BBA - Reviews on Cancer (v.1796, #2)

Considering the role of pyruvate in tumor cells during hypoxia by Emilie Roudier; Anne Perrin (55-62).
Impairment of oxygen supply occurs in many pathological situations. In the case of cancer, both chronic and acute hypoxic areas are found in the tumor. Tumor hypoxia is associated with poor clinical prognoses and is correlated with tumor growth and metastasis development.Pyruvate is a common metabolite, as it is an end-product of glycolysis and an energy substrate for the mitochondrial Krebs cycle. It is also well known for its protective properties against stressful conditions, particularly hypoxia. Its presence determines cellular fate when there is a lack of oxygen. Interestingly, pyruvate metabolism is altered during cancer development. For years, this was assumed to be a consequence of malignant transformation. However, it now is becoming clear that pyruvate could contribute to cancer progression. The role of pyruvate during hypoxia has been widely studied in non-tumor tissues and cells; it is less documented whether or not the protective effect of pyruvate could also take place in cancer cells. If so, pyruvate might be deleterious for cancer patients. The present paper reviews data that highlight the role of pyruvate in cancer cells and tumors during hypoxic stress.
Keywords: Hypoxia; Pyruvate; Cancer; Resistance to anti-cancer therapy; Tumor angiogenesis;

Should I stay or should I go: β-catenin decides under stress by Diana Hoogeboom; Boudewijn M.T. Burgering (63-74).
Reactive oxygen species (ROS) are essential for efficient and proper execution of a large number of cellular processes including signalling induced by exogenous factors. However, ROS are highly reactive in nature and excessive or prolonged ROS formation can result in considerable damage to cellular constituents and is implicated in the onset of a large variety of diseases as well as in the process of ageing [reviewed in [1] T.M. Paravicini, R.M. Touyz, Redox signaling in hypertension, Cardiovasc. Res. 71 (2006) 247–258, [2] P. Chiarugi, From anchorage dependent proliferation to survival: lessons from redox signalling, IUBMB life 60 (2008) 301–307, [3] M. Valko, D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, J. Telser, Free radicals and antioxidants in normal physiological functions and human disease, Int. J. Biochem. Cell Biol. 39 (2007) 44–84]. Management of ROS to prevent potential damage, yet enabling its signalling function is achieved through numerous enzyme systems e.g. peroxidases, superoxide dismutases etc. and small molecules e.g. glutathione that collectively form the cellular anti-oxidant system. The O-class of Forkhead box (FOXO) transcription factors regulates amongst others cellular resistance against oxidative stress [[4] Y. Honda, S. Honda, The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans, Faseb J. 13 (1999) 1385–1393]. In turn FOXOs themselves are regulated by ROS and cellular oxidative stress results in the activation of FOXOs [[5] M.A. Essers, S. Weijzen, A.M. de Vries-Smits, I. Saarloos, N.D. de Ruiter, J.L. Bos, B.M. Burgering, FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK, EMBO J. 23 (2004) 4802–4812]. A prominent feature of ROS-induced FOXO activation is ROS-induced binding of β-catenin to FOXO [[6] M.A. Essers, L.M. de Vries-Smits, N. Barker, P.E. Polderman, B.M. Burgering, H.C. Korswagen, Functional interaction between beta-catenin and FOXO in oxidative stress signaling, Science (New York, NY) 308 (2005) 1181–1184, [7] M. Almeida, L. Han, M. Martin-Millan, C.A. O'Brien, S.C. Manolagas, Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription, J. Biol. Chem. 282 (2007) 27298–27305, [8] D. Hoogeboom, M.A. Essers, P.E. Polderman, E. Voets, L.M. Smits, B.M. Burgering, Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity, J. Biol. Chem. 283 (2008) 9224–9230]. However, ROS affect many transcriptional programs besides that of FOXOs. Here, we discuss the recent progress in our understanding as to how ROS may regulate the interplay between some of the ROS-sensitive transcription factors through diverting β-catenin binding to these transcription factors. We propose that β-catenin acts as a key switch between the various ROS-sensitive transcription programs.
Keywords: Cancer; Oxidative stress; Signalling pathway; Beta-catenin; Forkhead; Transcription;

Epithelial–mesenchymal transition (EMT) is a key step during embryogenesis. Accumulating evidence suggests a critical role in cancer progression, through which tissue epithelial cancers invade and metastasise. Cell characteristics are highly affected during EMT, resulting in altered cell–cell and cell–matrix interactions, cell motility and invasiveness. Nevertheless, the demonstration of this process in human cancer has been proven difficult and controversial. Besides the fact that the acquisition of mesenchymal characteristics is not a prerequisite for cell migration/invasion, it is a transient event that concerns only few cells in a tumour mass. The induction of EMT depends on the tumour type and its genetic alterations as well as on its interaction with the extracellular matrix. In parallel, trials for EMT identification in clinical samples lack of a widely accepted methodology, nomenclature and reliable markers. This review summarizes the main EMT characteristics and proposes methodologies for better analysis in vitro. It also highlights recent studies identifying cells with EMT characteristics in human cancer and proposes certain markers to identify them in tumour samples. Finally, it cites the recent literature concerning the mechanisms of drug resistance related to EMT in the context of anti-tumour therapies and proposes related new targets for therapy.
Keywords: Epithelial–mesenchymal transition; Cancer; Clinic; Marker; Metastasis; Drug resistance;

Rho GTPase function in tumorigenesis by R. Karlsson; E.D. Pedersen; Z. Wang; Cord Brakebusch (91-98).
Malignant tumor cells display uncontrolled proliferation, loss of epithelial cell polarity, altered interactions with neighboring cells and the surrounding extracellular matrix, and enhanced migratory properties. Proteins of the Rho GTPase family regulate all these processes in cell culture and, for that reason, Rho GTPases, their regulators, and their effectors have been suggested to control tumor formation and progression in humans. However, while the tumor-relevant functions of Rho GTPases are very well documented in vitro, we are only now beginning to assess their contribution to cancer in human patients and in animal models. This review will give a very brief overview of Rho GTPase function in general and then focus on in vivo evidence for a role of Rho GTPases in malignant tumors, both in human patients and in genetically modified mice.
Keywords: Rho GTPases;

The role of mammalian ribonucleases (RNases) in cancer by Wan-Cheol Kim; Chow H. Lee (99-113).
Ribonucleases (RNases) are a group of enzymes that cleave RNAs at phosphodiester bonds resulting in remarkably diverse biological consequences. This review focuses on mammalian RNases that are capable of, or potentially capable of, cleaving messenger RNA (mRNA) as well as other RNAs in cells and play roles in the development of human cancers. The aims of this review are to provide an overview of the roles of currently known mammalian RNases, and the evidence that associate them as regulators of tumor development. The roles of these RNases as oncoproteins and/or tumor suppressors in influencing cell growth, apoptosis, angiogenesis, and other cellular hallmarks of cancer will be presented and discussed. The RNases under discussion include RNases from the conventional mRNA decay pathways, RNases that are activated under cellular stress, RNases from the miRNA pathway, and RNases with multifunctional activity.
Keywords: Ribonuclease; Mammalian; Cancer; mRNA degradation;

The RASSF proteins in cancer; from epigenetic silencing to functional characterization by Antje M. Richter; Gerd P. Pfeifer; Reinhard H. Dammann (114-128).
The Ras-Association Domain Family (RASSF) comprises ten members, termed RASSF1 to RASSF10. RASSF1 to RASSF6 harbor a C-terminal Ras-association (RA) domain and RASSF7 to RASSF10 contain an N-terminal RA domain. Interestingly, it was observed that in various tumor types distinct RASSFs transcripts (e.g. RASSF1A and RASSF2A) are missing due to hypermethylation of their CpG island promoter. Since methylation of the RASSF1A promoter is described as an early and frequent event in tumorigenesis, RASSF1A could serve as a useful diagnostic marker in cancer screens. RASSFs are implicated in various cellular mechanisms including apoptosis, cell cycle control and microtubule stabilization, though little is known about the underlying mechanisms. Tumor suppressing functions were reported for several members. Here we review the current literature on RASSF members focusing on structural, functional and epigenetic aspects. Characterizing the cellular mechanisms that regulate the signaling pathways RASSFs are involved in, could lead to a deeper understanding of tumor development and, furthermore, to new strategies in cancer treatment.
Keywords: RASSF; Tumor suppressor; Microtubule; RAS; Apoptosis; Epigenetics;

A systems biology view of cancer by Reinhard Laubenbacher; Valerie Hower; Abdul Jarrah; Suzy V. Torti; Vladimir Shulaev; Pedro Mendes; Frank M. Torti; Steven Akman (129-139).
In order to understand how a cancer cell is functionally different from a normal cell it is necessary to assess the complex network of pathways involving gene regulation, signaling, and cell metabolism, and the alterations in its dynamics caused by the several different types of mutations leading to malignancy. Since the network is typically complex, with multiple connections between pathways and important feedback loops, it is crucial to represent it in the form of a computational model that can be used for a rigorous analysis. This is the approach of systems biology, made possible by new -omics data generation technologies. The goal of this review is to illustrate this approach and its utility for our understanding of cancer. After a discussion of recent progress using a network-centric approach, three case studies related to diagnostics, therapy, and drug development are presented in detail. They focus on breast cancer, B-cell lymphomas, and colorectal cancer. The discussion is centered on key mathematical and computational tools common to a systems biology approach.
Keywords: Systems biology; Cancer; Mathematical modeling;

Cancer gene discovery in mouse and man by Jenny Mattison; Louise van der Weyden; Tim Hubbard; David J. Adams (140-161).
The elucidation of the human and mouse genome sequence and developments in high-throughput genome analysis, and in computational tools, have made it possible to profile entire cancer genomes. In parallel with these advances mouse models of cancer have evolved into a powerful tool for cancer gene discovery. Here we discuss the approaches that may be used for cancer gene identification in both human and mouse and discuss how a cross-species ‘oncogenomics’ approach to cancer gene discovery represents a powerful strategy for finding genes that drive tumourigenesis.
Keywords: Cancer genome; Resequencing; Cross-species analysis; DNA copy number analysis; Mouse cancer models; Forward genetic screens;

Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E2/ERβ-mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC.
Keywords: Breast cancer; CXC chemokine; CXCL8; ERα; ERβ; Estrogen carcinogenesis; GRCP-30/EGFR; microRNAs; Therapeutic approaches for TN-breast cancer; Triple negative breast cancer;

Biomarkers are molecular indicators of a biological status, and as biochemical species can be assayed to evaluate the presence of cancer and therapeutic interventions. Through a variety of mechanisms cancer cells provide the biomarker material for their own detection. Biomarkers may be detectable in the blood, other body fluids, or tissues. The expectation is that the level of an informative biomarker is related to the specific type of disease present in the body. Biomarkers have potential both as diagnostic indicators and monitors of the effectiveness of clinical interventions. Biomarkers are also able to stratify cancer patients to the most appropriate treatment. Effective biomarkers for the early detection of cancer should provide a patient with a better outcome which in turn will translate into more efficient delivery of healthcare. Technologies for the early detection of cancer have resulted in reductions in disease-associated mortalities from cancers that are otherwise deadly if allowed to progress. Such screening technologies have proven that early detection will decrease the morbidity and mortality from cancer. An emerging theme in biomarker research is the expectation that panels of biomarker analytes rather than single markers will be needed to have sufficient sensitivity and specificity for the presymptomatic detection of cancer. Biomarkers may provide prognostic information of disease enabling interventions using targeted therapeutic agents as well as course-corrections in cancer treatment. Novel genomic, proteomic and metabolomic technologies are being used to discover and validate tumor biomarkers individually and in panels.
Keywords: Diagnostic biomarkers; Epitomics; Genomics; Mass spectroscopy; miRNA; Proteomics; RNA expression profiling;

Estrogens, MSI and Lynch syndrome-associated tumors by Ana Monteiro Ferreira; Helga Westers; André Albergaria; Raquel Seruca; Robert M.W. Hofstra (194-200).
Estrogens play a major role in the biology of hormone-responsive tissues but also in the normal physiology of various non-typical hormone-responsive tissues. In disease, estrogens have been associated with tumor development, in particular with tumors such as breast, endometrium, ovary and prostate.In this paper we will review the molecular mechanisms by which estrogens are involved in cancer development, with a special focus in Lynch syndrome related neoplasia. Further, we discuss the role estrogens might have on cell proliferation and apoptosis, how estrogens metabolites can induce DNA damage and we discuss a possible connection between estrogens and changes in DNA (hypo- and hyper) methylation. In this review we will also address the protective effect that high levels of estrogens have in MMR related neoplasias.
Keywords: Estrogen; Estrogen-receptor pathway; Lynch syndrome; Mismatch repair system; Microsatellite instability;

Translocations in epithelial cancers by J. Chad Brenner; Arul M. Chinnaiyan (201-215).
Genomic translocations leading to the expression of chimeric transcripts characterize several hematologic, mesenchymal and epithelial malignancies. While several gene fusions have been linked to essential molecular events in hematologic malignancies, the identification and characterization of recurrent chimeric transcripts in epithelial cancers has been limited. However, the recent discovery of the recurrent gene fusions in prostate cancer has sparked a revitalization of the quest to identify novel rearrangements in epithelial malignancies. Here, the molecular mechanisms of gene fusions that drive several epithelial cancers and the recent technological advances that increase the speed and reliability of recurrent gene fusion discovery are explored.
Keywords: Translocation; Epithelial; Rearrangement; Gene fusion; Chimera; MLL; ERG; ALK; HMGA2; COPA;

Ion beam radiobiology and cancer: Time to update ourselves by Emmanouil Fokas; Gerhard Kraft; Hanxiang An; Rita Engenhart-Cabillic (216-229).
High-energy protons and carbon ions exhibit an inverse dose profile allowing for increased energy deposition with penetration depth. Additionally, heavier ions like carbon beams have the advantage of a markedly increased biological effectiveness characterized by enhanced ionization density in the individual tracks of the heavy particles, where DNA damage becomes clustered and therefore more difficult to repair, but is restricted to the end of their range. These superior biophysical and biological profiles of particle beams over conventional radiotherapy permit more precise dose localization and make them highly attractive for treating anatomically complex and radioresistant malignant tumors but without increasing the severe side effects in the normal tissue. More than half a century since Wilson proposed their use in cancer therapy, the effects of particle beams have been extensively investigated and the biological complexity of particle beam irradiation begins to unfold itself. The goal of this review is to provide an as comprehensive and up-to-date summary as possible of the different radiobiological aspects of particle beams for effective application in cancer treatment.
Keywords: Particle beam; Radiobiology; High LET; RBE; Cancer;

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has many beneficial physiological functions ranging from enhancing fatty acid catabolism, improving insulin sensitivity, inhibiting inflammation and increasing oxidative myofibers allowing for improved athletic performance. Thus, given the potential for targeting PPARβ/δ for the prevention and/or treatment of diseases including diabetes, dyslipidemias, metabolic syndrome and cancer, it is critical to clarify the functional role of PPARβ/δ in cell proliferation and associated disorders such as cancer. However, there is considerable controversy whether PPARβ/δ stimulates or inhibits cell proliferation. This review summarizes the literature describing the influence of PPARβ/δ on cell proliferation, with an emphasis toward dissecting the data that give rise to opposing hypotheses. Suggestions are offered to standardize measurements associated with these studies so that interlaboratory comparisons can be accurately assessed.
Keywords: Peroxisome proliferator-activated receptor-β/δ; Cell proliferation; Apoptosis; Differentiation; Cancer;

JNK1, a potential therapeutic target for hepatocellular carcinoma by Fei Chen; Kevin Beezhold; Vince Castranova (242-251).
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Despite tremendous efforts to diagnose and institute new treatment regimens, the prognosis is still extremely poor. Therefore, knowledge of the molecular mechanisms governing the initiation, maintenance and progression of HCC is urgently needed. Recently, several groups have attributed an important role for c-Jun N-terminal kinase 1 (JNK1) in the pathogenesis of human HCC and its close association with the expression of HCC signature genes. In this review the various associations between JNK1 and HCC are discussed with the hope that targeting this pivotal kinase may lead to novel therapeutic approaches for this fatal disease.
Keywords: JNK1; HCC; Signature genes; ROS; Progenitor cells; Epigenetics;

Tumor cell energy metabolism and its common features with yeast metabolism by R. Diaz-Ruiz; S. Uribe-Carvajal; A. Devin; M. Rigoulet (252-265).
During the last decades a considerable amount of research has been focused on cancer. A number of genetic and signaling defects have been identified. This has allowed the design and screening of a number of anti-tumor drugs for therapeutic use. One of the main challenges of anti-cancer therapy is to specifically target these drugs to malignant cells. Recently, tumor cell metabolism has been considered as a possible target for cancer therapy. It is widely accepted that tumors display an enhanced glycolytic activity and oxidative phosphorylation down-regulation (Warburg effect). Therefore, it seems reasonable that disruption of glycolysis might be a promising candidate for specific anti-cancer therapy.Nonetheless, the concept of aerobic glycolysis as the paradigm of tumor cell metabolism has been challenged, as some tumor cells use oxidative phosphorylation. Mitochondria are of special interest in cancer cell energy metabolism, as their physiology is linked to the Warburg effect. Besides, their central role in apoptosis makes these organelles a promising “dual hit target” for selectively eliminate tumor cells.Thus, it is desirable to have an easy-to-use and reliable model in order to do the screening for energy metabolism-inhibiting drugs to be used in cancer therapy. From a metabolic point of view, the fermenting yeast Saccharomyces cerevisiae and tumor cells share several features. In this paper we will review these common metabolic properties and we will discuss the possibility of using S. cerevisiae as an early screening test in the research for novel anti-tumor compounds used for the inhibition of tumor cell metabolism.
Keywords: Cancer; Metabolism; Crabtree effect; Yeast; Mitochondria; Warburg effect;

Therapeutic options for triple-negative breast cancers with defective homologous recombination by Janneke E. Jaspers; Sven Rottenberg; Jos Jonkers (266-280).
Breast cancer is the most common malignancy among women in developed countries, affecting more than a million women per year worldwide. Over the last decades, our increasing understanding of breast cancer biology has led to the development of endocrine agents against hormone receptor-positive tumors and targeted therapeutics against HER2-expressing tumors. However, no targeted therapy is available for patients with triple-negative breast cancer, lacking expression of hormone receptors and HER2. Overlap between BRCA1-mutated breast cancers and triple-negative tumors suggests that an important part of the triple-negative tumors may respond to therapeutics targeting BRCA1-deficient cells. Here, we review the features shared between triple-negative, basal-like and BRCA1-related breast cancers. We also discuss the development of novel therapeutic strategies to target BRCA1-mutated tumors and triple-negative tumors with BRCA1-like features. Finally, we highlight the utility of mouse models for BRCA1-mutated breast cancer to optimize (combination) therapy and to understand drug resistance.
Keywords: Triple-negative breast cancer; Basal-like breast cancer; BRCA1; Homologous recombination; Chemotherapy; Multidrug resistance;

Roles of P67/MetAP2 as a tumor suppressor by Bansidhar Datta (281-292).
A precise balance between growth promoting signals and growth inhibitory signals plays important roles in the maintenance of healthy mammalian cells. Any deregulation of this critical balance converts normal cells into abnormal or cancerous cells. Several macromolecules are being identified and characterized that are involved in the regulation of cell signaling pathways that connect to the cell cycle and thus they play roles as tumor promoters or tumor suppressors. In situ tumor formation needs active angiogenesis, a process that generates new blood vessels from existing ones either by splitting or sprouting. Several small molecule inhibitors and proteins have been identified as inhibitors of angiogenesis. One such protein, p67/MetAP2 also known as methionine aminopeptidase 2 (MetAP2), has been shown to bind covalently to fumagillin and its derivatives that have anti-angiogenic activity. In addition to fumagillin or its derivatives, several other small molecule inhibitors of p67/MetAP2 have been recently identified and some of these drugs are in phase III trials for cancer therapy. Although molecular details of actions toward tumor suppression by these drugs are largely unknown, a significant progress has been made to understand the structure–function relationship of p67/MetAP2 and its roles in the maintenance of the levels of phosphorylation of the ∝-subunit of eukaryotic initiation factor 2 (eIF2∝) and extracellular signal-regulated kinases 1 and 2 (ERK1/2). In this article, roles of p67/MetAP2 in the suppression of cancer development are also discussed.
Keywords: EIF-2-associated glycoprotein, p67/MetAP2; p67/MetAP2 inhibitors; eIF2α phosphorylation; ERK1/2, extracellular signal-regulated kinases; Angiogenesis; Tumorigenesis;

Metastasis mechanisms by Thomas R. Geiger; Daniel S. Peeper (293-308).
Metastasis, the spread of malignant cells from a primary tumor to distant sites, poses the biggest problem to cancer treatment and is the main cause of death of cancer patients. It occurs in a series of discrete steps, which have been modeled into a “metastatic cascade”. In this review, we comprehensively describe the molecular and cellular mechanisms underlying the different steps, including Epithelial–Mesenchymal Transition (EMT), invasion, anoikis, angiogenesis, transport through vessels and outgrowth of secondary tumors. Furthermore, we implement recent findings that have broadened and challenged the classical view on the metastatic cascade, for example the establishment of a “premetastatic niche”, the requirement of stem cell-like properties, the role of the tumor stroma and paracrine interactions of the tumor with cells in distant anatomical sites. A better understanding of the molecular processes underlying metastasis will conceivably present us with novel targets for therapeutic intervention.
Keywords: Cancer; Metastasis; EMT; Anoikis; Stem cells; Microenvironment;

Trop2: A possible therapeutic target for late stage epithelial carcinomas by Rafael Cubas; Min Li; Changyi Chen; Qizhi Yao (309-314).
Trop2 is a cell-surface glycoprotein overexpressed in a variety of late stage epithelial carcinomas with low to no expression in normal tissues. Some of the important roles that Trop2 plays in epithelial cancers have recently been revealed. Trop2 overexpression is associated with decreased patient survival as well as increased tumor aggressiveness and metastasis. Its overexpression in metastatic tissue makes it a very attractive and potential therapeutic target for late stage disease. This protein can transduce an intracellular calcium signal and contains a conserved phosphatidylinositol 4,5-bisphosphate (PIP2) binding motif as well as a serine phosphorylation site which interacts with protein kinase C. This protein has recently being found to be expressed in cells with stem-like properties which allude to a potential role in progenitor cell biology. Further understanding of the signaling pathways involved with this molecule and its important role in metastasis will shed new light on the mechanism of Trop2 overexpression in late stage disease and could result in the development of new therapies targeting this widely overexpressed oncogene.
Keywords: Trop2; Oncogene; Tumor metastasis; Epithelial carcinomas;

Molecular pathology of RUNX3 in human carcinogenesis by Manish Mani Subramaniam; Jason Yongsheng Chan; Khay Guan Yeoh; Timothy Quek; Kosei Ito; Manuel Salto-Tellez (315-331).
A major goal of molecular biology is to elucidate the mechanisms underlying cancer development and progression in order to achieve early detection, better diagnosis and staging and novel preventive and therapeutic strategies. We feel that an understanding of Runt-related transcription factor 3 (RUNX3)-regulated biological pathways will directly impact our knowledge of these areas of human carcinogenesis. The RUNX3 transcription factor is a downstream effector of the transforming growth factor-beta (TGF-β) signaling pathway, and has a critical role in the regulation of cell proliferation and cell death by apoptosis, and in angiogenesis, cell adhesion and invasion. We previously identified RUNX3 as a major gastric tumor suppressor by establishing a causal relationship between loss of function and gastric carcinogenesis. More recently, we showed that RUNX3 functions as a bona fide initiator of colonic carcinogenesis by linking the Wnt oncogenic and TGF-β tumor suppressive pathways. Apart from gastric and colorectal cancers, a multitude of epithelial cancers exhibit inactivation of RUNX3, thereby making it a putative tumor suppressor in human neoplasia. This review highlights our current understanding of the molecular mechanisms of RUNX3 inactivation in the context of cancer development and progression.
Keywords: RUNX; RUNX3; Cancer; Epigenetics; Methylation; Protein expression; Preneoplastic lesions; Carcinogenesis; Tumor suppressor gene; Oncogene; Apoptosis;