < 00001) Microvessel counts increased with increasing Gleason's score (P < 00001), but this increase was present predominantly in the poorly differentiated tumors Although Gleason's score also correlated with metastasis (P = 001), multivariate analysis showed that Gleason's score added no additional information to that provided by microvessel count alone Assay of microvessel density within invasive tumors may prove valuable in selecting patients for aggressive adjuvant therapies in early prostate carcinoma
1,737 citations