Since the initial observations made at the beginning of the last century, it has been established that solid tumors contain regions of low oxygenation (hypoxia). Tumor cells can survive in these ...hypoxic conditions and are a major factor in tumor radioresistance. This significance has resulted in hypoxia becoming the most cited biological topic in translational radiation oncology. Identifying hypoxic cells in human tumors has become paramount, and the ability to do this has been improved by the help of new imaging techniques and the use of predictive gene profiles. Substantial data confirm the presence of hypoxia in many types of human tumors, although with considerable heterogeneity among individual tumors. Various approaches have been investigated for eliminating the hypoxic population. These include increasing oxygen availability, directly radiosensitizing or killing the hypoxic cells, indirectly affecting them by targeting the tumor vascular supply, increasing the radiation dose to this resistant population, or by using radiation with a high linear energy transfer, for which hypoxia is believed to be less of an issue. Many of these approaches have undergone controlled clinical trials during the last 50 years, and the results have shown that hypoxic radiation resistance can indeed be overcome. Thus, ample data exists to support a high level of evidence for the benefit of hypoxic modification. However, such hypoxic modification still has no impact on general clinical practice. In this review we summarize the biological rationale, and the current activities and trials, related to identifying and overcoming hypoxia in modern radiotherapy.
Tumor hypoxia is a common feature of the microenvironment in solid tumors, primarily due to an inadequate, and heterogeneous vascular network. It is associated with resistance to radiotherapy and ...results in a poorer clinical outcome. The presence of hypoxia in tumors can be identified by various invasive and non-invasive techniques, and there are a number of approaches by which hypoxia can be modified to improve outcome. However, despite these factors and the ongoing extensive pre-clinical studies, the clinical focus on hypoxia is still to a large extent lacking. Hypoxia is a major cellular stress factor and affects a wide range of molecular pathways, and further understanding of the molecular processes involved may lead to greater clinical applicability of hypoxic modifiers. This review is a discussion of the characteristics of tumor hypoxia, hypoxia-related molecular pathways, and the role of hypoxia in treatment resistance. Understanding the molecular aspects of hypoxia will improve our ability to clinically monitor hypoxia and to predict and modify the therapeutic response.
Poor microenvironmental conditions are a characteristic feature of solid tumors. Such conditions occur because the tumor vascular supply, which develops from the normal host vasculature by the ...process of angiogenesis, is generally inadequate in meeting the oxygen and nutrient demands of the growing tumor mass. Regions of low oxygenation (hypoxia) is believed to be the most critical deficiency, since it has been well documented to play a significant role in influencing the response to conventional radiation and chemotherapy treatments, as well as influencing malignant progression in terms of aggressive growth and recurrence of the primary tumor and its metastatic spread. As a result, significant emphasis has been placed on finding clinically applicable approaches to identify those tumors that contain hypoxia and realistic methods to target this hypoxia. However, most studies consider hypoxia as a single entity, yet we now know that it is multifactorial. Furthermore, hypoxia is often associated with other microenvironmental parameters, such as elevated interstitial fluid pressure, glycolysis, low pH, and reduced bioenergetic status, and these can also influence the effects of hypoxia. Here, we review the various aspects of hypoxia, but also discuss the role of the other microenvironmental parameters associated with hypoxia.
Tumor regions that are transiently or chronically undersupplied with oxygen (hypoxia) and nutrients, and enriched with acidic waste products, are common due to an abnormal and inefficient tumor ...vasculature, and a deviant highly glycolytic energy metabolism. There is compelling evidence that tumor hypoxia is strongly linked to poor prognosis since oxygen-deprived cells are highly resistant to therapy including radio- and chemotherapy, and survival of such cells is a primary cause of disease relapse. Despite a general improvement in cancer survival rates, hypoxia remains a formidable challenge. Recent progress in radiation delivery systems with improved spatial accuracy that allows dose escalation to hypoxic tumors or even tumor subvolumes, and the development of hypoxia-selective drugs, including bioreductive prodrugs, holds great promise for overcoming this obstacle. However, apart from one notable exception, translation of promising preclinical therapies to the clinic have largely been disappointing. A major obstacle in clinical trials on hypoxia-targeting strategies has been the lack of reliable information on tumor hypoxia, which is crucial for patient stratification into groups of those that are likely to benefit from intervention and those who are not. Further, in many newer trials on hypoxia-selective drugs the choice of cancer disease and combination therapy has not always been ideal, especially not for clinical proof of principle trials. Clearly, there is a pending need for clinical applicable methodologies that may allow us to quantify, map and monitor hypoxia. Molecular imaging may provide the information required for narrowing the gap between potential and actual patient benefit of hypoxia-targeting strategies. The grand majority of preclinical and clinical work has focused on the usefulness of PET-based assessment of hypoxia-selective tracers. Since hypoxia PET has profound inherent weaknesses, the use of other methodologies, including more indirect methods that quantifies blood flow or oxygenation-dependent flux changes through ATP-generating pathways (eg, anaerobic glycolysis) is being extensively studied. In this review, we briefly discuss established and emerging hypoxia-targeting strategies, followed by a more thorough evaluation of strengths and weaknesses of clinical applicable imaging methodologies that may guide timely treatment intensification to overcome hypoxia-driven resistance. Historically, most evidence for the linkage between hypoxia and poor outcome is based on work in the field of radiotherapy. Therefore, main emphasis in this review is on targeting and imaging of hypoxia for improved radiotherapy.
The tumor microenvironment is increasingly recognized as a major factor influencing the success of therapeutic treatments and has become a key focus for cancer research. The progressive growth of a ...tumor results in an inability of normal tissue blood vessels to oxygenate and provide sufficient nutritional support to tumor cells. As a consequence the expanding neoplastic cell population initiates its own vascular network which is both structurally and functionally abnormal. This aberrant vasculature impacts all aspects of the tumor microenvironment including the cells, extracellular matrix, and extracellular molecules which together are essential for the initiation, progression and spread of tumor cells. The physical conditions that arise are imposing and manifold, and include elevated interstitial pressure, localized extracellular acidity, and regions of oxygen and nutrient deprivation. No less important are the functional consequences experienced by the tumor cells residing in such environments: adaptation to hypoxia, cell quiescence, modulation of transporters and critical signaling molecules, immune escape, and enhanced metastatic potential. Together these factors lead to therapeutic barriers that create a significant hindrance to the control of cancers by conventional anticancer therapies. However, the aberrant nature of the tumor microenvironments also offers unique therapeutic opportunities. Particularly interventions that seek to improve tumor physiology and alleviate tumor hypoxia will selectively impair the neoplastic cell populations residing in these environments. Ultimately, by combining such therapeutic strategies with conventional anticancer treatments it may be possible to bring cancer growth, invasion, and metastasis to a halt.
It has long been established that hyperthermia increases the therapeutic benefit of radiation and chemotherapy in cancer treatment. During the last few years there have been substantial technical ...improvements in the sources used to apply and measure heat, which greatly increases enthusiasm for the clinical use of hyperthermia. These advances are converging with a better understanding of the physiological and molecular effects of hyperthermia. Therefore, we are now at a juncture where the parameters that will influence the efficacy of hyperthermia in cancer treatment can be optimised in a more systematic and rational manner. In addition, the novel insights in hyperthermia's many biological effects on tumour cells will ultimately result in new treatment regimes. For example, the molecular effects of hyperthermia on the essential cellular process of DNA repair suggest novel combination therapies, with DNA damage response targeting drugs that should now be clinically explored. Here, we provide an overview of recent studies on the various macroscopic and microscopic biological effects of hyperthermia. We indicate the significance of these effects on current treatments and suggest how they will help design novel future treatments.
Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a ...significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39⁻45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.
Imaging hypoxia to improve radiotherapy outcome Horsman, Michael R; Mortensen, Lise Saksø; Petersen, Jørgen B ...
Nature reviews. Clinical oncology,
12/2012, Letnik:
9, Številka:
12
Journal Article
Recenzirano
Reduced oxygen levels (hypoxia) is one of the most important factors influencing clinical outcome after radiotherapy. This is primarily because hypoxic cells are resistant to radiation treatment; ...hence, the greater the number of clonogenic cancer stem cells that exist under hypoxia, the lower the local tumour control. Reduced local control will influence overall survival, as may the hypoxic conditions by increasing malignant progression; however, to fight hypoxia, we should first be able to see it. We need noninvasive approaches that can accurately and reliably image hypoxia in tumours, especially using techniques that are routinely available in the clinic, such as PET, MRI and CT. All these imaging methods are already under clinical evaluation in this context. Such data should allow us to identify those patients on an individual basis who have hypoxic tumours and, thus, at the very least should receive some form of hypoxic modifier in conjunction with radiotherapy. Alternatively, the radiation dose could be either increased to the whole tumour or, if the imaging is accurate enough, only to the hypoxic subvolumes. The aim of this Review is to critically assess the potential use of imaging to help improve clinical outcome to radiotherapy.
The tumor microenvironment is characterized by regions of hypoxia and acidosis which are linked to poor prognosis. This occurs due to an aberrant vasculature as well as high rates of glycolysis and ...lactate production in tumor cells even in the presence of oxygen (the Warburg effect), which weakens the spatial linkage between hypoxia and acidosis.
Five different human squamous cell carcinoma cell lines (SiHa, FaDuDD, UTSCC5, UTSCC14 and UTSCC15) were treated with hypoxia, acidosis (pH 6.3), or a combination, and gene expression analyzed using microarray. SiHa and FaDuDD were chosen for further characterization of cell energetics and protein synthesis. Total cellular ATP turnover and relative glycolytic dependency was determined by simultaneous measurements of oxygen consumption and lactate synthesis rates and total protein synthesis was determined by autoradiographic quantification of the incorporation of 35S-labelled methionine and cysteine into protein.
Microarray analysis allowed differentiation between genes induced at low oxygen only at normal extracellular pH (pHe), genes induced at low oxygen at both normal and low pHe, and genes induced at low pHe independent of oxygen concentration. Several genes were found to be upregulated by acidosis independent of oxygenation. Acidosis resulted in a more wide-scale change in gene expression profiles than hypoxia including upregulation of genes involved in the translation process, for example Eukaryotic translation initiation factor 4A, isoform 2 (EIF4A2), and Ribosomal protein L37 (RPL37). Acidosis suppressed overall ATP turnover and protein synthesis by 50%. Protein synthesis, but not total ATP production, was also suppressed under hypoxic conditions. A dramatic decrease in ATP turnover (SiHa) and protein synthesis (both cell lines) was observed when hypoxia and low pHe were combined.
We demonstrate here that the influence of hypoxia and acidosis causes different responses, both in gene expression and in de novo protein synthesis, depending on whether the two factors induced alone or overlapping, and as such it is important for in vivo studies to take this into account.
Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, ...combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant normal tissues.
Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm
foot implanted C3H mammary carcinomas was assessed using percent tumor control at 90 days. Normal tissue effects were evaluated using early responding skin (development of moist desquamation in the foot at 11-30 days), and late responding bladder (50% reduction in reservoir function estimated by cystometry up to 9 months after treatment), and lung (20% increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p < .05).
The radiation dose controlling 50% of irradiated tumors was 52 Gy. This significantly decreased to 45 Gy with CA4P. The radiation doses inducing a change in skin, bladder and lung response in 50% of mice were 31 Gy, 14 Gy and 12 Gy, respectively. CA4P had no significant effect on the radiation response of any of these normal tissues.
VDAs significantly enhance tumor radiation response, but had absolutely no effect on the radiation response of early or late responding normal tissues.
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