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BBA - Reviews on Cancer (v.1806, #1)
The potential role of ubiquitin c-terminal hydrolases in oncogenesis by Ying Fang; Da Fu; Xi-Zhong Shen (pp. 1-6).
Deubiquitinating enzymes (DUBs), capable of removing ubiquitin (Ub) from protein substrates, are involved in numerous biological processes. The ubiquitin C-terminal hydrolases (UCHs) subfamily of DUBs consists of four members: UCH-L1, UCH-L3, UCH37 and BRCA1-associated protein-1 (BAP1). UCH-L1 possesses deubiquitinating activity and dimerization-dependent ubiquitin ligase activity, and functions as a mono-ubiquitin stabilizer; UCH-L3 does both deubiquitinating and deneddylating activity, except dimerization or ligase activity, and unlike UCH-L1, can interact with Lys48-linked Ub dimers to protect it from degradation and in the meanwhile to inhibit its hydrolase activity; UCH37 is responsible for the deubiquitinating activity in the 19S proteasome regulatory complex, and as indicated by the recent study, UCH37 is also associated with the human Ino80 chromatin-remodeling complex (hINO80) in the nucleus and can be activated via transient association of 19S regulatory particle- or proteasome-bound hRpn13 with hINO80; BAP1, binding to the wild-type BRCA1 RING finger domain, is regarded as a tumor suppressor, but for such suppressing activity, as demonstrated otherwise, both deubiquitinating activity and nucleus localization are required. There is growing evidence that UCH enzymes and human malignancies are closely correlated. Previous studies have shown that UCH enzymes play a crucial role in some signalings and cell-cycle regulation. In this review, we provided an insight into the relation between UCH enzymes and oncogenesis.
Keywords: Abbreviations; AD; Alzheimer's disease; BAP1; BRCA1-associated protein-1; CDK; cyclin-dependent kinase; di-Ub; Ub dimers; DUBs; deubiquitinating enzymes; HCF-1; host cell factor 1; hINO80; human Ino80 chromatin-remodeling complex; JAB1; Jun activation domain-binding protein-1; JAMM; Jab1/MPN domain-associated metalloisopeptidase; JNK; c-Jun N-terminal kinase; MAPK; mitogen activated protein kinase; MJDs; Josephin or Machado-Joseph disease protein domain proteases; mono-Ub; mono-ubiquitin; NF-κB; nuclear factor-κ B; NFRΚB; nuclear factor related to κB; NLS; nuclear localization signal; OTUs; ovarian tumor proteases; PD; Parkinson's disease; RNAi; RNA interfere; RP; regulatory particle; Smurf2; Smad ubiquitination regulatory factor 2; TGF-β; transforming growth factor-β; Ub; ubiquitin; UBLs; ubiquitin-like proteins; UBPs; ubiquitin-specific processing proteases; UCHs; ubiquitin C-terminal hydrolases; USPs; ubiquitin-specific proteasesDUBs; UCHs; Oncogenesis
T regulatory cells, the evolution of targeted immunotherapy by S. Nizar; B. Meyer; C. Galustian; D. Kumar; A. Dalgleish (pp. 7-17).
T regulatory cells are able to suppress anti-tumour immunity in pre-clinical models and in patients. This review highlights the important discoveries in Treg immunology critical to the evolution of targeted immunotherapy. We also describe the therapeutic applications that are currently being assessed and their future potential.
Keywords: T regulatory; Tregs; FOXP3; Cancer; Immunotherapy
Signalling pathways in vasculogenic mimicry by Yvette W.J. Paulis; Patricia M.M.B. Soetekouw; Henk M.W. Verheul; Vivianne C.G. Tjan-Heijnen; Arjan W. Griffioen (pp. 18-28).
Solid tumour growth is dependent on the development of an adequate blood supply. For years, sprouting angiogenesis has been considered an exclusive mechanism of tumour vascularization. However, over the last years, several other mechanisms have been identified, including vessel-co-option, intussusception, recruitment of endothelial precursor cells (EPCs) and even mechanisms that do not involve endothelial cells, a process called vasculogenic mimicry (VM). The latter describes a mechanism by which highly aggressive tumour cells can form vessel-like structures themselves, by virtue of their high plasticity. VM has been observed in several tumour types and its occurrence is strongly associated with a poor prognosis. This review will focus on signalling molecules and cascades involved in VM. In addition, we will discuss the presence of VM in relation to ongoing cancer research. Finally, we describe the clinical significance of VM regarding anti-angiogenesis treatment modalities.
Keywords: Angiogenesis; Cancer; Plasticity; Signalling pathways; Vasculogenesis; Vasculogenic mimicry
Carbon nanotubes in cancer diagnosis and therapy by Shun-rong Ji; Chen Liu; Bo Zhang; Feng Yang; Jin Xu; Jiang Long; Chen Jin; De-liang Fu; Quan-xing Ni; Xian-jun Yu (pp. 29-35).
During the past years, great progress has been made in the field of nanomaterials given their great potential in biomedical applications. Carbon nanotubes (CNTs), due to their unique physicochemical properties, have become a popular tool in cancer diagnosis and therapy. They are considered one of the most promising nanomaterials with the capability of both detecting the cancerous cells and delivering drugs or small therapeutic molecules to these cells. Over the last several years, CNTs have been explored in almost every single cancer treatment modality, including drug delivery, lymphatic targeted chemotherapy, thermal therapy, photodynamic therapy, and gene therapy. In this review, we will show how they have been introduced into the diagnosis and treatment of cancer. Novel SWNT-based tumor-targeted drug delivery systems (DDS) will be highlighted. Furthermore, the in vitro and in vivo toxicity of CNTs reported in recent years will be summarized.
Keywords: Carbon nanotubes; Cancer; Diagnosis; Therapy; Drug delivery; Toxicity
Transcription factor ZBP-89 in cancer growth and apoptosis by Chris Z.Y. Zhang; George G. Chen; Paul B.S. Lai (pp. 36-41).
ZBP-89, a Krüppel-type zinc-finger transcription factor that binds to GC-rich sequences, is involved in the regulation of cell growth and cell death. It maps to chromosome 3q21 and is composed of 794 residues. Having bifunctional regulatory domains, ZBP-89 may function as a transcriptional activator or repressor of variety of genes such as p16 and vimentin. ZBP-89 arrests cell proliferation through its interactions with p53 and p21waf1. It is able to stabilize p53 through directly binding and enhance p53 transcriptional activity by retaining it in the nucleus. In addition, ZBP-89 potentiates in butyrate-induced endogenous p21waf1 up-regulation. ZBP-89 is usually over-expressed in human cancer cells, where it can efficiently induce apoptosis through p53-dependent and -independent mechanisms. Moreover, ZBP-89 is capable of enhancing killing effects of several anti-cancer drugs. Therefore, ZBP-89 may be served as a potential target in cancer therapy.
Keywords: ZBP-89; p53; p21; waf1; Apoptosis; Cancer
CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer by Ling Deng; Nianyong Chen; Yan Li; Hong Zheng; Qianqian Lei (pp. 42-49).
Metastasis is considered the obvious mark for most aggressive cancers. However, little is known about the molecular mechanism of the regulation of cancer metastasis. Recent evidence increasingly suggests that the interaction between chemokines and chemokine receptors is pivotal in the process of metastasis. The chemokine receptor CXCR4 and its ligand CXCL12, for example, have been reported to play a vital role in cancer metastasis. Another chemokine and chemokine receptor pair, the CXCL16/CXCR6 axis, has been studied by several independent research groups. Here, we summarize recent advances in our knowledge of the function of CXC chemokine receptor CXCR6 and its ligand CXCL16 in regulating metastasis and invasion of cancer. CXCR6 and CXCL16 are up-regulated in multiple cancer tissue types and cancer cell lines relative to normal tissues and cell lines. In addition, both CXCR6 and CXCL16 levels increase as tumor malignancy increases. Trans-membranous CXCL16 chemokine reduces proliferation while soluble CXCL16 chemokine enhances proliferation and migration. TM-CXCL16 functions as an inducer for lymphocyte build-up around tumor sites. High trans-membranous CXCL16 expression correlates with a good prognosis. Moreover, the Akt/mTOR signal pathway is involved in activating the CXCR6/CXCL16 axis. These findings suggest multiple opportunities for blocking the CXCR6/CXCL16 axis and the Akt/mTOR signal pathway in novel cancer therapies.
Keywords: Abbreviations; TM-CXCL16; trans-membrane CXCL16; sCXCL16; soluble CXCL16; NPC; nasopharyngeal carcinoma; NSCLC; non-small cell lung cancer; PI3K; phosphoinositide-3-kinase; mTOR; the mammalian target of rapamycin; HIF-1; hypoxia induced factor-1; TILs; tumor-infiltrating lymphocytesCXCR6; CXCL16; Cancer; Metastasis; Invasiveness
Genome-wide hypomethylation in cancer may be a passive consequence of transformation by Laurence Wild; James M. Flanagan (pp. 50-57).
Epigenetics describes the study of stable, reversible alterations to the genome that affect gene expression and genome function, the most studied mechanisms are DNA methylation and histone modifications. Over recent years there has been rapid progress to elucidate the nature and role of the mechanisms involved in promoter hypermethylation during carcinogenesis, however, the mechanism behind one of the earliest epigenetic observations in cancer, genome-wide hypomethylation, remains unclear. Current evidence is divided between the hypotheses that hypomethylation is either an important early cancer-causing aberration or that it is a passive inconsequential side effect of carcinogenesis. With recent discoveries of gene–body methylation, fast cyclic methylation of hormone dependent genes and candidate proteins involved in DNA demethylation elucidation of the role of hypomethylation and the mechanism behind it appears ever closer. With the burgeoning use of DNA methyltransferase inhibitors as a cancer therapy there is an increased need to understand the mechanisms and importance of genome-wide hypomethylation in cancer. This review will discuss the timing and potential causes of genomic hypomethylation during carcinogenesis and will propose a way forward to understand the underlying mechanisms.
Keywords: Epigenetics; Methylation; Cancer; Global hypomethylation
Helicobacter pylori infection generates genetic instability in gastric cells by Ana Manuel Dantas Machado; Céu Figueiredo; Raquel Seruca; Lene Juel Rasmussen (pp. 58-65).
The discovery that Helicobacter pylori is associated with gastric cancer has led to numerous studies that investigate the mechanisms by which H. pylori induces carcinogenesis. Gastric cancer shows genetic instability both in nuclear and mitochondrial DNA, besides impairment of important DNA repair pathways. As such, this review highlights the consequences of H. pylori infection on the integrity of DNA in the host cells. By down-regulating major DNA repair pathways, H. pylori infection has the potential to generate mutations. In addition, H. pylori infection can induce direct changes on the DNA of the host, such as oxidative damage, methylation, chromosomal instability, microsatellite instability, and mutations. Interestingly, H. pylori infection generates genetic instability in nuclear and mitochondrial DNA.Based on the reviewed literature we conclude that H. pylori infection promotes gastric carcinogenesis by at least three different mechanisms: (1) a combination of increased endogenous DNA damage and decreased repair activities, (2) induction of mutations in the mitochondrial DNA, and (3) generation of a transient mutator phenotype that induces mutations in the nuclear genome.
Keywords: H. pylori; Gastric cancer; DNA repair; Genetic instability
Building a better understanding of the intracellular tyrosine kinase PTK6 — BRK by BRK by Patrick M. Brauer; Angela L. Tyner (pp. 66-73).
Protein tyrosine kinase 6 (PTK6), also referred to as breast tumor kinase BRK, is a member of a distinct family of kinases that is evolutionarily related to the SRC family of tyrosine kinases. While not expressed in the normal mammary gland, PTK6 expression is detected in a large proportion of human mammary gland tumors. In breast tumor cells, PTK6 promotes growth factor signaling and cell migration. PTK6 expression is also increased in a number of other epithelial tumors, including ovarian and colon cancer. In contrast, PTK6 is expressed in diverse normal epithelia, including the linings of the gastrointestinal tract, skin and prostate, where its expression correlates with cell cycle exit and differentiation. Disruption of the mouse Ptk6 gene leads to increased growth and impaired differentiation in the small intestine that is accompanied by increased AKT and Wnt signaling. Following total body irradiation, PTK6 expression is induced in proliferating progenitor cells of the intestine, where it plays an essential role in DNA-damage induced apoptosis. A distinguishing feature of PTK6 is its flexibility in intracellular localization, due to a lack of amino-terminal myristoylation/palmitoylation. Recently a number of substrates of PTK6 have been identified, including nuclear RNA-binding proteins and transcription factors. We discuss PTK6 signaling, its apparent conflicting roles in cancer and normal epithelia, and its potential as a therapeutic target in epithelial cancers.
Keywords: PTK6; BRK; Sik; Tyrosine kinase; Epithelia; Breast cancer; Colon cancer
Involvement of ADAMs in tumorigenesis and progression of hepatocellular carcinoma: Is it merely fortuitous or a real pathogenic link? by Antonio Mazzocca; Gianluigi Giannelli; Salvatore Antonaci (pp. 74-81).
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the most frequent types of cancer worldwide. It normally develops in patients with chronic liver disease, especially cirrhosis, although some cases without an apparent underlying liver disease have been reported. The pathogenesis of HCC is multi-factorial and complex. Hepatitis viruses are the main factors favoring the development of HCC. In fact, chronic inflammation associated with hepatitis C or B virus infection can lead to progressive liver fibrosis, cirrhosis and ultimately HCC. Chronic inflammation and liver fibrosis cause a continuous remodeling of the extracellular matrix (ECM), a dynamic process that involves several molecules including integrins and matrix processing enzymes. An increasing body of evidence indicates that ADAMs are involved in promoting tumor formation and progression of HCC. A Disintegrin And Metalloproteases (ADAMs) are a group of proteins belonging to the zinc protease superfamily. ADAMs are usually transmembrane proteins that contain disintegrin and metalloprotease domains and are, therefore, able to carry out both cell adhesion and protease activities. Soluble isoforms of ADAMs have also been discovered and characterized. In this review, we focus on the contribution of ADAM proteins to HCC tumorigenesis and cancer progression. The potential role of ADAMs as key modulators of tumor–stroma interactions during tumor progression, by means of the activities of their constituent domains, is also discussed.
Keywords: Abbreviations; HCC; hepatocellular carcinoma; ADAMs; A Disintegrin And Metalloproteases; SVMP; snake venom metalloproteases; ADAMTS; A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif; ECM; extracellular matrix; IGF-I; insulin-like growth factor-I; IGFBP; insulin-like growth factor-binding proteins; EGF; epidermal growth factor; GPCRs; G protein-coupled receptors; HB-EGF; heparin-binding epidermal growth factor; TGF-α; transforming growth factor-alpha; FGFR2; fibroblast growth factor receptor 2; TNFα; transforming necrosis factor-alpha; TACE/ADAM-17; tumor necrosis factor-alpha converting enzyme/A Disintegrin And Metalloprotease-17; HBV; hepatitis B virus; HCV; hepatitis C virusHepatocellular carcinoma; ADAMs; Tumor–stromal interactions; Cancer associated myo/fibroblasts; Invasion; Metastasis
The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells by Jolanta Szenajch; Gabriel Wcislo; Jee-Yeong Jeong; Cezary Szczylik; Laurie Feldman (pp. 82-95).
Recombinant human erythropoietin (rhEPO) has been used clinically to alleviate cancer- and chemotherapy-related anemia. However, recent clinical trials have reported that rhEPO also may adversely impact disease progression and survival. The expression of functional EPO receptors (EPOR) has been demonstrated in many human cancer cells where, at least in vitro, rhEPO can stimulate cell growth and survival and may induce resistance to selected therapies.Responses to rhEPO measured by alterations in tumor cell growth or survival, activation of signaling pathways or modulation of sensitivity to anticancer agents are variable. Both methodological and inherent biological issues underlie the differential cell responses, including reported difficulties in EPOR protein detection, potential involvement of EPOR isoforms or of cytoplasmic EPOR, possible differential structure and/or binding affinities of hematopoietic versus non-hematopoietic cell EPOR, possible aberrant regulation of EPOR activity, and a functional EPO/EPOR autocrine/paracrine loop.The modulation by rhEPO of tumor cell response to anticancer agents is coincident with modulation of multiple signaling pathways, BCL-2 family proteins, caspases and NFkB. The molecular interplay of pro-survival and pro-death signals, triggered by EPO and/or by anticancer agents, is multifactorial and tightly coordinated. Expression microarray analysis may prove critical for deciphering this potentially novel network and its broad spectrum of genes and proteins.
Keywords: Abbreviations; βcR; beta common receptor; CIS; cytokine-inducible SH2 domain; DAG; diacylglycerol; EPO; erythropoietin; EPOR; erythropoietin receptor; ER; estrogen receptor; ESAs; erythropoiesis stimulating agents; ERK; extracellular signal regulated kinases; GPI; glycosylphosphatidylinositol; HIF; hypoxia inducible factor; HNSCC; head and neck squamous cell carcinoma; HSP70; heat shock protein 70; IkB; inhibitors of NFkB; IKK; IkB kinases; JAK2; Janus protein tyrosine kinase 2; JNK(SAPK); c-Jun N-terminal kinases (stress-activated protein kinases); MAPK; mitogen activated protein kinases; NFkB; nuclear factor kappa B; NSCLC; non-small cell lung carcinoma; PI; phosphatidylinositol; PI3K; phosphatidylinositol 3 kinase; PIP3; phosphatidylinositol 3,4,5-triphosphate; PKC; protein kinase C; PLC-γ; phospholipase C-γ; RCC; renal cell carcinoma; rhEPO; recombinant human erythropoietin; shRNA; short hairpin RNA; SOCS; suppressors of cytokine signaling; STAT5 (3); signal transducer and activator of transcription 5 (3)Erythropoietin; Erythropoietin receptor; Cancer; Signaling; Drug resistance; Radioresistance
Biomaterial-based technologies for brain anti-cancer therapeutics and imaging by G. Orive; O.A. Ali; E. Anitua; J.L. Pedraz; D.F. Emerich (pp. 96-107).
Treating malignant brain tumors represents one of the most formidable challenges in oncology. Contemporary treatment of brain tumors has been hampered by limited drug delivery across the blood–brain barrier (BBB) to the tumor bed. Biomaterials are playing an increasingly important role in developing more effective brain tumor treatments. In particular, polymer (nano)particles can provide prolonged drug delivery directly to the tumor following direct intracerebral injection, by making them physiochemically able to cross the BBB to the tumor, or by functionalizing the material surface with peptides and ligands allowing the drug-loaded material to be systemically administered but still specifically target the tumor endothelium or tumor cells themselves. Biomaterials can also serve as targeted delivery devices for novel therapies including gene therapy, photodynamic therapy, anti-angiogenic and thermotherapy. Nanoparticles also have the potential to play key roles in the diagnosis and imaging of brain tumors by revolutionizing both preoperative and intraoperative brain tumor detection, allowing early detection of pre-cancerous cells, and providing real-time, longitudinal, non-invasive monitoring/imaging of the effects of treatment. Additional efforts are focused on developing biomaterial systems that are uniquely capable of delivering tumor-associated antigens, immunotherapeutic agents or programming immune cells in situ to identify and facilitate immune-mediated tumor cell killing. The continued translation of current research into clinical practice will rely on solving challenges relating to the pharmacology of nanoparticles but it is envisioned that novel biomaterials will ultimately allow clinicians to target tumors and introduce multiple, pharmaceutically relevant entities for simultaneous targeting, imaging, and therapy in a unique and unprecedented manner.
Keywords: Biomaterials; Brain tumors; Nanoparticles; Imaging; Immunotherapy; Drug delivery
Vascular endothelial growth factor receptor-2 in breast cancer by Shanchun Guo; Laronna S. Colbert; Miles Fuller; Yuanyuan Zhang; Ruben R. Gonzalez-Perez (pp. 108-121).
Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis and carcinogenesis. The vascular endothelial growth factor receptor (VEGFR) family in mammals contains three members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4), which are transmembrane tyrosine kinase receptors that regulate the formation of blood and lymphatic vessels. In the early 1990s, the above VEGFR was structurally characterized by cDNA cloning. Among these three receptors, VEGFR-2 is generally recognized to have a principal role in mediating VEGF-induced responses. VEGFR-2 is considered as the earliest marker for endothelial cell development. Importantly, VEGFR-2 directly regulates tumor angiogenesis. Therefore, several inhibitors of VEGFR-2 have been developed and many of them are now in clinical trials. In addition to targeting endothelial cells, the VEGF/VEGFR-2 system works as an essential autocrine/paracrine process for cancer cell proliferation and survival. Recent studies mark the continuous and increased interest in this related, but distinct, function of VEGF/VEGFR-2 in cancer cells: the autocrine/paracrine loop. Several mechanisms regulate VEGFR-2 levels and modulate its role in tumor angiogenesis and physiologic functions, i.e.: cellular localization/trafficking, regulation of cis-elements of promoter, epigenetic regulation and signaling from Notch, cytokines/growth factors and estrogen, etc. In this review, we will focus on updated information regarding VEGFR-2 research with respect to the molecular mechanisms of VEGFR-2 regulation in human breast cancer. Investigations in the activation, function, and regulation of VEGFR-2 in breast cancer will allow the development of new pharmacological strategies aimed at directly targeting cancer cell proliferation and survival.
Keywords: VEGF; VEGFR-2; Tumor angiogenesis; Breast cancer; Autocrine/paracrine loop; Leptin
Emerging roles of PDGF-D signaling pathway in tumor development and progression by Zhiwei Wang; Aamir Ahmad; Yiwei Li; Dejuan Kong; Asfar S. Azmi; Sanjeev Banerjee; Fazlul H. Sarkar (pp. 122-130).
Platelet-derived growth factor-D (PDGF-D) can regulate many cellular processes, including cell proliferation, apoptosis, transformation, migration, invasion, angiogenesis and metastasis. Therefore PDGF-D signaling has been considered to be important in human malignancies, and thus PDGF-D signaling may represent a novel therapeutic target, and as such suggests that the development of agents that will target PDGF-D signaling is likely to have a significant therapeutic impact on human cancers. This mini-review describes the mechanisms of signal transduction associated with PDGF-D signaling to support the role of PDGF-D in the carcinogenesis. Moreover, we summarize data on several PDGF-D inhibitors especially naturally occurring “chemopreventive agent” such an indole compound, which we believe could serve as a novel agent for the prevention of tumor progression and/or treatment of human malignancies by targeted inactivation of PDGF-D signaling.
Keywords: PDGF-D; Cancer; Signaling; Therapy; Nutrition