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BBA - Reviews on Cancer (v.1826, #1)

Editorial Board (pp. i).

ETV1, 4 and 5: An oncogenic subfamily of ETS transcription factors by Sangphil Oh; Sook Shin; Ralf Janknecht (pp. 1-12).

The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are an underlying cause of carcinogenesis. Likewise, chromosomal rearrangements of the ETV1, ETV4 or ETV5 gene occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer. In addition, these three ETS proteins are implicated in melanomas, breast and other types of cancer. Complex posttranslational modifications govern the activity of PEA3 factors, which can promote cell proliferation, motility and invasion. Here, we review evidence for a role of ETV1, 4 and 5 as oncoproteins and describe modes of their action. Modulation of their activation or interaction with cofactors as well as inhibiting crucial target gene products may ultimately be exploited to treat various cancers that are dependent on the PEA3 group of ETS transcription factors.

Keywords: Cancer; Chromosomal translocation; ETS; Posttranslational modification; Transcription factor

Glucose regulated protein 78: A critical link between tumor microenvironment and cancer hallmarks by Zongwei Li; Zhuoyu Li (pp. 13-22).

Glucose regulated protein 78 (GRP78) has long been recognized as a molecular chaperone in the endoplasmic reticulum (ER) and can be induced by the ER stress response. Besides its location in the ER, GRP78 has been found to be present in cell plasma membrane, cytoplasm, mitochondria, nucleus as well as cellular secretions. GRP78 is implicated in tumor cell proliferation, apoptosis resistance, immune escape, metastasis and angiogenesis, and its elevated expression usually correlates with a variety of tumor microenvironmental stresses, including hypoxia, glucose deprivation, lactic acidosis and inflammatory response. GRP78 protein acts as a centrally located sensor of stress, which feels and adapts to the alteration in the tumor microenvironment. This article reviews the potential contributions of GRP78 to the acquisition of cancer hallmarks based on intervening in stress responses caused by tumor niche alterations. The paper also introduces several potential GRP78 relevant targeted therapies.

Keywords: Glucose regulated protein 78; Microenvironment; Cancer hallmarks

E-cadherin's dark side: Possible role in tumor progression by Fausto J. Rodriguez; Laura J. Lewis-Tuffin; Panos Z. Anastasiadis (pp. 23-31).

In the context of cancer, E-cadherin has traditionally been categorized as a tumor suppressor, given its essential role in the formation of proper intercellular junctions, and its downregulation in the process of epithelial–mesenchymal transition (EMT) in epithelial tumor progression. Germline or somatic mutations in the E-cadherin gene ( CDH1) or downregulation by epigenetic mechanisms have been described in a small subset of epithelial cancers. However, recent evidence also points toward a promoting role of E-cadherin in several aspects of tumor progression. This includes preserved (or increased) E-cadherin expression in microemboli of inflammatory breast carcinoma, a possible “mesenchymal to epithelial transition” (MET) in ovarian carcinoma, collective cell invasion in some epithelial cancers, a recent association of E-cadherin expression with a more aggressive brain tumor subset, as well as the intriguing possibility of E-cadherin involvement in specific signaling networks in the cytoplasm and/or nucleus. In this review we address a lesser-known, positive role for E-cadherin in cancer.

Keywords: E-cadherin; Epithelial–mesenchymal transition; Mesenchymal–epithelial transition; Oncogene; Tumorigenesis; Adherens junctions

Secretory miRNAs as novel cancer biomarkers by Jian Zhang; Huadong Zhao; Yuan Gao; Wei Zhang (pp. 32-43).

MicroRNAs (miRNAs) are a class of small non-coding RNAs that degrade or block target mRNAs at the post-transcriptional level. Many studies have shown that miRNA dysregulation is involved in cancer initiation, invasion, metastasis, and so forth. Notably, recent studies have revealed secretory miRNA levels in blood and other body fluids to correlate significantly with cancer progression, therapeutic response and patient survival. Thus, secretory miRNAs have demonstrated great potential as powerful and non-invasive cancer biomarkers. Herein, we summarize the current progress of secretory miRNAs in different cancer types and analyze the potential mechanisms of miRNA secretion. Then, we discuss the different approaches to miRNA detection in body fluids and the advantages of secretory miRNAs as biomarkers for early cancer diagnosis and the prediction of therapeutic efficacy. Finally, we list the current progress of secretory miRNAs as cancer biomarkers in clinical trials. Although several issues remain to be clarified, such as the mechanisms of miRNA secretion, it is only a matter of time before miRNAs are widely utilized as cancer biomarkers.

Keywords: Secretory miRNAs; Cancer; Biomarkers; Bio-messenger

MAP17 and the double-edged sword of ROS by Amancio Carnero (pp. 44-52).

Reactive oxygen species, ROS, are beneficially involved in many signaling pathways that control development and maintain cellular homeostasis. In physiological conditions, a tightly regulated redox balance protects cells from injurious ROS activity, but if the balance is altered, it promotes various pathological conditions including cancer. Understanding the duality of ROS as cytotoxic molecules and key mediators in signaling cascades may provide novel opportunities for improved cancer therapy.MAP17 is a small 17-kDa non-glycosylated membrane protein that is overexpressed in many tumors of different origins, including carcinomas. Immunohistochemical analysis of MAP17 during cancer progression demonstrates that overexpression of the protein strongly correlates with the progression of most types of tumor. Tumor cells that overexpress MAP17 show an increased tumoral phenotype associated with an increase in ROS. However, in non-tumor cells MAP17 increases ROS, resulting in senescence or apoptosis. Therefore, in tumor cells, MAP17 could be a marker for increased oxidative stress and could define new therapeutic approaches. Here, we review the role of MAP17 as a putative oncogene, as well as its role in cancer and anticancer therapies.

Keywords: Abbreviations; PDZ; P; ost-synaptic density 95,; D; isk large,; Z; onula occludens 1; PDZK1; PDZ domain-containing 1; CLAMP; c-terminal linking and modulating protein; CAP70; CFTR-associated protein, 70-kDa; MAP17; membrane associated protein, 17-kDa; NHeRF; Na; ⁺; /H; ⁺; exchanger regulatory factor; IKEPP; intestinal and kidney enriched PDZ protein; SGLT; Na; ⁺; /glucose cotransporterMAP17; Cancer; Oncogene; Reactive oxygen species; Tumorigenesis

Angiogenesis inhibition for the improvement of photodynamic therapy: The revival of a promising idea by Andrea Weiss; Hubert van den Bergh; Arjan W. Griffioen; Patrycja Nowak-Sliwinska (pp. 53-70).

Photodynamic therapy (PDT) is a minimally invasive form of treatment, which is clinically approved for the treatment of angiogenic disorders, including certain forms of cancer and neovascular eye diseases. Although the concept of PDT has existed for a long time now, it has never made a solid entrance into the clinical management of cancer. This is likely due to secondary tissue reactions, such as inflammation and neoangiogenesis. The recent development of clinically effective angiogenesis inhibitors has lead to the initiation of research on the combination of PDT with such angiostatic targeted therapies. Preclinical studies in this research field have shown promising results, causing a revival in the field of PDT. This review reports on the current research efforts on PDT and vascular targeted combination therapies. Different combination strategies with angiogenesis inhibition and vascular targeting approaches are discussed. In addition, the concept of increasing PDT selectivity by targeted delivery of photosensitizers is presented. Furthermore, the current insights on sequencing the therapy arms of such combinations will be discussed in light of vascular normalization induced by angiogenesis inhibition.

Keywords: Abbreviations; ALA; aminolevulinic acid; AMD; age-related macular degeneration; AP-1; activator protein-1; AlPcS; ₄; tetrasulfonated aluminum phthalocyanine; APRPG; Ala-Pro-Arg-Pro-Gly peptide; ATP; adenosine triphosphate; bFGF; basic fibroblast growth factor; CAM; chorioallantoic membrane; CCH; circumscribed choroidal haemangioma; COX-2; cyclooxygenase-2; DMXAA; 5,6-dimethylxanthenone-4-acetic acid; EGF; epidermal growth factor; GM-CSF; granulocyte-macrophage colony stimulating factor; HeLa; human cervix carcinoma; HIF-1α; hypoxia-inducible factor 1-alpha; ICG; Indocyanine Green; IL-1β; interleukin 1-beta; MMP; matrix metalloproteinase; n.a.; not applicable; NF-κB; nuclear factor κB; NPC; nasopharyngeal carcinoma; NPC; nasopharyngeal carcinoma; NSCLC; non-small-cell lung cancer; PCI; photochemical internalization; PDGF(R); platelet derived growth factor (receptor); PDT; photodynamic therapy; PS; photosensitizer; PEG; polyethylene glycol; PGE2; prostaglandin E2; PMN; polymorphonuclear; PNET; Pancreatic Neuroectodermal Tumor; RCH; retinal capillary haemangioma; RGD; Arg-Gly-Asp tri-peptide; RIF; radiation-induced fibrosarcoma; SCC; squamous-cell carcinoma; SIP; small immune protein; TNF-α; tumor necrosis factor alpha; TTT; transpupillary thermotherapy; VDA; vascular disrupting agent; VEGF; vascular endothelial cell growth factor; vWF; von Willebrand factorAngiogenesis inhibitors; Endothelial cells; Photodynamic therapy; Photosensitizer; Targeting; Vascular normalization

O⁶-Methylguanine-DNA methyltransferase in glioma therapy: Promise and problems by John R. Silber; Michael S. Bobola; A. Blank; Marc C. Chamberlain (pp. 71-82).

Gliomas are the most frequent adult primary brain tumor, and are invariably fatal. The most common diagnosis glioblastoma multiforme (GBM) afflicts 12,500 new patients in the U.S. annually, and has a median survival of approximately one year when treated with the current standard of care. Alkylating agents have long been central in the chemotherapy of GBM and other gliomas. The DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT), the principal human activity that removes cytotoxic O⁶-alkylguanine adducts from DNA, promotes resistance to anti-glioma alkylators, including temozolomide and BCNU, in GBM cell lines and xenografts. Moreover, MGMT expression assessed by immunohistochemistry, biochemical activity or promoter CpG methylation status is associated with the response of GBM to alkylator-based therapies, providing evidence that MGMT promotes clinical resistance to alkylating agents. These observations suggest a role for MGMT in directing adjuvant therapy of GBM and other gliomas. Promoter methylation status is the most clinically tractable measure of MGMT, and there is considerable enthusiasm for exploring its utility as a marker to assign therapy to individual patients. Here, we provide an overview of the biochemical, genetic and biological characteristics of MGMT as they relate to glioma therapy. We consider current methods to assess MGMT expression and discuss their utility as predictors of treatment response. Particular emphasis is given to promoter methylation status and the methodological and conceptual impediments that limit its use to direct treatment. We conclude by considering approaches that may improve the utility of MGMT methylation status in planning optimal therapies tailored to individual patients.

Keywords: Abbreviations; BCNU; 1,3-bis(2-chloroethyl)-1-nitrosourea, carmustine; CCNU; 3-(2-chloroethyl)-3-cyclohexyl-1-nitrosouea, lomustine; GBM; glioblastoma multiforme; IHC; immunohistochemistry; MGMT; O; ⁶; -methylguanine-DNA methyltransferase; MSP; methylation-specific PCR; PCV; procarbazine, CCNU, vincristine; TMZ; temozolomideAlkylating agents; Biomarker; Glioblastoma; Glioma; MGMT; Chemotherapy resistance

On the epigenetic origin of cancer stem cells by Audrey Vincent; Isabelle Van Seuningen (pp. 83-88).

Epigenetic mechanisms are the key component of the dynamic transcriptional programming that occurs along the process of differentiation from normal stem cells to more specialized cells. In the development of cancer and according to the cancer stem cell model, aberrant epigenetic changes may ensure the property of cancer cells to switch cancer stem cell markers on and off in order to generate a heterogeneous population of cells. The tumour will then be composed of tumourigenic (cancer stem cells) and non-tumourigenic (the side population that constitutes the bulk of the tumour) cells. Characterizing epigenetic landscapes may thus help discriminate aberrant marks (good candidates for tumour detection) from cancer stem cell specific profiles. In this review, we will give some insights about what epigenetics can teach us about the origin of cancer stem cells. We will also discuss how identification of epigenetic reprogramming may help designing new drugs that will specifically target cancer stem cells.

Keywords: Abbreviations; ESC; embryonic stem cell; CSC; cancer stem cell; HP1; heterochromatin protein 1; PcG; polycomb group protein; HDAC; histone deacetylase; DNMT; DNA methyltransferase; BMI-1; B cell Moloney murine leukemia virus Insertion regionCancer; Cancer stem cell; Epigenetics; Differentiation; DNA methylation; Histone modifications

Genetics and epigenetics of cutaneous malignant melanoma: A concert out of tune by Karin van den Hurk; Hanneke E.C. Niessen; Jürgen Veeck; Joost J. van den Oord; Maurice A.M. van Steensel; Axel zur Hausen; Manon van Engeland; Véronique J.L. Winnepenninckx (pp. 89-102).

Cutaneous malignant melanoma (CMM) is the most life-threatening neoplasm of the skin and is considered a major health problem as both incidence and mortality rates continue to rise. Once CMM has metastasized it becomes therapy-resistant and is an inevitably deadly disease. Understanding the molecular mechanisms that are involved in the initiation and progression of CMM is crucial for overcoming the commonly observed drug resistance as well as developing novel targeted treatment strategies. This molecular knowledge may further lead to the identification of clinically relevant biomarkers for early CMM detection, risk stratification, or prediction of response to therapy, altogether improving the clinical management of this disease. In this review we summarize the currently identified genetic and epigenetic alterations in CMM development. Although the genetic components underlying CMM are clearly emerging, a complete picture of the epigenetic alterations on DNA (DNA methylation), RNA (non-coding RNAs), and protein level (histone modifications, Polycomb group proteins, and chromatin remodeling) and the combinatorial interactions between these events is lacking. More detailed knowledge, however, is accumulating for genetic and epigenetic interactions in the aberrant regulation of the INK4b– ARF– INK4a and microphthalmia-associated transcription factor ( MITF) loci. Importantly, we point out that it is this interplay of genetics and epigenetics that effectively leads to distorted gene expression patterns in CMM.

Keywords: Melanoma; Genetics; Epigenetics; DNA methylation; MicroRNA; Chromatin remodeling

Tumor cell-derived exosomes: A message in a bottle by Pedram Kharaziha; Sophia Ceder; Qiao Li; Theocharis Panaretakis (pp. 103-111).

Exosomes constitute the newest mode of intercellular communication, transmitting information between cells. This exchange of molecular information is facilitated by their unique composition which is enriched with enzymes, structural proteins, adhesion molecules, lipid rafts and RNAs. Following the discovery that cancer cells secrete excessive amounts of exosomes compared to normal cells, it became evident that i) these vesicles can be used as diagnostic markers; ii) their active secretion has functional implications, albeit unknown whether they are tumor promoting or suppressing. Notably, the interplay via the exchange of exosomes between cancer cells and between cancer cells and the tumor stroma may promote the transfer of oncogenes (e.g. β-catenin, CEA, HER2, Melan-A/Mart-1 and LMP-1) and onco-microRNAs (e.g. let7, miR1, miR15, miR16 and miR375) from one cell to another, leading to the reprogramming of the recipient cells. The molecular composition and functional role of tumor cell-derived exosomes in tumorigenesis, metastasis and response to therapy are slowly decrypted and the latest findings as well as potential therapeutic strategies are discussed in this review.

Keywords: Exosomes; Molecular profile; Multivesicular bodies; Microenvironment; Metastatic niche; Cancer therapy

Role of glial cell line-derived neurotrophic factor in perineural invasion of pancreatic cancer by Han Liu; Xuqi Li; Qinhong Xu; Shifang Lv; Junhui Li; Qingyong Ma (pp. 112-120).

Perineural invasion (PNI) is the initial infiltration of tumor cells into the retroperitoneal nerve plexus and along the nerves. It precludes curative resection, is thought to be the major cause of local recurrence following resection, and is a special metastatic route in pancreatic cancer. Glial cell line-derived neurotrophic factor (GDNF) was recently recognized as a key player in the PNI process. This review covers the most recently published studies on the role of GDNF in pancreatic cancer. We introduce the players in PNI, summarize the distribution of GDNF and its receptors in pancreatic cancer, and discuss the effects and underlying mechanism of GDNF in the PNI process. Finally, we also review some potential inhibitors for GDNF-targeted therapy.

Keywords: Neurotrophic factor; Perineural invasion; Pancreatic cancer; Neuro-cancer interaction; RET; Targeted therapy

Small nucleolar RNAs in cancer by Kaiissar Mannoor; Jipei Liao; Feng Jiang (pp. 121-128).

Non-coding RNAs (ncRNAs) are important regulatory molecules involved in various physiological and cellular processes. Alterations of ncRNAs, particularly microRNAs, play crucial roles in tumorigenesis. Accumulating evidence indicates that small nucleolar RNAs (snoRNAs), another large class of small ncRNAs, are gaining prominence and more actively involved in carcinogenesis than previously thought. Some snoRNAs exhibit differential expression patterns in a variety of human cancers and demonstrate capability to affect cell transformation, tumorigenesis, and metastasis. We are beginning to comprehend the functional repercussions of snoRNAs in the development and progression of malignancy. In this review, we will describe current studies that have shed new light on the functions of snoRNAs in carcinogenesis and the potential applications for cancer diagnosis and therapy.

Keywords: Cancer; Non-coding RNAs; Small nucleolar RNAs; Diagnosis; Therapy

The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer by Subhankar Chakraborty; Sukhwinder Kaur; Sushovan Guha; Surinder K. Batra (pp. 129-169).

Neutrophil gelatinase associated lipocalin (NGAL), also known as oncogene 24p3, uterocalin, siderocalin or lipocalin 2, is a 24kDa secreted glycoprotein originally purified from a culture of mouse kidney cells infected with simian virus 40 (SV-40). Subsequent investigations have revealed that it is a member of the lipocalin family of proteins that transport small, hydrophobic ligands. Since then, NGAL expression has been reported in several normal tissues where it serves to provide protection against bacterial infection and modulate oxidative stress. Its expression is also dysregulated in several benign and malignant diseases. Its small size, secreted nature and relative stability have led to it being investigated as a diagnostic and prognostic biomarker in numerous diseases including inflammation and cancer. Functional studies, conducted primarily on lipocalin 2 (Lcn2), the mouse homologue of human NGAL have revealed that Lcn2 has a strong affinity for iron complexed to both bacterial siderophores (iron-binding proteins) and certain human proteins like norepinephrine. By sequestering iron-laden siderophores, Lcn2 deprives bacteria of a vital nutrient and thus inhibits their growth (bacteriostatic effect). In malignant cells, its proposed functions range from inhibiting apoptosis (in thyroid cancer cells), invasion and angiogenesis (in pancreatic cancer) to increasing proliferation and metastasis (in breast and colon cancer). Ectopic expression of Lcn2 also promotes BCR-ABL induced chronic myelogenous leukemia in murine models. By transporting iron into and out of the cell, NGAL also regulates iron responsive genes. Further, it stabilizes the proteolytic enzyme matrix metalloprotease-9 (MMP-9) by forming a complex with it, and thereby prevents its autodegradation. The factors regulating NGAL expression are numerous and range from pro-inflammatory cytokines like interleukins, tumor necrosis factor-α and interferons to vitamins like retinoic acid. The purpose of this review article is to examine the expression, structure, regulation and biological role of NGAL and critically assess its potential as a novel diagnostic and prognostic marker in both benign and malignant human diseases.

Keywords: Abbreviations; Adp; Adult Periodontitis; AKI; Acute Kidney Injury; AMI; Acute Myocardial Infarction; APACHE-II; Acute Physiology And Chronic Health Evaluation; APKD; Adult Polycystic Kidney Disease; BFGF; Basic Fibroblast Growth Factor; BMI; Body-Mass-Index; BMSCs; Bone Marrow Derived Mesenchymal Stem Cells; CAD; Coronary Artery Disease; CD; Crohn's Disease; CKD; Chronic Kidney Disease; CMB; Carboxymycobactin; CML; Chronic Myeloid Leukemia; COPD; Chronic Obstructive Pulmonary Disease; COX-2; Cytochrome c Oxidase-2; CSC; Cancer Stem Cells; CSF; Cerebrospinal Fluid; DFO; Iron-Chelator Deferoxamine; E2; 17-Β Estradiol; EC; Endometrial Carcinoma; EGF; Epidermal Growth Factor; EGFR; Epidermal Growth Factor Receptor; eGFR; Estimated Glomerular Filtration Rate; ER; Estrogen Receptor; ERCP; Endoscopic Retrograde Cholangiopancreatography; ERE; Estrogen Response Element; FAK; Focal Adhesion Kinase; GFR; Glomerular Filtration Rate; GRs; Glucocorticoid Receptors; H.R.; Hazards Ratio; HCC; Hepatocellular Carcinoma; HIF-1α; Hypoxia Inducible Factor-1; Holo-Tf; Transferrin Loaded With Iron; IGF-1; Insulin Like Growth Factor-1; IHC; Immunohistochemistry; IL; Interleukin; IRI; Ischemia Reperfusion Injury; JAK2; Janus-Associated Kinase 2; Lcn2; Lipocalin 2; Lcn2; Mouse Lipocalin 2; LJP; Localized Juveline Periodontitis; LMW; Low Molecular Weight; LRP2; Lipoprotein Receptor Related Protein; MEFs; Mouse Embryonic Fibroblasts; MHC; Major Histocompatibility Antigen; MMP-9; Matrix Metalloprotease-9; Mouse Ngal; 24p3; MPO; Myloperoxidase Peroxidase; NGAL; Neutrophil Gelatinase Associated Lipocalin; NMR; Nuclear Magnetic Resonance; NOD/SCID; Non-Obese Diabetic/Severe Combined Immunodeficient; OSPC; Ovarian Serous Papillary Carcinoma; PGC-1α; Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha; PHKs; Primary Human Keratinocytes; RCC; Renal Cell Carcinoma; ROS; Reactive Oxygen Species; s.c.; Subcutaneous; SAPS-II; Simplified Acute Physiology Score; SOFA; Sequential Organ Failure Assessment; TGF-α; Transforming Growth Factor Alpha; TICs; Tumor Initiating Cells; TIMP-1; Tissue Inhibitor Of Metalloproteinase-1; TLR; Toll-Like Receptor; TNF-α; Tumor Necrosis Factor Alpha; VEGF; Vascular Endothelial Growth Factor; α2-MRP; α2-Microglobulin Related ProteinNGAL; Lipocalin 2; 24p3; Uterocalin; Diagnosis; Prognosis

Stroma and pancreatic ductal adenocarcinoma: An interaction loop by Guopei Luo; Jiang Long; Bo Zhang; Chen Liu; Jin Xu; Quanxing Ni; Xianjun Yu (pp. 170-178).

Pancreatic ductal adenocarcinom a (PDA) has two exceptional features. First, it is a highly lethal disease, with a median survival of less than 6months and a 5-year survival rate less than 5%. Second, PDA tumor cells are surrounded by an extensive stroma, which accounts for up to 90% of the tumor volume. It is well recognized that stromal microenvironment can accelerate malignant transformation, tumor growth and progression. More importantly, the interaction loop between PDA and its stroma greatly contributes to tumor growth and progression. We propose that the extensive stroma of PDA is closely linked to its poor prognosis. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed. Targeting the stroma may thus provide novel prevention, earlier detection and therapeutic options to this deadly malignancy. Accordingly, in this review, we will summarize the mechanism of PDA stroma formation, the role of the stroma in tumor progression and therapy resistance and the potential of stroma-targeted therapeutics strategies.

Keywords: Abbreviations; PDA; pancreatic ductal adenocarcinoma; PSCs; pancreatic stellate cells; ECM; extracellular matrix; NGFs; nerve growth factors; α-SMA; α-smooth muscle actin; PDGF; platelet derived growth factor; TGF-β; transforming growth factor β; FGF; fibroblast growth factor; TNF-α; tumor necrosis factor α; IL; interleukin; MMPs; matrix metalloproteinases; TIMPs; tissue inhibitor of metalloproteinases; COX-2; cyclooxygenase-2; FAP; fibroblast activation protein; CAFs; cancer-associated fibroblasts; SDF-1; stromal cell-derived factor 1; IGF1; insulin-like growth factor 1; HGF; hepatocyte growth factor; M-CSF; macrophage colony stimulating factor; TAMs; Tumor-associated macrophages; EGF; epidermal growth factor; EMT; epithelial-mesenchymal transition; MSCs; mesenchymal stem cells; Shh; Sonic hedgehog; SPARC; secreted protein acidic and rich in cysteine; VEGFA; vascular endothelial growth factor; PanIN; pancreatic intraepithelial neoplasia; ZO-1; zonula occludens-1; ZEB1; zinc-finger E-box binding homeobox 1Pancreatic ductal adenocarcinoma; Stroma; Tumor microenvironment; Targeted therapy

The role of protein tyrosine phosphatases in colorectal cancer by Elmer Hoekstra; Maikel P. Peppelenbosch; Gwenny M. Fuhler (pp. 179-188).

Colorectal cancer is one of the most common oncogenic diseases in the Western world. Several cancer associated cellular pathways have been identified, in which protein phosphorylation and dephosphorylation, especially on tyrosine residues, are one of most abundant regulatory mechanisms. The balance between these processes is under tight control by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Aberrant activity of oncogenic PTKs is present in a large portion of human cancers. Because of the counteracting role of PTPs on phosphorylation-based activation of signal pathways, it has long been thought that PTPs must act as tumor suppressors. This dogma is now being challenged, with recent evidence showing that dephosphorylation events induced by some PTPs may actually stimulate tumor formation. As such, PTPs might form a novel attractive target for anticancer therapy. In this review, we summarize the action of different PTPs, the consequences of their altered expression in colorectal cancer, and their potential as target for the treatment of this deadly disease.Three major CRC related signaling pathways, and their modulation by the PTPs are reviewed.Display Omitted

Keywords: Protein tyrosine phosphatases; Colorectal cancer; Signaling pathways; Novel treatment targets

CD95 signaling in colorectal cancer by Frederik J.H. Hoogwater; Ernst J.A. Steller; B. Florien Westendorp; Inne H.M. Borel Rinkes; Onno Kranenburg (pp. 189-198).

CD95 and its ligand (CD95L) are widely expressed in colorectal tumors, but their role in shaping tumor behavior is unclear. CD95 activation on tumor cells can lead to apoptosis, while CD95L attracts neutrophils, suggesting a function in tumor suppression. However, CD95 can also promote tumorigenesis, at least in part by activating non-apoptotic signaling pathways that stimulate tumor cell proliferation, invasion and survival. In addition, CD95 signaling in stromal cells and tumor-infiltrating inflammatory cells has to be taken into account when addressing the function of CD95 and its ligand in colorectal tumor biology. We present a model in which the tumor-suppressing and tumor-promoting activities of CD95/CD95L together determine colorectal tumor behavior. We also discuss how these multiple activities are changing our view of CD95 and CD95L as potential therapeutic targets in the treatment of colorectal cancer. We conclude that locking CD95 in apoptosis-mode may be a more promising anti-cancer strategy than simply inhibiting or stimulating CD95.

Keywords: CD95; Colorectal; Invasion; Metastasis; Apoptosis; KRAS

Challenges in the clinical utility of the serum test for HER2 ECD by Lian Lam; Nicholas McAndrew; Marla Yee; Ting Fu; Julia C. Tchou; Hongtao Zhang (pp. 199-208).

Approximately 15–30% of breast cancers over-express the HER2/neu receptor. Historically, over-expression of HER2/neu has been identified using IHC or FISH, both of which are invasive approaches requiring tissue samples. Recent evidence has shown that some tumors identified as “negative” using these methods can respond to HER2/neu targeted therapy. Shedding of the extracellular domain (ECD) of the receptor into the circulation has led to the development of a serum test of HER2 ECD as an additional approach to probe HER2/neu overexpression. The serum test will be able to monitor the dynamic changes of HER2 status over the course of disease progression. Some studies further suggest that the serum HER2 ECD level and its change may serve as a biomarker to reflect patients' response to therapy. Yet more than 10years after the first serum HER2 ECD test was approved by the FDA, serum HER2 testing has yet to be widely used in clinical practice. In this article we will review the progress of the serum HER2 ECD test and discuss some obstacles impeding its incorporation into broad clinical practice. We will also discuss recent improvements in the sensitivity and specificity of the assay that offer some hope for the future of serum HER2 test.Display Omitted

Keywords: HER2; Extracellular domain (ECD); Targeted therapy; Serum biomarker; Detection

Adipose tissue cells, lipotransfer and cancer: A challenge for scientists, oncologists and surgeons by Francesco Bertolini; Visnu Lohsiriwat; Jean-Yves Petit; Mikhail G. Kolonin (pp. 209-214).

Despite recent evidence of the cancer-promoting role of adipose tissue-derived progenitor and differentiated cells, the use of lipotransfer for tissue/organ reconstruction after surgical removal of cancer is increasing worldwide. Here we discuss in a multidisciplinary fashion the preclinical data connecting obesity, adipose cells and cancer progression, as well as the clinical data concerning safety of lipotransfer procedures in cancer patients. A roadmap towards a more rationale use of lipotransfer in oncology is urgently needed and should include preclinical studies to dissect the roles of different adipose tissue-derived cells, the evaluation of drugs currently candidate to inhibit the interaction between adipose and tumor cells, and carefully designed clinical trials to investigate the safety of lipotransfer procedures in cancer patients.

Keywords: Cancer; adipose tissue; adipose progenitors; obesity; angiogenesis

Deregulation of signalling pathways in prognostic subtypes of hepatocellular carcinoma: Novel insights from interspecies comparison by Diego F. Calvisi; Maddalena Frau; Maria L. Tomasi; Francesco Feo; Rosa M. Pascale (pp. 215-237).

Hepatocellular carcinoma is a frequent and fatal disease. Recent researches on rodent models and human hepatocarcinogenesis contributed to unravel the molecular mechanisms of hepatocellular carcinoma dedifferentiation and progression, and allowed the discovery of several alterations underlying the deregulation of cell cycle and signalling pathways. This review provides an interpretive analysis of the results of these studies. Mounting evidence emphasises the role of up-regulation of RAS/ERK, PI3K/AKT, IKK/NF-kB, WNT, TGF-β, NOTCH, Hedgehog, and Hippo signalling pathways as well as of aberrant proteasomal activity in hepatocarcinogenesis. Signalling deregulation often occurs in preneoplastic stages of rodent and human hepatocarcinogenesis and progressively increases in carcinomas, being most pronounced in more aggressive tumours. Numerous changes in signalling cascades are involved in the deregulation of carbohydrate, lipid, and methionine metabolism, which play a role in the maintenance of the transformed phenotype. Recent studies on the role of microRNAs in signalling deregulation, and on the interplay between signalling pathways led to crucial achievements in the knowledge of the network of signalling cascades, essential for the development of adjuvant therapies of liver cancer. Furthermore, the analysis of the mechanisms involved in signalling deregulation allowed the identification of numerous putative prognostic markers and novel therapeutic targets of specific hepatocellular carcinoma subtypes associated with different biologic and clinical features. This is of prime importance for the selection of patient subgroups that are most likely to obtain clinical benefit and, hence, for successful development of targeted therapies for liver cancer.

Keywords: Abbreviations; ACAC; acetyl-CoA carboxylase; ACLY; ATP citrate lyase; AEG-1; astrocyte elevated gene-1; AKT; v-AKT murine thymoma viral oncogene homolog; AMPK; AMP kinase; APC/C(CDH1); Anaphase Promoting Complex/Cyclosome, and its activator CDH1); AUF1; AUrich RNA binding factor 1; AURKA; Aurora A; BHMT; betaine-homocysteine methyltransferase; CD25; interleukin 2 receptor, alpha); CDC2; cell cycle controller-2; CDC37; cell division cycle 37; CDC25B; cell division cycle 25B; CDC14B; cell division cycle 14,; Saccharomyces cerevisiae; homolog B; CDK; cyclin-dependent kinase; CDKN1α; cyclin-dependent kinase inhibitor 1α,p21; ^WAF1; chREBP; (carbohydrate responsive element binding protein); CK1δ/ε; casein kinase 1δ/ε; CKS1; Cdc28 protein kinase 1; COL1A2; type I collagen a2; COXII; cytochrome oxidase subunit II; CRM1; required for Chromosome region maintenance 1; CTGF; connective tissue growth factor; DELTEX; DELTEX Drosophila homolog; DMBT1; deleted in malignant brain tumours 1; DN; dysplastic nodule; DUSP1; dual-specificity phosphatase 1; EGFR; epidermal growth factor receptor; EMT; epithelial to mesenchymal transition; EpCAM; epithelial cell adhesion molecule; ERK1/2; extracellular signal-regulated kinase 1/2; EZH2; enhancer of ZESTE, drosophila, homolog 2; FASN; fatty acid synthase; FCCP; carbonyl cyanide p-trifluoromethoxyphenylhydrazone; FOXM1; Forkhead box M1; FOXO1; forkhead box O1; G6PD; glucose-6-phosphate dehydrogenase; GADD45g; growth arrest and DNA-damage-inducible-γ; GI; genomic instability; GLI; glioma-associated oncogene homolog 1; GNMT; glycine N-methyltransferase; GSK3β; glycogen synthase kinase-3β; GLUT; glucose transporter; HDAC10; histone deacetylase 10; HBV; hepatitis B virus; HCC; hepatocellular carcinoma; HCCB; HCC with better prognosis; HCCP; HCC with poorer prognosis; HCV; hepatitis C virus; HES-1; hairy/enhancer of split, Drosophila homolog 1; HINT1; histidine triad nucleotide-binding protein 1; HIF-1a; hypoxia-inducible factor 1α; HKII; hexokinase II; HMGCR; 3-hydroxy-3-methylglutaryl-CoA reductase; HSP90; heat shock protein 90; HuR; AUrich RNA binding factor 1; IGFR; insulin-like growth factor receptor; IKK; inhibitor of kappa light chain gene enhancer in b cells, kinase of, beta; IL1A; interleukin 1A; LATS1/2; Wts homologues; LDH; lactic dehydrogenase; LINC; MYBL2–LIN9 complex; LKB1; liver kinase b1; LXR-β; liver X receptor β; MAPK; Mitogen Activated Protein Kinase; MAT; methionine adenosyltransferase; MDK; Midkine; ME; malic enzyme; MET; hepatocyte growth factor receptor; MICA; major histocompatibility complex class I chain-related gene A; 5-MTHF-HMT; N; ⁵; -methyltetrahydrofolate homocysteine methyltransferase; mTOR; mammalian target of Rapamycin; mTORC1; mTOR complex 1; MST1/2; homologues of Hpo; MVK; mevalonate kinase; NADPH; nicotinamide adenine dinucleotide phosphate; NASH; non-alcoholic steatohepatitis; NCOA1; nuclear receptor coactivator 1; NEK2; never in mitosis gene A-related kinase 2; NF-kB; nuclear factor kB; NO; Nitric oxide; NOS; nitric oxide synthase; NRDG3; N-myc downstream-regulated gene 3; NRIP1; nuclear receptor-interacting protein 1; PAI-1; plasminogen activator inhibitor-1; PAPSS1; 3′-phosphoadenosine 50-phosphosulfate synthase-1; PFK2; phosphofructokinase 2; PDGFRα, PDGFRβ; platelet derived growth factor α,β; PDK-1; pyruvate dehydrogenase kinase-1; PK; pyruvate kinase; PI3K; phosphatydilinositol 3-kinase; PP1CA; protein phosphatase 1 catalytic subunit alpha; PTCH; patched; PTEN; Phosphatase and tensin homologue deleted on chromosome 10; RASSF1A; Ras association domain family 1A; RhoGDIA; RhoGDP dissociation inhibitor; ROCK2; RHO-associated coiled-coil-containing protein kinase 2; SAH; S-adenosylhomocysteine; SAM; S-adenosylmethionine; Sav1; Salvador; SCD1; stearoyl-CoA desaturase 1; SCO-2; synthesis of cytochrome c oxidase 2; SKP2; S-phase kinase-associated protein 2; SMAD; mothers against decapentaplegic, drosophila, homolog of; SMO; smoothened; SNAIL; snail Drosophila homolog; SQS; squalene synthetase; SREBP2; sterol regulatory element binding protein 2; STMN1; Stathmin; SUFU; Suppressor of fused; TGF-β; tumour growth factor-β; TIGAR; TP53-induced glycolysis and apoptosis regulator; TIMP3; tissue inhibitor of metalloproteinase 3; TKL-1; transketolase 1; TNFAIP3; tumour necrosis factor alpha-induced protein 3; VEGF-α; vascular endothelial growth factor-α; ZEB1/2; zinc finger e box-binding homeobox 1/2Hepatocarcinogenesis; Signal transduction; MicroRNA; Prognostic marker; Therapeutic target; Interspecies comparison

Mitochondrial remodeling in cancer metabolism and survival: Potential for new therapies by Inês A. Barbosa; Nuno G. Machado; Andrew J. Skildum; Patricia M. Scott; Paulo J. Oliveira (pp. 238-254).

Mitochondria are semi-autonomous organelles that play essential roles in cellular metabolism and programmed cell death pathways. Genomic, functional and structural mitochondrial alterations have been associated with cancer. Some of those alterations may provide a selective advantage to cells, allowing them to survive and grow under stresses created by oncogenesis. Due to the specific alterations that occur in cancer cell mitochondria, these organelles may provide promising targets for cancer therapy. The development of drugs that specifically target metabolic and mitochondrial alterations in tumor cells has become a matter of interest in recent years, with several molecules undergoing clinical trials. This review focuses on the most relevant mitochondrial alterations found in tumor cells, their contribution to cancer progression and survival, and potential usefulness for stratification and therapy.

Keywords: Abbreviations; ACL; acute promyelocytic leukemia; AIF; apoptosis-inducing factor; AKT; serine/threonine protein kinase; AMP; adenosine monophosphate; AMPK; AMP-activated protein kinase; ANT; adenine nucleotide translocase; Apaf1; apoptotic peptidase activating factor 1; ATP; adenosine triphosphate; BAD; Bcl-2 associated agonist of cell death; Bcl-2; B-cell CLL/lymphoma 2; Bcl-X; _L; B-cell lymphoma extra large; Bak; Bcl-2 antagonist/killer; Bax; Bcl-2 associated X protein; COX; cytochrome c oxidase; DCA; dichloroacetate; 2-DG; 2-deoxyglucose; DNA; deoxyribonucleic acid; mtDNA; mitochondrial DNA; EGCG; epigallocatechin-3-gallate; ETC; electron transport chain; ER; estrogen receptor; ERK; extracellular signal-regulated kinase; FDG; 2-deoxy-2-[F-18]fluoro-; d; -glucose; FES; 16α[; ¹⁸; F]fluoro-17βestradiol; FH; fumarate hydratase; GLS; glutaminase; GLUT; glucose transporter; GPx; glutathione peroxidase; GRed; glutathione reductase; GS; glycogen synthase; GSH; glutathione; GSK-3; glycogen synthase kinase 3; GST; glutathione S-transferase; HIF-1α; hypoxia inducible factor 1, alpha subunit; HK2; hexokinase 2; HTRA2; high temperature requirement protein A2; α-KG; alpha ketoglutarate; LDHA; lactate dehydrogenase A; LKB1; serine/threonine kinase 11; MAPK; mitogen-activated protein kinase; 2-ME; 2-methoxyestradiol; MOMP; mitochondrial outer membrane permeabilization; MPT; mitochondria permeability transition; MYC; v-Myc myelocytomatosis viral oncogene homolog; NADH; nicotinamide adenine dinucleotide; Noxa; phorbol-12-myristate-13-acetate-induced protein 1; NQO1; NAD(P)H quinone oxidoreductase 1; NRF; nuclear respiratory factor; OXPHOS; oxidative phosphorylation; PBR; peripheral benzodiazepine receptor; PDH; pyruvate dehydrogenase; PDK1; pyruvate dehydrogenase kinase, isoenzyme 1; PEITC; phenyl ethyl isothiocyanates; PET; positron emission tomography; PGC1a; PPARγ coactivator 1 alpha; PHD; prolyl hydroxylase; PIK3; phosphatidylinositol 3-kinase; PIP; phosphatidylinositol phosphate; PKM2; pyruvate kinase, muscle 2; PPARγ; peroxisome proliferator activated receptor gamma; PPP; pentose phosphate pathway; PTEN; phosphatase and tensin homolog; PUMA; p53-upregulated modulator of apoptosis; RAS; rat sarcoma protein; RNA; ribonucleic acid; rRNA; ribosomal RNA; tRNA; transfer RNA; ROS; reactive oxygen species; SDH; succinate dehydrogenase; SLC5A1; solute carrier family 5 (sodium/glucose cotransporter), member 1; SMAC/Diablo; second mitochondrial-derived activator of caspases/direct IAP-binding protein with low isoelectric point; SOD; superoxide dismutase; TCA; tricarboxylic acid cycle; mTOR; mechanistic target of rapamycin (serine/threonine kinase); α-TOS; alpha tocopherol succinate; TRAP1; tumor necrosis factor receptor-associated protein 1; TSPO; 18; kDa translocator protein; VDAC; voltage-dependent anion channel; VHL; Von Hippel–Lindau tumor suppressorCancer; Chemotherapeutics; Metabolic remodeling; Mitochondria; Oxidative stress

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BBA - Reviews on Cancer (v.1826, #1)