BBA - Reviews on Cancer (v.1825, #1)

MicroRNAs: Potential diagnostic markers and therapeutic targets for EBV-associated nasopharyngeal carcinoma by Ming-Liang He; Millore X-M Luo; Marie C. Lin; Hsiang-fu Kung (1-10).
Nasopharyngeal carcinoma (NPC) is a highly malignant cancer with local invasion and early distant metastasis. NPC is highly prevalent in the Southern China and South-eastern Asia. The genetic susceptibility, endemic environment factors, and Epstein–Barr virus (EBV) infection are believed to be the major etiologic factors of NPC. Once metastasis occurs, the prognosis is very poor. It is urgently needed to develop biomarkers for early clinical diagnosis/prognosis, and novel effective therapies for nasopharyngeal carcinoma. In this paper, we systematically reviewed the current progress of miRNA studies in NPC. It has been shown that both host encoded miRNAs and EBV encoded miRNAs play key roles in almost all the steps of epithelia cell carcinogenesis, including epithelial–mesenchymal to stem-like transition, cell growth, migration, invasion, and tumorigenesis. More importantly, some miRNAs could be secreted out and play a role in the microenvironments. The level of sera miRNAs is correlated with the copy numbers of host miRNAs in tumor biopsies. Promising results of gene therapy have been also achieved by lentiviral delivered miRNAs. Taken together, cell free miRNAs would be potential biomarkers of early clinical diagnosis/prognosis; while some miRNAs could be further developed into therapeutic agents in the future.
Keywords: Nasopharyngeal carcinoma; MicroRNAs; Biomarkers; Therapeutic targets;

Skp2: A novel potential therapeutic target for prostate cancer by Zhiwei Wang; Daming Gao; Hidefumi Fukushima; Hiroyuki Inuzuka; Pengda Liu; Lixin Wan; Fazlul H. Sarkar; Wenyi Wei (11-17).
Prostate cancer is the most frequently diagnosed tumor in men and the second most common cause of cancer-related death for males in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of prostate cancer, such as androgen receptor (AR), Akt, Wnt, Hedgehog (Hh) and Notch. Recently, burgeoning amounts of evidence have implicated that the F-box protein Skp2 (S-phase kinase associated protein 2), a well-characterized oncoprotein, also plays a critical role in the development and progression of prostate cancer. Therefore, this review discusses the recent literature regarding the function and regulation of Skp2 in the pathogenesis of prostate cancer. Furthermore, we highlight that Skp2 may represent an attractive therapeutic target, thus warrants further development of agents to target Skp2, which could have significant therapeutic impact on prostate cancer.
Keywords: Skp2; Prostate cancer; p27; Androgen receptor;

Aberrant activation of the Wnt signaling pathway is a major trait of many human cancers. Due to its vast implications in tumorigenesis and progression, the Wnt pathway has attracted considerable attention at several molecular levels, also with respect to developing novel cancer therapeutics. Indeed, research in Wnt biology has recently provided numerous clues, and evidence is accumulating that the secreted Wnt antagonist Dickkopf-related protein 3 (Dkk-3) and its regulators may constitute interesting therapeutic targets in the most important human cancers. Based on the currently available literature, we here review the knowledge on the biological role of Dkk-3 as an antagonist of the Wnt signaling pathway, the involvement of Dkk-3 in several stages of tumor development, the genetic and epigenetic mechanisms disrupting DKK3 gene function in cancerous cells, and the potential clinical value of Dkk-3 expression/DKK3 promoter methylation as a biomarker and molecular target in cancer diseases.In conclusion, Dkk-3 rapidly emerges as a key player in human cancer with auspicious tumor suppressive capacities, most of all affecting apoptosis and proliferation. Its gene expression is frequently downregulated by promoter methylation in almost any solid and hematological tumor entity. Clinically, evidence is accumulating of Dkk-3 being both a potential tumor biomarker and effective anti-cancer agent. Although further research is needed, re-establishing Dkk-3 expression in cancer cells holds promise as novel targeted molecular tumor therapy.
Keywords: Dickkopf-related protein 3 (Dkk-3); Wnt pathway; Apoptosis; Cancer epigenetics; Biomarker; Cancer therapeutics;

This review focuses on matrix metalloproteinases (MMPs)-2 (gelatinase A) and -9 (gelatinase B), both of which are cancer-associated, secreted, zinc-dependent endopeptidases. Gelatinases cleave many different targets (extracellular matrix, cytokines, growth factors, chemokines and cytokine/growth factor receptors) that in turn regulate key signaling pathways in cell growth, migration, invasion, inflammation and angiogenesis. Interactions with cell surface integral membrane proteins (CD44, αVβ/αβ1/αβ2 integrins and Ku protein) can occur through the gelatinases' active site or hemopexin-like C-terminal domain. This review evaluates the recent literature on the non-enzymatic, signal transduction roles of surface-bound gelatinases and their subsequent effects on cell survival, migration and angiogenesis. Gelatinases have long been drug targets. The current status of gelatinase inhibitors as anticancer agents and their failure in the clinic is discussed in light of these new data on the gelatinases' roles as cell surface transducers — data that may lead to the design and development of novel, gelatinase-targeting inhibitors.
Keywords: Gelatinase; Cell surface binding; Cancer; Inhibitor; Function; Outside-in signaling;

MEK5/ERK5 pathway: The first fifteen years by Barbara A. Drew; Matthew E. Burow; Barbara S. Beckman (37-48).
While conventional MAP kinase pathways are one of the most highly studied signal transduction molecules, less is known about the MEK5 signaling pathway. This pathway has been shown to play a role in normal cell growth cycles, survival and differentiation. The MEK5 pathway is also believed to mediate the effects of a number of oncogenes. MEK5 is the upstream activator of ERK5 in many epithelial cells. Activation of the MEK–MAPK pathway is a frequent event in malignant tumor formation and contributes to chemoresistance and anti-apoptotic signaling. This pathway may be involved in a number of more aggressive, metastatic varieties of cancer due to its role in cell survival, proliferation and EMT transitioning. Further study of this pathway may lead to new prognostic factors and new drug targets to combat more aggressive forms of cancer.
Keywords: Mitogen-activated protein kinase; Big-mitogen activated protein kinase; Erk5; Cellular signaling; Epithelial-to-mesenchymal transition; Kinase inhibitors;

COX-derived prostanoid pathways in gastrointestinal cancer development and progression: Novel targets for prevention and intervention by Mary-Clare Cathcart; Kenneth J. O'Byrne; John V. Reynolds; Jacintha O'Sullivan; Graham P. Pidgeon (49-63).
Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies.COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE2, which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA2 in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD2 and its metabolite 15d-PGJ2, PGF and PGI2. Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity.A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field.
Keywords: Cancer; Esophagus; Stomach; Colorectal; Cyclooxygenases; Prostanoids;

The 26S proteasome complex: An attractive target for cancer therapy by Sarah Frankland-Searby; Sukesh R. Bhaumik (64-76).
The 26S proteasome complex engages in an ATP-dependent proteolytic degradation of a variety of oncoproteins, transcription factors, cell cycle specific cyclins, cyclin-dependent kinase inhibitors, ornithine decarboxylase, and other key regulatory cellular proteins. Thus, the proteasome regulates either directly or indirectly many important cellular processes. Altered regulation of these cellular events is linked to the development of cancer. Therefore, the proteasome has become an attractive target for the treatment of numerous cancers. Several proteasome inhibitors that target the proteolytic active sites of the 26S proteasome complex have been developed and tested for anti-tumor activities. These proteasome inhibitors have displayed impressive anti-tumor functions by inducing apoptosis in different tumor types. Further, the proteasome inhibitors have been shown to induce cell cycle arrest, and inhibit angiogenesis, cell–cell adhesion, cell migration, immune and inflammatory responses, and DNA repair response. A number of proteasome inhibitors are now in clinical trials to treat multiple myeloma and solid tumors. Many other proteasome inhibitors with different efficiencies are being developed and tested for anti-tumor activities. Several proteasome inhibitors currently in clinical trials have shown significantly improved anti-tumor activities when combined with other drugs such as histone deacetylase (HDAC) inhibitors, Akt (protein kinase B) inhibitors, DNA damaging agents, Hsp90 (heat shock protein 90) inhibitors, and lenalidomide. The proteasome inhibitor bortezomib is now in the clinic to treat multiple myeloma and mantle cell lymphoma. Here, we discuss the 26S proteasome complex in carcinogenesis and different proteasome inhibitors with their potential therapeutic applications in treatment of numerous cancers.
Keywords: 26S proteasome complex; Proteasome inhibitors; Cancers;

The CpG island methylator phenotype in colorectal cancer: Progress and problems by Laura A.E. Hughes; Carolina A.J. Khalid-de Bakker; Kim M. Smits; Piet A. van den Brandt; Daisy Jonkers; Nita Ahuja; James G. Herman; Matty P. Weijenberg; Manon van Engeland (77-85).
In recent years, attention has focused on the biology and potential clinical importance of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). While it is generally well accepted that etiologically and clinically distinct subgroups exist in this disease, a precise definition of CIMP remains to be established. Here, we summarize existing literature that documents the prevalence of CIMP in CRC, with particular attention to the various methods and definitions used to classify a tumor as CIMP positive. Through a systematic review on both case-series and population based studies, we examined only original research articles reporting on sporadic CRC and/or adenomas in unselected cases. Forty-eight papers published between January 1999 and August 2011 met the inclusion criteria. We describe the use of multiple gene panels, marker threshold values, and laboratory techniques which results in a wide range in the prevalence of CIMP. Because there is no universal standard or consensus on quantifying the phenotype, establishing its true prevalence is a challenge. This bottleneck is becoming increasingly evident as molecular pathological epidemiology continues to offer possibilities for clear answers regarding environmental risk factors and disease trends. For the first time, large, unselected series of cases are available for analysis, but comparing populations and pooling data will remain a challenge unless a universal definition of CIMP and a consensus on analysis can be reached, and the primary cause of CIMP identified.
Keywords: Colorectal carcinoma; Colorectal adenoma; Epigenetics; CpG island; Promoter methylation; CIMP;

No fully validated biological markers currently exist to predict responsiveness to or the development of evasion to anti-angiogenic therapy of cancer. The identification of such biomarkers is vital to move these therapies forward, as failure to respond to these treatments is often associated with rapid tumor progression that could have been averted had the intrinsic or acquired evasion to anti-angiogenic therapy been identified in a timely fashion. Furthermore, the high cost of antiangiogenic therapies makes it important to avoid utilizing them in the setting of lack of response or developing evasion, making the identification of biomarkers even more important. A number of potential physiologic, circulating, tissue, and imaging biomarkers have emerged from recently completed preclinical animal studies and clinical trials. In this review, we define 5 different types of biomarkers (physiologic, circulating, intratumoral, genetic polymorphisms, and radiographic); discuss the challenges in establishing biomarkers of antiangiogenic therapy in animal models and in clinical trials; and discuss future strategies to identify and validate biomarkers of anti-angiogenic therapy.
Keywords: Biomarkers; Angiogenesis; Cancer; Evasion;

Many human pathological conditions, not linked to genetic alterations of oncogenes or tumor suppressors, are nevertheless associated with an increased risk of developing cancer, and some of them are characterized by quantitative and/or qualitative changes in ribosome biogenesis. Indeed, there is evidence that both an up-regulation of ribosome biogenesis, such as that occurring during the abnormal stimulation of cell growth, and intrinsic dysfunctions of ribosomes, such as those characterizing a series of inherited disorders, show an increased incidence of tumor onset. Here we discuss some recent insights into the mechanisms by which these alterations in ribosome biogenesis may facilitate tumorigenesis.
Keywords: Ribosome biogenesis; Cancer; Tumor suppressor; p53; p27;

Understanding the central role of citrate in the metabolism of cancer cells by Philippe Icard; Laurent Poulain; Hubert Lincet (111-116).
Cancers cells strongly stimulate glycolysis and glutaminolysis for their biosynthesis. Pyruvate derived from glucose is preferentially diverted towards the production of lactic acid (Warburg effect). Citrate censors ATP production and controls strategic enzymes of anabolic and catabolic pathways through feedback reactions. Mitochondrial citrate diffuses in the cytosol to restore oxaloacetate and acetyl-CoA. Whereas acetyl-CoA serves de novo lipid synthesis and histone acetylation, OAA is derived towards lactate production via pyruvate and / or a vicious cycle reforming mitochondrial citrate. This cycle allows cancer cells to burn their host's lipid and protein reserves in order to sustain their own biosynthesis pathways. In vitro, citrate has demonstrated anti-cancer properties when administered in excess, sensitizing cancer cells to chemotherapy. Understanding its central role is of particular relevance for the development of new strategies for counteracting cancer cell proliferation and overcoming chemoresistance.
Keywords: Glycolysis; Warburg; Vicious cycle; Adaptative metabolism; Citrate; Cancer;

The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer by Verbeke Hannelien; Geboes Karel; Van Damme Jo; Struyf Sofie (117-129).
Chronic inflammation may increase the risk to develop cancer, for instance esophagitis or gastritis may lead to development of esophageal or gastric cancer, respectively. The key molecules attracting leukocytes to local inflammatory sites are chemokines. We here provide a systematic review on the impact of CXC chemokines (binding the receptors CXCR1, CXCR2, CXCR3 and CXCR4) on the transition of chronic inflammation in the upper gastrointestinal tract to neoplasia. CXCR2 ligands, including GRO-α,β,γ/CXCL1,2,3, ENA-78/CXCL5 and IL-8/CXCL8 chemoattract pro-tumoral neutrophils. In addition, angiogenic CXCR2 ligands stimulate the formation of new blood vessels, facilitating tumor progression. The CXCR4 ligand SDF-1/CXCL12 also promotes tumor development by stimulating angiogenesis and by favoring metastasis of CXCR4-positive tumor cells to distant organs producing SDF-1/CXCL12. Furthermore, these angiogenic chemokines also directly enhance tumor cell survival and proliferation. In contrast, the CXCR3 ligands Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 are angiostatic and attract anti-tumoral T lymphocytes and may therefore mediate tumor growth retardation and regression. Thus, chemokines exert diverging, sometimes dual roles in tumor biology as described for esophageal and gastric cancer. Therefore extensive research is needed to completely unravel the complex chemokine code in specific cancers. Possibly, chemokine-targeted cancer therapy will have to be adapted to the individual's chemokine profile.
Keywords: Angiogenesis; Chemokine; Cancer; Esophagitis; Gastritis; Inflammation;