Why Do Tumors Metastasize? - Universidad de Sevilla

[Cancer Biology & Therapy 6:2, 141-144; February 2007]; ©2007 Landes Bioscience

Journal Club

Why Do Tumors Metastasize? Abstract

Correspondence to: Miguel López-Lázaro; Department of Pharmacology; Faculty of Pharmacy; University of Seville; C/ Profesor Garcia Gonzalez; Sevilla 41012 Spain; Tel.: +34.954.55.61.24; Fax: +34.954.23.37.65; Email: [email protected]

Approximately 90% of all cancer deaths can be attributed to the metastatic spread of primary tumors. An understanding of the process by which cells from a localized tumor invade adjacent tissues and migrate to distant organs is crucial for the development of anticancer strategies that can efficiently prevent this process. Although our knowledge of cancer has increased in recent years, the molecular mechanisms of tumor invasion and metastasis still remain elusive. This report discusses recent data that suggest that tumors metastasize because tumor cells have an alteration in oxygen metabolism (dysoxia). This alteration in oxygen metabolism would drive tumor invasion and metastasis via glycol‑ ysis‑mediated extracellular acidification, excessive production of hydrogen peroxide (H2O2) and hypoxia‑inducible factor 1 (HIF‑1) activation. This new model might help develop cancer chemopreventive strategies for preventing tumor metastasis and thus reduce cancer mortality.

Key words

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invasion, metastasis, chemoprevention, glycolysis, extracellular acidification, hypoxiainducible factor 1, hydrogen peroxide, dysoxia

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Previously published online as a Cancer Biology & Therapy E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=3950

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Original manuscript submitted: 01/25/07 Manuscript accepted: 02/03/07

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Miguel López-Lázaro

Introduction

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Cancer starts as a localized disease that, if detected early, can usually be treated successfully by surgery and radiation therapy. When a primary tumor metastasizes, however, the effectiveness of cancer therapies decreases dramatically. In fact, approximately 90% of all cancer deaths can be attributed to the metastatic spread of primary tumors, and the mean survival for people with common metastatic cancers is generally very low. An understanding of the process of metastasis may lead to the development of new strategies to prevent this process and therefore reduce the burden of this disease.1‑5 It is recognized that during the multistage process of metastasis, tumor cells must separate from the primary tumor, invade adjacent tissues and migrate to the bloodstream or the lymphatic system. These cells can thus reach and colonize target organs, where they can grow and form new tumors. It is also becoming apparent that metastasis involves several processes (e.g., cell‑cell adhesion, cell‑extracellular matrix adhesion, cell migration/ motility, degradation of the extracellular matrix, etc.) in which an increasing number of molecules are known to participate (e.g., cadherins, integrins, growth factors, matrix metalloproteinases, etc.).1‑4 Despite this knowledge, the molecular mechanisms involved in metastasis are not well understood. Indeed, although cancer is considered to be a genetic disease, none of the many abnormalities in cancer genes are known to be specifically associated with the metastatic stage.6 The fundamental reason that makes tumor cells invade adjacent tissues and migrate to distant organs remains to be elucidated. The present report does not seek to review the increasing number of processes and molecules that have been shown to play a role in tumor metastasis (see refs. 1–4 for detailed reviews on our current knowledge on tumor metastasis). This article discusses recent evidence that suggests that the fundamental reason that drives tumor metastasis is an alteration in oxygen (O2) metabolism in the tumor cells (dysoxia). This novel and simple approach might be exploited for the development of anticancer strategies for preventing tumor metastasis.

Hypothesis: The Driving Force of Tumor Invasion and Metastasis May be an Alteration in Oxygen Metabolism in the Tumor Cells (Dysoxia) Our cells can obtain energy through the O2‑dependent pathway of oxidative phosphorylation (oxphos) and through the O2‑independent pathway of glycolysis. In cells under aerobic conditions, glycolysis is inhibited (Pasteur effect) and energy is obtained www.landesbioscience.com

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Why Do Tumors Metastasize?

via oxphos. In the process of oxphos, ATP generation is coupled with a reaction in which O2 is reduced to H2O.7 But under certain conditions, O2 can also be reduced to H2O via the generation of the O2‑derived species superoxide anion (O2•—) and hydrogen peroxide (H2O2). The new model represented in (Fig. 1) proposes that the key event involved in tumor invasion and metastasis is an excessive deviation of O2 metabolism from the route that generates ATP to the route that generates O2•— and H2O2 (dysoxia). This alteration in O2 metabolism would drive tumor invasion and metastasis via glycolysis‑mediated extracellular acidification, excessive production of H2O2 and hypoxia‑inducible factor 1 (HIF‑1) activation.

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Figure 1. Dysoxia‑mediated tumor invasion and metastasis. This model proposes that an excessive deviation of O2 metabolism from the route that generates ATP to the route that generates O2•— and H2O2 (dysoxia) controls tumor invasion and metastasis via glycolysis‑mediated extracellular acidification (↓ pHe), excessive production of H2O2 and HIF‑1 activation. Experimental data have shown that tumor cells commonly have oxphos repression, glycolysis activation, extracellular acidification, increased O2•— and H2O2 production and HIF‑1 activation. Evidence suggests that extracel‑ lular acidification, H2O2 and HIF‑1 play an essential role in invasion and metastasis.

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Several decades ago, the German Biochemist Otto Warburg observed that tumor cells had increased glycolytic rates even in the presence of an adequate O2 supply (aerobic glycolysis or Warburg effect);8 this phenomenon has repeatedly been confirmed.9‑13 Recent data suggest that cancer cells may depend on glycolysis for ATP generation and that cancer cells’ dependence on glycolytic energy progressively increases as malignant transformation occurs.13‑16 Experimental data suggest that the high rates of aerobic glycolysis of tumor cells may be associated with oxphos repression. Thus, it has been observed that cells from the most common cancer types have decreased expression of ATP synthase, a mitochondrial protein complex required for ATP generation through oxphos.17‑20 It has also been shown that the inactivation of p53 may produce oxphos repression; p53 is involved in the activity of cytochrome c oxidase, a protein complex involved in oxphos.21 Overall, these experimental data support that tumor cells have oxphos repression and glycolysis activation; the activation of glycolysis would compensate the decreased ATP generation through oxphos (see Fig. 1). It is known that the activation of glycolysis increases the production of H+ (lactic acid) in the cytosol,7 which are extruded from the tumor cells via activation of the Na+/H+‑exchanger and H+/lactate cotransporter.22 Because of the activation of these H+ extruders, tumor cells are known to have intracellular alkalinization (pHi 7.12–7.65 compared with 6.99–7.20 in normal tissues) and extracellular acidification (pHe 6.2–6.9 compared with 7.3–7.4 in normal tissues).22,23 Accumulating evidence suggests that tumor cells produce high levels of O2•— and H2O2.24‑31 For instance, Szatrowski and Nathan reported that several tumor cell lines, representing a variety of tissue types, constitutively produced large amounts of H2O2. They observed that the cumulative amount of H2O2 produced after 4h by these tumor cells was comparable to the amount of H2O2 produced by similar numbers of phorbol ester‑triggered neutrophils.24 It has recently been suggested that a high cellular production of O2•– and H2O2 may play a crucial role in cancer development.30,31 A growing body of research strongly suggests that the activation of the transcription factor HIF‑1 may be a key alteration in cancer.32‑34 HIF‑1 overexpression is observed in the most common cancer types and has been associated with increased patient mortality. For instance, Zhong et al. identified increased HIF‑1 expression (relative to adjacent normal tissue) in 13 tumor types including lung, prostate, breast, and colon carcinoma, which are the leading causes of cancer mortality in developed countries.35 As represented in Figure 1, recent research has established that an increase in the cellular concentrations of H2O2 results in HIF‑1 activation; indeed, overexpression of the H2O2‑detoxifying enzyme catalase prevents the activation of HIF‑1

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Do Tumor Cells Have an Alteration in O2 Metabolism?

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induced by different stimuli.36‑41 It has also been found that the activation of glycolysis in cancer cells can keep high HIF‑1 levels (in the presence of O2) via accumulation of glucose metabolites.42‑44 In addition, it has been proposed recently that the key cellular event involved in HIF‑1 activation in both normal and tumor cells may be an alteration in O2 metabolism.45 In short, the model proposed in Figure 1 shows that an alteration in oxygen metabolism (dysoxia) produces tumor invasion and metastasis via oxphos repression, glycolysis activation, extracellular acidification, increased H2O2 production and HIF‑1 activation. Experimental data have revealed that all these cellular changes are commonly observed in tumor cells; this supports the idea that tumor cells have this alteration in O2 metabolism.

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Can this Alteration in O2 Metabolism Produce Tumor Invasion And Metastasis? Figure 1 represents that an alteration in O2 metabolism produces tumor invasion and metastasis via three events commonly observed in cancer: increased production of H2O2, extracellular acidification and HIF‑1 activation. Interestingly, an increasing number of reports are showing that these three events can alter important processes and molecules involved in tumor invasion and metastasis. For instance, it has been observed that HIF‑1 regulates the expression of genes encoding cathepsin D, matrix metalloproteinase‑2, urokinase plasminogen activator receptor (UPAR), fibronectin 1; keratins 14, 18 and 19, vimentin, transforming growth factor a, and autocrine motility factor; these are proteins that play established roles in the pathophysiology of invasion.46 Cadherins, which are important mediators of cell‑cell adhesion, seem to be repressed by HIF‑1 activation.47,48 It has also been proposed that H2O249 and HIF‑150 may mediate lysyl oxidase (LOX) activity and expression, respectively, therefore facilitating invasion and metastasis. Focal adhesion kinase


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experimental data have shown that the attenuation of glycolysis in cancer cells results in stimulation of oxphos;69,70 this suggests that tumor cells have oxphos repression instead of irreversible damages to oxphos. But, what causes oxphos repression in tumor cells? The alkaline intracellular pH of tumor cells22,23,71 may cause oxphos repression, as ATP generation through oxphos requires an electrochemical H+ gradient across the inner mitochondrial membrane and intracellular alkalinization decreases such gradient.7,45 The increased HIF‑1 levels of cancer cells may also result in oxphos repression, as this transcription factor induces pyruvate dehydrogenase kinase 1 (PDK1); this enzyme decreases the activity of the tricarboxylic acid (TCA) cycle and attenuates oxphos.72‑74 This suggests that the induction of intracellular acidification (e.g., by inhibiting the H+ extruders Na+/H+‑exchanger and the H+/lactate cotransporter) or the inhibition of HIF‑1 might restore oxphos activity and prevent tumor metastasis. Figure 1 shows that dysoxia‑induced tumor invasion and metastasis is produced via glycolysis‑mediated extracellular acidification, excessive production of H2O2 and HIF‑1 activation. Tumor metastasis might therefore be prevented by attenuating glycolysis, by decreasing extracellular acidification, by reducing the levels of H2O2 or by inhibiting HIF‑1 activity. Several strategies have already been proposed to attenuate glycolysis,13,69 prevent extracellular acidification,22,71 decrease H2O2 levels62‑65 and prevent HIF‑1 activation.34 These strategies may prevent the metastatic spread of primary tumors. In summary, since metastatic disease is the primary cause of death for most cancer patients, it is crucial to understand why tumors metastatize. This knowledge will probably help develop better anticancer approaches and improve patient outcome. Although tumor invasion and metastasis are clinically the most relevant processes involved in carcinogenesis, it is recognized that they are the least well understood at the molecular level. The present report discusses evidence that suggests that the key event responsible for tumor invasion and metastasis may be an alteration in oxygen metabolism in the tumor cells. This new model might help develop anticancer strategies to prevent metastatic disease.

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(FAK), a critical mediator of adhesion and migration, is also modulated by H2O249 and HIF‑1.51 Acidic extracellular pH,52 HIF‑146,53 and H2O254,55 can increase the expression of matrix metalloproteinases, a group of proteins that degrade the extracellular matrix. It has also been reported that the metastatic activity of Met (a critical mediator of cell motility) may be mediated by H2O256 and is regulated by HIF‑1.57 Several other studies suggest that an acidic extracellular pH is important for tumor invasion and metastasis.22,58‑61 Indeed, it has been proposed that extracellular acidification is a key event in tumor invasion,61 the initial step of the metastatic process. The key role of H2O2 in metastasis is also supported by experimental data that have revealed that the H2O2‑detoxifying enzyme catalase can inhibit metastasis.54,62‑65 These examples support that the alteration in O2 metabolism depicted in Figure 1 is a key event in tumor invasion and metastasis. Recent investigations have demonstrated a consistent link between hypoxia and tumor invasion and metastasis. In fact, hypoxia is well known to produce HIF‑1 activation and, as mentioned above, the activation of HIF‑1 has been implicated in key aspects of tumor invasion and metastasis. It is important to note that the alteration in O2 metabolism represented in Figure 1 (dysoxia) can be induced both by hypoxia and by non-hypoxic stimuli.45 On the one hand, hypoxia is known to increase the cellular levels of O2•- and H2O2; it has been shown that hypoxia‑induced HIF‑1 activation is fundamentally mediated by H2O2.36‑39 Hypoxia is also known to decrease oxphos activity and activate glycolysis (Pasteur effect). On the other hand, it is well known that cells under non-hypoxic condition can increase their levels of O2•– and H2O2, repress oxphos and activate glycolysis. For instance, it has been shown that, under normoxic conditions, tumor cells produce high levels of O2•- and H2O2,24,25 have oxphos repression and increased glycolytic rates (aerobic glycolysis or Warbug effect),9,21 and keep high HIF‑1 levels.42,44,45,66 In brief, the model proposed in Figure 1 implies that anything (i.e., hypoxia or nonhypoxic stimuli) that causes an excessive deviation of O2 metabolism from the route that generates ATP (oxphos) to the route that generates O2•– and H2O2 can favor tumor invasion and metastasis.

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Relevance to cancer chemoprevention.

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It is recognized that cancer chemoprevention (the use of chemicals to prevent, stop or reverse the process of carcinogenesis) is an essential approach to controlling cancer.67 Since most cancer deaths are caused by metastatic disease, chemopreventive strategies aimed at preventing tumor metastasis hold great promise for reducing cancer mortality. However, successful implementation of cancer chemoprevention depends on a mechanistic understanding of the carcinogenesis process, and the key mechanism responsible for tumor metastasis remains unknown. In other words, it is not easy to design a chemopreventive strategy aimed at preventing metastasis if we do not know which the driving force of metastasis is. The present report discusses recent data that suggest that the driving force of tumor metastasis is an alteration in O2 metabolism in the tumor cells. This new model may help develop chemopreventive strategies for preventing metastasis. In addition, it has been proposed recently that tumor growth may also be mediated by an alteration in O2 metabolism.68 Any strategy capable of decreasing this alteration in O2 metabolism might therefore prevent tumor growth and metastasis and be clinically useful. The alteration in O2 metabolism shown in Figure 1 may be prevented by restoring oxphos activity. Although Warburg proposed that tumor cells have irreversible damages to oxphos,8 recent www.landesbioscience.com

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