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BBA - Reviews on Cancer (v.1765, #2)
The roles of heterogeneous nuclear ribonucleoproteins in tumour development and progression by Brian Carpenter; Catriona MacKay; Ayham Alnabulsi; Morven MacKay; Colin Telfer; William T. Melvin; Graeme I. Murray (pp. 85-100).
The heterogeneous nuclear ribonucleoproteins (hnRNP) are a family of proteins which share common structural domains, and extensive research has shown that they have central roles in DNA repair, telomere biogenesis, cell signaling and in regulating gene expression at both transcriptional and translational levels. Through these key cellular functions, individual hnRNPs have a variety of potential roles in tumour development and progression including the inhibition of apoptosis, angiogenesis and cell invasion. The aims of this review are to provide an overview of the multi functional roles of the hnRNPs, and how such roles implicate this family as regulators of tumour development. The different stages of tumour development that are potentially regulated by the hnRNPs along with their aberrant expression profiles in tumour tissues will also be discussed.
Keywords: Heterogeneous nuclear ribonucleoproteins; Structure; Cellular function; Neoplasm; Tumour; Diagnosis; Treatment; Gene expression
Lysosomes and lysosomal proteins in cancer cell death (new players of an old struggle) by Claudine Tardy; Patrice Codogno; Hélène Autefage; Thierry Levade; Nathalie Andrieu-Abadie (pp. 101-125).
Death of cancer cells influences tumor development and progression, as well as the response to anticancer therapies. This can occur through different cell death programmes which have recently been shown to implicate components of the acidic organelles, lysosomes. The role of lysosomes and lysosomal enzymes, including cathepsins and some lipid hydrolases, in programmed cell death associated with apoptotic or autophagic phenotypes is presented, as evidenced from observations on cultured cells and living animals. The possible molecular mechanisms that underlie the action of lysosomes during cell death are also described. Finally, the contribution of lysosomal proteins and lysosomes to tumor initiation and progression is discussed. Elucidation of this role and the underlying mechanisms will shed a new light on these ‘old’ organelles and hopefully pave the way for the development of novel anticancer strategies.
Keywords: Abbreviations; IGF-II; insulin-like growth factor-II; LAMP; lysosome-associated membrane protein; M6P; mannose 6-phosphate; MMP; mitochondrial membrane permeabilization; MPR; mannose 6-phosphate receptor; PCD; programmed cell death; PPT1; palmitoyl protein thioesterase 1; ROS; reactive oxygen species; SMase; sphingomyelinase; TNF; tumor necrosis factorHydrolase; Apoptosis; Autophagy; Lysosome; Cathepsin
Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition by F. Feo; M.R. De Miglio; M.M. Simile; M.R. Muroni; D.F. Calvisi; M. Frau; R.M. Pascale (pp. 126-147).
The different frequency of hepatocellular carcinoma (HCC) in humans at risk suggests a polygenic predisposition. However, detection of genetic variants is difficult in genetically heterogeneous human population. Studies on mouse and rat models identified 7 hepato carcinogenesissusceptibility ( Hcs) and 2 resistance ( Hcr) loci in mice, and 7 Hcs and 9 Hcr loci in rats, controlling multiplicity and size of neoplastic liver lesions. Six liver neoplastic nodule remodeling ( Lnnr) loci control number and volume of re-differentiating lesions in rat. A Hcs locus, with high phenotypic effects, and various epistatic gene–gene interactions were identified in rats, suggesting a genetic model of predisposition to hepatocarcinogenesis with different subset of low-penetrance genes, at play in different subsets of population, and a major locus. This model is in keeping with human HCC epidemiology. Several putative modifier genes in rodents, deregulated in HCC, are located in chromosomal segments syntenic to sites of chromosomal aberrations in humans, suggesting possible location of predisposing loci. Resistance to HCC is associated with lower genomic instability and downregulation of cell cycle key genes in preneoplastic and neoplastic lesions. p16INK4A upregulation occurs in susceptible and resistant rat lesions. p16INK4A-induced growth restraint was circumvented by Hsp90/Cdc37 chaperons and E2f4 nuclear export by Crm1 in susceptible, but not in resistant rats and human HCCs with better prognosis. Thus, protective mechanisms seem to be modulated by HCC modifiers, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
Keywords: Hepatocarcinogenesis; Genetic predisposition; Quantitative trait loci; Modifier genes; Polygenic disease; Redifferentiation
Methionine aminopeptidase 2 and cancer by Ponniah Selvakumar; Ashakumary Lakshmikuttyamma; Jonathan R. Dimmock; Rajendra K. Sharma (pp. 148-154).
Methionine aminopeptidase (MetAP) is a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. In yeasts and humans, two proteins are known to possess MetAP activity, which are known as MetAP1 and MetAP2. MetAP2 has attracted much more attention than MetAP1 due to the discovery of MetAP2 as a target molecule of the anti-angiogenic compounds, fumallin and ovalicin. MetAP2 plays an important role in the development of different types of cancer. Recently, we observed a high expression of MetAP2 in human colorectal cancer tissues and colon cancer cell lines. In addition, pp60c-src expression was correlated with the expression of MetAP2 and N-myristoyltransferase. In this review, we discuss the recent developments of MetAP2 and its inhibitors. Future detailed studies related to MetAP2 and apoptosis will shed light on the involvement of this enzyme in the regulation of various apoptotic factors.
Keywords: Tumorigenesis; Lipid modification; Methionine aminopeptidase 2; Myristoyltransferase; Myristoyltransferase inhibitor protein
Antiangiogenic peptides and proteins: From experimental tools to clinical drugs by Curzio Rüegg; Meriem Hasmim; Ferdy J. Lejeune; Gian Carlo Alghisi (pp. 155-177).
The formation of a ‘tumor-associated vasculature’, a process referred to as tumor angiogenesis, is a stromal reaction essential for tumor progression. Inhibition of tumor angiogenesis suppresses tumor growth in many experimental models, thereby indicating that tumor-associated vasculature may be a relevant target to inhibit tumor progression. Among the antiangiogenic molecules reported to date many are peptides and proteins. They include cytokines, chemokines, antibodies to vascular growth factors and growth factor receptors, soluble receptors, fragments derived from extracellular matrix proteins and small synthetic peptides. The polypeptide tumor necrosis factor (TNF, Beromun) was the first drug registered for the regional treatment of human cancer, whose mechanisms of action involved selective disruption of the tumor vasculature. More recently, bevacizumab (Avastin), an antibody against vascular endothelial growth factor (VEGF)-A, was approved as the first systemic antiangiogenic drug that had a significant impact on the survival of patients with advanced colorectal cancer, in combination with chemotherapy. Several additional peptides and antibodies with antiangiogenic activity are currently tested in clinical trials for their therapeutic efficacy. Thus, peptides, polypeptides and antibodies are emerging as leading molecules among the plethora of compounds with antiangiogenic activity.In this article, we will review some of these molecules and discuss their mechanism of action and their potential therapeutic use as anticancer agents in humans.
Keywords: Tumor angiogenesis; Lymphangiogenesis; Cancer; Therapy; Peptide; Antibody
Regulation of tumor angiogenesis by thrombospondin-1 by Bin Ren; Karen O. Yee; Jack Lawler; Roya Khosravi-Far (pp. 178-188).
Angiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Expression of TSP-1 is up-regulated by the tumor suppressor gene, p53, and down-regulated by oncogenes such as Myc and Ras. TSP-1 inhibits angiogenesis by inhibiting endothelial cell migration and proliferation and by inducing apoptosis. In addition, activation of transforming growth factor beta (TGF-β) by TSP-1 plays a crucial role in the regulation of tumor progression. An understanding of the molecular basis of TSP-1-mediated inhibition of angiogenesis and tumor progression will aid in the development of novel therapeutics for the treatment of cancer.
Keywords: Thrombospondin-1; Angiogenesis; Tumor progression; Metastasis; Gene; TGF-beta
Regulation of mucin expression: Mechanistic aspects and implications for cancer and inflammatory diseases by Mahefatiana Andrianifahanana; Nicolas Moniaux; Surinder K. Batra (pp. 189-222).
Mucins are large multifunctional glycoproteins whose primary functions are to protect and lubricate the surfaces of epithelial tissues lining ducts and lumens within the human body. Several lines of evidence also support the involvement of mucins in more complex biological processes such as epithelial cell renewal and differentiation, cell signaling, and cell adhesion. Recent studies have uncovered the role of select mucins in the pathogenesis of cancer, underscoring the importance of a detailed knowledge about mucin biology. Under normal physiological conditions, the production of mucins is optimally maintained by a host of elaborate and coordinated regulatory mechanisms, thereby affording a well-defined pattern of tissue-, time-, and developmental state-specific distribution. However, mucin homeostasis may be disrupted by the action of environmental and/or intrinsic factors that affect cellular integrity. This results in an altered cell behavior that often culminates into a variety of pathological conditions. Deregulated mucin production has indeed been associated with numerous types of cancers and inflammatory disorders. It is, therefore, crucial to comprehend the underlying basis of molecular mechanisms controlling mucin production in order to design and implement adequate therapeutic strategies for combating these diseases. Herein, we discuss some physiologically relevant regulatory aspects of mucin production, with a particular emphasis on aberrations that pertain to pathological situations. Our views of the achievements, the conceptual and technical limitations, as well as the future challenges associated with studies of mucin regulation are exposed.
Keywords: Mucin; MUC; Regulation; Cancer; Inflammation
The biology of Ku and its potential oncogenic role in cancer by Charles Gullo; Melvin Au; Ge Feng; Gerrard Teoh (pp. 223-234).
Ku is a heterodimeric protein made up of two subunits, Ku70 and Ku80. It was originally identified as an autoantigen recognized by the sera of patients with autoimmune diseases. It is a highly versatile regulatory protein that has been implicated in multiple nuclear processes, e.g., DNA repair, telomere maintenance and apoptosis. Accordingly, Ku is thought to play a crucial role in maintenance of chromosomal integrity and cell survival. Recent reports suggest that there is a positive relationship between Ku and the development of cancer, making Ku an important candidate target for anticancer drug development. Specifically, prior studies suggest that a delicate balance exists in Ku expression, as overexpression of Ku proteins promotes oncogenic phenotypes, including hyperproliferation and resistance to apoptosis; whereas deficient or low expression of Ku leads to genomic instability and tumorigenesis. Such observations through various experimental models indicate that Ku may act as either a tumor suppressor or an oncoprotein. Hence, understanding the link between the various functions of Ku and the development of cancer in different cell systems may help in the development of novel anticancer therapeutic agents that target Ku. These studies may also increase our understanding of how Ku autoantibodies are generated in autoimmune diseases.
Keywords: Carcinogenesis; Apoptosis; Genomic instability; DNA repair
Calcium transport and signaling in the mammary gland: Targets for breast cancer by Won Jae Lee; Gregory R. Monteith; Sarah J. Roberts-Thomson (pp. 235-255).
The mammary gland is subjected to extensive calcium loads during lactation to support the requirements of milk calcium enrichment. Despite the indispensable nature of calcium homeostasis and signaling in regulating numerous biological functions, the mechanisms by which systemic calcium is transported into milk by the mammary gland are far from completely understood. Furthermore, the implications of calcium signaling in terms of regulating proliferation, differentiation and apoptosis in the breast are currently uncertain. Deregulation of calcium homeostasis and signaling is associated with mammary gland pathophysiology and as such, calcium transporters, channels and binding proteins represent potential drug targets for the treatment of breast cancer.
Erratum to “Mouse models of K-ras-initiated carcinogenesis� [Biochem. Biophys. Act. 1756 (2005) 145–154]
by Klaus-Peter Janssen; Miguel Abal; Fatima El Marjou; Daniel Louvard; Sylvie Robine (pp. 256-256).