Check out our New Publishers' Select for Free Articles

BBA - Reviews on Cancer (v.1815, #2)

Editorial Board (pp. i).

The complexities of obesity and diabetes with the development and progression of pancreatic cancer by Bin Bao; Zhiwei Wang; Yiwei Li; Dejuan Kong; Shadan Ali; Sanjeev Banerjee; Aamir Ahmad; Fazlul H. Sarkar (pp. 135-146).

Pancreatic cancer (PC) is one of the most lethal malignant diseases with the worst prognosis. It is ranked as the fourth leading cause of cancer-related deaths in the United States. Many risk factors have been associated with PC. Interestingly, large numbers of epidemiological studies suggest that obesity and diabetes, especially type-2 diabetes, are positively associated with increased risk of PC. Similarly, these chronic diseases (obesity, diabetes, and cancer) are also a major public health concern. In the U.S. population, 50 percent are overweight, 30 percent are medically obese, and 10 percent have diabetes mellitus (DM). Therefore, obesity and DM have been considered as potential risk factors for cancers; however, the focus of this article is restricted to PC. Although the mechanisms responsible for the development of these chronic diseases leading to the development of PC are not fully understood, the biological importance of the activation of insulin, insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) signaling pathways in insulin resistance mechanism and subsequent induction of compensatory hyperinsulinemia has been proposed. Therefore, targeting insulin/IGF-1 signaling with anti-diabetic drugs for lowering blood insulin levels and reversal of insulin resistance could be useful strategy for the prevention and/or treatment of PC. A large number of studies have demonstrated that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers, suggesting that these agents might be useful anti-tumor agents for the treatment of PC. In this review article, we will discuss the potential roles of metformin and TZD anti-diabetic drugs as anti-tumor agents in the context of PC and will further discuss the complexities and the possible roles of microRNAs (miRNAs) in the pathogenesis of obesity, diabetes, and PC.

Keywords: Obesity; Diabetes mellitus; Pancreatic cancer; Metformin; TZD

The multifaceted proteins Reptin and Pontin as major players in cancer by Aude Grigoletto; Patrick Lestienne; Jean Rosenbaum (pp. 147-157).

Reptin and Pontin belong to the family of AAA+ ATPases (ATPases Associated with various cellular Activities). Several studies have reported their overexpression in cancer, including hepatocellular carcinoma and colorectal cancer. Functional studies have implicated them in many cellular processes highly relevant to cancer. They thus interact with the oncogenes c-myc and β-catenin, and modulate their transcriptional activities. They participate in large molecular complexes such as the INO80 or the TIP60 complexes that are involved in chromatin remodeling or DNA damage repair. They are also required for the biogenesis of telomerase. Studies that used RNA interference or expression of mutated proteins have concluded at their role in cell growth and viability. Interestingly, not all their functions require an intact ATPase domain. Besides their roles as nuclear proteins, recent evidence suggests that they also have cytosolic functions such as regulation of the nonsense mediated decay of mRNAs. Finally, silencing experiments in xenografts indicate that they may be suitable targets for cancer therapy.

Keywords: Abbreviations; AAA+; ATPases Associated with various cellular Activities; PIKKs; phosphatidylinositol 3-kinase; -; related protein kinases; HCC; hepatocellular carcinoma; NMD; nonsense-mediated decayATPase; Helicase; AAA+; Chromatin; Transcription; DNA damage; Beta-catenin; c-myc; Telomerase; Hepatocellular carcinoma

Cigarette smoking, cyclooxygenase-2 pathway and cancer by Run-Yue Huang; George G. Chen (pp. 158-169).

Cigarette smoking is a major cause of mortality and morbidity worldwide. Cyclooxygenase (COX) and its derived prostanoids, mainly including prostaglandin E2 (PGE2), thromboxane A2 (TxA2) and prostacyclin (PGI2), have well-known roles in cardiovascular disease and cancer, both of which are associated with cigarette smoking. This article is focused on the role of COX-2 pathway in smoke-related pathologies and cancer. Cigarette smoke exposure can induce COX-2 expression and activity, increase PGE2 and TxA2 release, and lead to an imbalance in PGI2 and TxA2 production in favor of the latter. It exerts pro-inflammatory effects in a PGE2-dependent manner, which contributes to carcinogenesis and tumor progression. TxA2 mediates other diverse biologic effects of cigarette smoking, such as platelet activation, cell contraction and angiogenesis, which may facilitate tumor growth and metastasis in smokers. Among cigarette smoke components, nicotine and its derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are the most potent carcinogens. COX-2 and PGE2 have been shown to play a pivotal role in many cancers associated with cigarette smoking, including cancers of lung, gastric and bladder, while the information for the role of TxA2 and PGI2 in smoke-associated cancers is limited. Recent findings from our group have revealed how NNK influences the TxA2 to promote the tumor growth. Better understanding in the above areas may help to generate new therapeutic protocols or to optimize the existing treatment strategy.

Keywords: Abbreviations; AA; arachidonic acid; PLA2; phospholipase A2; COX; cyclooxygenase; PGE2; prostaglandin E2; TxA2; thromboxane A2; TxB2; thromboxane B2; PGI2; prostacyclin; PGES; prostaglandin E synthase; TxAS; thromboxane synthase; PGIS; prostacyclin synthase; GPCR; G-protein-coupled receptors; EP; prostaglandin E receptor; TP; thromboxane A2 receptor; IP; prostacyclin receptor; PPAR; peroxisome-proliferator-activated receptor; α7-nAChR; alpha7-nicotinic acetylcholine receptor; EGFR; epidermal growth factor receptor; TSNAs; tobacco-specific; N; -nitrosamines; PAH; polycyclic aromatic hydrocarbons; NNK; nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNN; N; ′-nitrosonornicotine; NAB; N; ′-nitrosoanabasine; NAT; N; ′-nitrosoanatabine; NNAL; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; iso-NNAL; 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol; iso-NNAC; 4-(methylnitrosamino)-4-3-pyridyl)butyric acid; NSCLC; non-small cell lung cancer; SCLC; small cell lung cancer; HNSCC; head and neck squamous cell carcinoma; NF-κB; nuclear factor kappa B; CREB; cyclic adenosine monophosphate response element-binding; p38MAPK; p38 mitogen-activated protein kinase; ERK; extracellular signal-regulated kinases; cAMP; cyclic adenosine monophosphate; AC; adenylate cyclase; PKA; protein kinase A; PKC; protein kinase C; MEK; mitogen-activated protein kinase kinase; MMP; Matrix metallopeptidase; NSAIDs; non-steroidal anti-inflammatory drugs; COXIBs; selective COX-2 inhibitors; IL; interleukin; TNF; tumor necrosis factor; IFN; interferon; BLA; bronchoalveolar; ICAM-1; intercellular adhesion molecule-1; VEGF; vascular endothelial growth factor; PCNA; proliferating-cell nuclear antigenCigarette smoking; Nicotine; NNK; Cyclooxygenase; Prostaglandin E2; Thromboxane A2; Prostacyclin; Cancer

The RasGrf family of mammalian guanine nucleotide exchange factors by Fernandez-Medarde Alberto Fernández-Medarde; Eugenio Santos (pp. 170-188).

RasGrf1 and RasGrf2 are highly homologous mammalian guanine nucleotide exchange factors which are able to activate specific Ras or Rho GTPases. The RasGrf genes are preferentially expressed in the central nervous system, although specific expression of either locus may also occur elsewhere. RasGrf1 is a paternally-expressed, imprinted gene that is expressed only after birth. In contrast, RasGrf2 is not imprinted and shows a wider expression pattern. A variety of isoforms for both genes are also detectable in different cellular contexts. The RasGrf proteins exhibit modular structures composed by multiple domains including CDC25H and DHPH motifs responsible for promoting GDP/GTP exchange, respectively, on Ras or Rho GTPase targets. The various domains are essential to define their intrinsic exchanger activity and to modulate the specificity of their functional activity so as to connect different upstream signals to various downstream targets and cellular responses.Despite their homology, RasGrf1 and RasGrf2 display differing target specificities and non overlapping functional roles in a variety of signaling contexts related to cell growth and differentiation as well as neuronal excitability and response or synaptic plasticity. Whereas both RasGrfs are activatable by glutamate receptors, G-protein-coupled receptors or changes in intracellular calcium concentration, only RasGrf1 is reported to be activated by LPA, cAMP, or agonist-activated Trk and cannabinoid receptors. Analysis of various knockout mice strains has uncovered a specific functional contribution of RasGrf1 in processes of memory and learning, photoreception, control of post-natal growth and body size and pancreatic β-cell function and glucose homeostasis. For RasGrf2, specific roles in lymphocyte proliferation, T-cell signaling responses and lymphomagenesis have been described.

Keywords: Abbreviations; GEFs; guanine nucleotide exchange factors; NMDA; N-methyl-; d; -aspartate; AMPA; α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CNS; Central Nervous System; DMD; differentially methylated domain; CTCF; CCCTC-binding protein; CDB; cyclin destruction box; PH domain; pleckstrin homology domain; CC; coiled coil domain; IQ motif; isoleucine (I)/glutamine (Q) motif; DH domain; Dbl homology domain; ITIM; immunoreceptor tyrosine-based inhibition motif; REM; Ras exchange motif; PEST rich region; proline (P), glutamic acid (E), proline (S) and threonine (T) rich region; LTD; long term depression; LTP; long term potentiation; GPCR; G-protein coupled receptors; RTK; receptor tyrosine kinase; GWAS; genome wide association study; YY1; Yin and Yang 1 protein; PRC2; polycomb repressive complex-2; DMT; DNA methyl transferase; MK27; methylated lysine 27; ND; neurological domain; CAM; calmodulin; CamKK; calmodulin kinase kinase; CaMKI; calmodulin kinase I; P(Y); phosphotyrosine; P(S); phosphoserineRasGrf1; RasGrf2; RasGEF; Guanine nucleotide exchange factor; Signal transduction; Cell growth/differentiation

The role of blood platelets in tumor angiogenesis by Siamack Sabrkhany; Arjan W. Griffioen; Mirjam G.A. oude Egbrink (pp. 189-196).

Coagulation abnormalities occur frequently in cancer patients. It is becoming evident that blood platelets have an important function in this process. However, understanding of the underlying mechanisms is still very modest. In this review, we discuss the role of platelets in tumor angiogenesis and growth and suggest their potential significance in malignancies. Platelets contain various pro-and antiangiogenic molecules, which seem to be endocytosed and sequestered in different populations of α-granules. Furthermore, tumor endothelial cells are phenotypically and functionally different from endothelial cells in healthy tissue, stimulating local platelet adhesion and subsequent activation. As a consequence, platelets are able to secrete their angiogenic and angiostatic content, most likely in a regulated manner. The overall effect of these platelet–endothelium interactions appears to be proangiogenic, stimulating tumor angiogenesis. We favor the view that local adhesion and activation of blood platelets and dysregulation of coagulation represent underestimated pathways in the progression of cancer.

Keywords: Blood platelets; Cancer; Endothelium; Tumor angiogenesis

Role of Notch and its oncogenic signaling crosstalk in breast cancer by Shanchun Guo; Mingli Liu; Ruben R. Gonzalez-Perez (pp. 197-213).

The Notch signaling plays a key role in cell differentiation, survival, and proliferation through diverse mechanisms. Notch signaling is also involved in vasculogenesis and angiogenesis. Moreover, Notch expression is regulated by hypoxia and inflammatory cytokines (IL-1, IL-6 and leptin). Entangled crosstalk between Notch and other developmental signaling (Hedgehog and Wnt), and signaling triggered by growth factors, estrogens and oncogenic kinases, could impact on Notch targeted genes. Thus, alterations of the Notch signaling can lead to a variety of disorders, including human malignancies. Notch signaling is activated by ligand binding, followed by ADAM/tumor necrosis factor-α-converting enzyme (TACE) metalloprotease and γ-secretase cleavages that produce the Notch intracellular domain (NICD). Translocation of NICD into the nucleus induces the transcriptional activation of Notch target genes. The relationships between Notch deregulated signaling, cancer stem cells and the carcinogenesis process reinforced by Notch crosstalk with many oncogenic signaling pathways suggest that Notch signaling may be a critical drug target for breast and other cancers. Since current status of knowledge in this field changes quickly, our insight should be continuously revised. In this review, we will focus on recent advancements in identification of aberrant Notch signaling in breast cancer and the possible underlying mechanisms, including potential role of Notch in breast cancer stem cells, tumor angiogenesis, as well as its crosstalk with other oncogenic signaling pathways in breast cancer. We will also discuss the prognostic value of Notch proteins and therapeutic potential of targeting Notch signaling for cancer treatment.

Keywords: Abbreviations; 4T1 cells; mouse mammary cancer cell line; ADAM; a disintegrin and metalloprotease; Akt; protein kinase B; ALDH; aldehyde dehydrogenase; ANK; ankyrin; Axin2; the Axin-related protein; BALB/c; an albino, laboratory-bred strain of the house mouse; Bcl-2; B-cell lymphoma 2; Bcl-xl; B-cell lymphoma-extra large; BCSC; breast cancer stem cells; BMP; bone morphogenetic protein; Br4; brain metastatic cell line; CaSki; cervical carcinoma cell; CBF1; centromere-binding factor 1; CD4; cluster of differentiation 4; CD8; cluster of differentiation 8; C/EBPβ; CCAAT/enhance binding protein β; CFCs; bipotent colony forming cells; c-myc; Myc proto-oncogene protein; Co-A; recruites coactivator; Co-R; corepressor; CpdE; compound E; CSC; cancer stem cell; CSL; CBF1/Su(H)/Lag-1; Cyclin D1; kinase and regulator of cell cycle D1; DAPT; N; -[; N; -(3,5-difluorophenacetyl)-; l; -alanyl]-; S; -phenylglycine; t; -butyl ester; DBZ; dibenzazipene; DDP; cisplatin; DLL-1; Delta-like 1; DOS; Delta and OSM-11-like proteins; DSL; Delta/Serrate/LAG-2; E2; 17β-estradiol; EC; endothelial cells; EGF; epidermal growth factor; EGFR; epidermal growth factor receptor; EMD; company name; EMT; epithelial-mesenchymal transformation; EMT6; a mouse mammary adenocarcinoma cell line; ER; estrogen receptor; ERK 1/2; extracellular regulated kinase 1 and 2; GBM; glioblastoma; GSI; a γ-secretase inhibitor; HD; heterodimerization; HDAC; histone deacetylases; HIF-1α; hypoxia regulated factor-1 α; HT-29; colon cancer cell line; HUVECs; human umbilical vein endothelial cells; ICN; intracellular region of Notch; IGF-1; insulin like growth factor-1; IL-1; interleukin-1; IL-1R tI; interleukin-1 type I receptor; IL-6; interleukin-6; IL-6R; interleukin-6 receptor; JAK2; Janus kinase 2; MAPK; mitogen-activated protein kinase; MCF-7; ER positive human breast cancer cell line; MDA-MB231; ER negative human breast cancer cell line; MFE; mammosphere-forming efficiency; miRNA; microRNA; mTOR; mammalian target of rapamycin; NECD; Notch extracelluare domain; NEXT; Notch extracelluar truncation; NF-κB; eukaryotic nuclear transcription factor kappa B; NICD; Notch intracellular domain; NRR; negative regulatory region; OB-R; leptin receptor; PDAC; pancreatic ductal adenocarcinoma; PDGF; platelet-derived growth factor; PEST; proline, glutamine, serine and threonine residue; PI-3K; phosphoinositide 3-kinase; RhoC; Ras homolog gene family, member C; Src; a proto-oncogenic tyrosine kinase; SiHa; human cervical tumor cell; STAT3; signal transducer and activator of transcription 3; TACE; tumor necrosis factor-α-converting enzyme; TAD; transactivation domain; TAM; tamoxifen; T-ALL; T-cell acute lymphoblastic leukemia; TGF-β; transforming growth factor beta; TNF-α; tumor necrosis factor alpha; TSA; trichostatin A; U87MG; a glioma cell line; VEGF; vascular endothelial growth factor; VEGFR-2; vascular endothelial growth factor receptor 2 or KDR or Flk-1Notch; Breast cancer; Leptin; Tumor angiogenesis; Carcinogenesis; Cancer stem cell; NILCO, IL-1

Inhibiting TGF-β signaling in hepatocellular carcinoma by Gianluigi Giannelli; Antonio Mazzocca; Emilia Fransvea; Michael Lahn; Salvatore Antonaci (pp. 214-223).

One of the main complications in patients with liver fibrosis is the development of hepatocellular carcinoma (HCC). An understanding of the molecular mechanisms leading to HCC is important in order to be able to design new pharmacological agents serving either to prevent or mitigate the outcome of this malignancy. The transforming growth factor-beta (TGF-β) cytokine and its isoforms initiate a signaling cascade which is closely linked to liver fibrosis, cirrhosis and subsequent progression to HCC. Because of its role in these stages of disease progression, TGF-β appears to play a unique role in the molecular pathogenesis of HCC. Thus, it is a promising target for pharmacological treatment strategies. Recent studies have shown that inhibition of TGF-β signaling results in multiple synergistic down-stream effects which will likely improve the clinical outcome in HCC. We also review a number of TGF-β inhibitors, most of which are still in a preclinical stage of development, but may soon be available for trial in HCC patients. Hence, it is anticipated that there will soon be new agents available for clinical investigations to evaluate the role of the TGF-β-associated signaling in this deadly cancer.

Keywords: Hepatocellular carcinoma; Small molecule inhibitors of TGF-β receptor kinase; Target-based therapies; Stromal-tumor interactions

Mucins in the pathogenesis of breast cancer: Implications in diagnosis, prognosis and therapy by Partha Mukhopadhyay; Subhankar Chakraborty; Moorthy P. Ponnusamy; Imayavaramban Lakshmanan; Maneesh Jain; Surinder K. Batra (pp. 224-240).

Mucins are high molecular weight, multifunctional glycoproteins comprised of two structural classes—the large transmembrane mucins and the gel-forming or secreted mucins. The primary function of mucins is to protect and lubricate the luminal surfaces of epithelium-lined ducts in the human body. Recent studies have identified a differential expression of both membrane bound (MUC1, MUC4 and MUC16) and secreted mucins (MUC2, MUC5AC, MUC5B and MUC6) in breast cancer tissues when compared with the non-neoplastic breast tissues. Functional studies have also uncovered many unique roles of mucins during the progression of breast cancer, which include modulation in proliferative, invasive and metastatic potential of tumor cells. Mucins function through many unique domains that can form complex association with various signaling molecules including growth factor receptors and intercellular adhesion molecules. While there is growing information about mucins in various malignancies including breast cancer, no focused review is there on the expression and functional roles of mucins in breast cancer. In this present review, we have discussed the differential expression and functional roles of mucins in breast cancer. The potential of mucins as diagnostic and prognostic markers and as therapeutic targets in breast cancer have also been discussed.

Keywords: Abbreviations; BC; breast cancer; UEH; usual epithelial hyperplasia (also called ductal hyperplasia DH); ADH; atypical ductal hyperplasia; CIS; carcinoma; in situ; SRCC; signet ring cell carcinoma; FGF; fibroblast growth factor; EGFR; epidermal growth factor receptor (also called ErbB1); MUC1; cytoplasmic tail (MUC1-CT); EGF; epidermal growth factor; PTD; Protein transduction domains; MTS; membrane translocating sequences; MCA; mucin-like carcinoma associated antigenMucins; Polymorphic epithelial mucins; MUC1 (DF3); MUC4; MUC16 (CA125); Cancer; Breast cancer; Cell survival; Apoptosis

Protected from the inside: Endogenous histone deacetylase inhibitors and the road to cancer by Lucia Di Marcotullio; Gianluca Canettieri; Paola Infante; Azzura Greco; Alberto Gulino (pp. 241-252).

Histone deacetylases (HDACs) play a crucial role in several physiological and pathological cell functions, including cell development and cancer, by deacetylating both histones and others proteins. HDACs belong to a large family of enzymes including Class I, II and IV as well as Class III or sirtuins subfamilies, that undergo a complex transcriptional and post-translational regulation. In current years, antitumor therapy is attempting to exploit several chemical classes of inhibitors that target HDACs, frequently reported to be misregulated in cancer. Nevertheless, the identity of gene products directly involved in tumorigenesis and preventing HDAC misregulation in cancer is still poorly understood. Recent evidence has demonstrated that the tumor suppressors HIC1 and DBC1 induce direct repression of Sirt1 function, whereas Chfr and REN^{KCTD11/KASH family} downregulate HDAC1, by inducing its ubiquitin-dependent degradation. Loss of these gene products leads to imbalanced enhancement of HDAC activity and subsequently to oncogenesis. All these genes are frequently deleted or silenced in human cancers, highlighting the role of endogenous HDAC inhibitors to counteracts HDAC-mediated tumorigenesis. Thus, endogenous HDAC inhibitors represent a promising class of “antitumor agents” thanks to which oncogenic addiction pathways may be selectively therapeutically targeted.

Keywords: HDACs; HDAC inhibitors; Cancer; HIC1; DBC1; Chfr; REN; ^KCTD11

Sections

Personal tools

BBA - Reviews on Cancer (v.1815, #2)

Sections

Personal tools

Local resources

BBA - Reviews on Cancer (v.1815, #2)