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BBA - Reviews on Cancer (v.1765, #1)

Editorial Board (pp. ii).

Amine oxidases in apoptosis and cancer by Antonio Toninello; Paola Pietrangeli; Umberto De Marchi; Mauro Salvi; Bruno Mondovì (pp. 1-13).
Amine oxidases, the major enzymes of biogenic amines metabolism, are considered to be biological regulators, especially for cell growth and differentiation. A primary involvement of amine oxidases in cancer growth inhibition and progression, especially by means of aldehydes, H2O2 and other reactive oxygen species, the amine oxidase-mediated products of biogenic amines oxidation, has been demonstrated.Amine oxidases are involved in cancer growth inhibition because of the higher content in tumour cells of biogenic amines in comparison to normal cells. The cytotoxic effect can be explained by a damage to cell membranes and/or nuclei or, indirectly, through modulation of membrane permeability transition and therefore apoptosis. The oxidation products of biogenic amines appears to be also carcinogenic, while acrolein, produced from the oxidation of spermine and spermidine, should be a key compound both carcinogenic and cytotoxic. The cancer inhibition/promotion effect of amine oxidases could be explained by taking into consideration the full pattern of the enzyme content of the cell. The balance of amine oxidases and antioxidant enzymes appear to be a crucial point for cancer inhibition or progression. A long lasting imbalance of these enzymes appears to be carcinogenic, while, for a short time, amine oxidases are cytotoxic for cancer cells.

Keywords: Abbreviations; BA; biogenic amine; AO; amine oxidase; FAD-AO; FAD-dependent amine oxidase; Cu-AO; copper-dependent amine oxidase; MAO; monoamine oxidase; PAO; polyamine oxidase; TPQ; trihydroxyphenylalanine quinone; BSAO; bovine serum amine oxidase; LSAO; lentil seedling amine oxidase; LTQ; lysyl tyrosyl quinone; LOX; lysyl oxidase; MPT; mitochondrial permeability transition; ROS; reactive oxygen species; ODC; ornithine decarboxylase; DFMO; 2-difluoromethylornithine; O; 2; −; superoxide anion; HO; hydroxyl radical; SSAT; spermine-spermidine acetyl transferase; ΔΨ; membrane potential; SMO; spermine oxidaseAmine oxidase; Apoptosis; Cancer; Polyamine; Aldehyde; Oxygen free radical; Hydrogen peroxide


β-catenin-mediated signaling: A novel molecular target for chemoprevention with anti-inflammatory substances by Joydeb Kumar Kundu; Kang-Yell Choi; Young-Joon Surh (pp. 14-24).
Inflammation is thought to play a role in the pathophysiology of cancer. Accumulating evidence from clinical and laboratory-based studies suggests that substances with anti-inflammatory activities are potential candidates for chemoprevention. Recent advances in cellular and molecular biology of cancer shed light on components of intracellular signaling cascades that can be potential molecular targets of chemoprevention with various anti-inflammatory substances. Although cyclooxygenase-2, a primary enzyme that mediates inflammatory responses, has been well recognized as a molecular target for chemoprevention by both synthetic and natural anti-inflammatory agents, the cellular signaling mechanisms that associate inflammation and cancer are not still clearly illustrated. Recent studies suggest that β-catenin-mediated signaling, which regulates developmental processes, may act as a potential link between inflammation and cancer. This review aims to focus on β-catenin-mediated signaling pathways, particularly in relation to its contribution to carcinogenesis, and the modulation of inappropriately activated β-catenin-mediated signaling by nonsteroidal anti-inflammatory drugs and chemopreventive phytochemicals possessing anti-inflammatory properties.

Keywords: Chemoprevention; β-catenin-mediated signaling; Cyclooxygenase-2; NSAID; Chemopreventive phytochemical


Endocan or endothelial cell specific molecule-1 (ESM-1): A potential novel endothelial cell marker and a new target for cancer therapy by S. Sarrazin; E. Adam; M. Lyon; F. Depontieu; V. Motte; C. Landolfi; H. Lortat-Jacob; D. Bechard; P. Lassalle; M. Delehedde (pp. 25-37).
Endocan, previously called endothelial cell specific molecule-1, is a soluble proteoglycan of 50 kDa, constituted of a mature polypeptide of 165 amino acids and a single dermatan sulphate chain covalently linked to the serine residue at position 137. This dermatan sulphate proteoglycan, which is expressed by the vascular endothelium, has been found freely circulating in the bloodstream of healthy subjects. Experimental evidence is accumulating that implicates endocan as a key player in the regulation of major processes such as cell adhesion, in inflammatory disorders and tumor progression. Inflammatory cytokines such as TNF-α, and pro-angiogenic growth factors such as VEGF, FGF-2 and HGF/SF, strongly increased the expression, synthesis or the secretion of endocan by human endothelial cells. Endocan is clearly overexpressed in human tumors, with elevated serum levels being observed in late-stage lung cancer patients, as measured by enzyme-linked immunoassay, and with its overexpression in experimental tumors being evident by immunohistochemistry. Recently, the mRNA levels of endocan have also been recognized as being one of the most significant molecular signatures of a bad prognosis in several types of cancer including lung cancer. Overexpression of this dermatan sulphate proteoglycan has also been shown to be directly involved in tumor progression as observed in mouse models of human tumor xenografts. Collectively, these results suggest that endocan could be a biomarker for both inflammatory disorders and tumor progression as well as a validated therapeutic target in cancer. On the basis of the recent successes of immunotherapeutic approaches in cancer, the preclinical data on endocan suggests that an antibody raised against the protein core of endocan could be a promising cancer therapy.

Keywords: Abbreviations; ESM-1; endothelial cell-specific molecule-1; PGs; proteoglycans; GAG; glycosaminoglycan; CS; chondroitin sulphate; DS; dermatan sulphate; HS; heparan sulphate; KS; keratan sulphate; HA; hyaluronic acid; TNF-α; tumor necrosis factor alpha; HGF/SF; hepatocyte growth factor/scatter factor; VEGF; vascular endothelial growth factor; FGF-2; fibroblast growth factor 2; PF-4; platelet factor 4; IL-1; interleukin 1; IFN-γ; interferon gamma; IGF; insulin-like growth factor; IGFBP; insulin-like growth factor binding-protein; SLRP; small leucine-rich repeat proteoglycan; HUVEC; human umbilical vein endothelial cells; CKII; casein kinase II; EGF; epidermal growth factor; EGFR; epidermal growth factor receptor; GalNAc; N-acetyl galactosamine; GlcA; glucuronic acid; IdoA; iduronic acidEndocan; ESM-1; Proteoglycan; Dermatan; Cancer; Inflammation; Immunotherapy


The flexible evolutionary anchorage-dependent Pardee's restriction point of mammalian cells. How its deregulation may lead to cancer by Thérèse David-Pfeuty (pp. 38-66).
Living cells oscillate between the two states of quiescence and division that stand poles apart in terms of energy requirements, macromolecular composition and structural organization and in which they fulfill dichotomous activities. Division is a highly dynamic and energy-consuming process that needs be carefully orchestrated to ensure the faithful transmission of the mother genotype to daughter cells. Quiescence is a low-energy state in which a cell may still have to struggle hard to maintain its homeostasis in the face of adversity while waiting sometimes for long periods before finding a propitious niche to reproduce. Thus, the perpetuation of single cells rests upon their ability to elaborate robust quiescent and dividing states. This led yeast and mammalian cells to evolve rigorous Start [L.H. Hartwell, J. Culotti, J. Pringle, B.J. Reid, Genetic control of the cell division cycle in yeast, Science 183 (1974) 46–51] and restriction (R) points [A.B. Pardee, A restriction point for control of normal animal cell proliferation, Proc. Natl. Acad. Sci. U. S. A. 71 (1974) 1286–1290], respectively, that reduce deadly interferences between the two states by enforcing their temporal insulation though still enabling a rapid transition from one to the other upon an unpredictable change in their environment. The constitutive cells of multicelled organisms are extremely sensitive in addition to the nature of their adhering support that fluctuates depending on developmental stage and tissue specificity. Metazoan evolution has entailed, therefore, the need for exceedingly flexible anchorage-dependent R points empowered to assist cells in switching between quiescence and division at various times, places and conditions in the same organism. Programmed cell death may have evolved concurrently in specific contexts unfit for the operation of a stringent R point that increase the risk of deadly interferences between the two states (as it happens notably during development). But, because of their innate flexibility, anchorage-dependent R points have also the ability to readily adjust to a changing structural context so as to give mutated cells a chance to reproduce, thereby encouraging tumor genesis. The Rb and p53 proteins, which are regulated by the two products of the Ink4a-Arf locus [C.J. Sherr, The INK4a/ARF network in tumor suppression, Nat. Rev., Mol. Cell Biol. 2 (2001) 731–737], govern separable though interconnected pathways that cooperate to restrain cyclin D- and cyclin E-dependent kinases from precipitating untimely R point transit. The expression levels of the Ink4a and Arf proteins are especially sensitive to changes in cellular shape and adhesion that entirely remodel at the time when cells shift between quiescence and division. The Arf proteins further display an extremely high translational sensitivity and can activate the p53 pathway to delay R point transit, but, only when released from the nucleolus, ‘an organelle formed by the act of building a ribosome’ [T. Mélèse, Z. Xue, The nucleolus: an organelle formed by the act of building a ribosome, Curr. Opin. Cell Biol. 7 (1995) 319–324]. In this way, the Ink4a/Rb and Arf/p53 pathways emerge as key regulators of anchorage-dependent R point transit in mammalian cells and their deregulation is, indeed, a rule in human cancers. Thus, by selecting the nucleolus to mitigate cell cycle control by the Arf proteins, mammalian cells succeeded in forging a highly flexible R point enabling them to match cell division with a growth rate imposed by factors controlling nucleolar assembling, such as nutrients and adhesion. It is noteworthy that nutrient control of critical size at Start in budding yeast has been shown recently to be governed by a nucleolar protein interaction network [P. Jorgensen, J.L. Nishikawa, B.-J. Breitkreutz, M. Tyers, Systematic identification of pathways that couple cell growth and division in yeast, Science 297 (2002) 395–400].

Keywords: Abbreviations; Cdk; cyclin-dependent kinase; MPF; maturation/mitosis promoting factor; R point; restriction point; mRNA/rRNA/tRNA; messenger/ribosomal/transfer RNA; Pol I/II/III; RNA polymerase I/II/III; RP; ribosomal protein; APC; anaphase-promoting complex; SCF; skp1-cullin-F-box protein complex; CKI; Cdk inhibitor; Rb; retinoblastoma; Ink4a; inhibitor of Cdk4; p53*; mutated p53; Arf; alternative reading frame; CNS/PNS; central/peripheral nervous system; G; c; critical growth rate; MEF; mouse embryonic fibroblast; HDF; human diploid fibroblast; Mcm; minichromosome maintenance; hTERT; human telomerase reverse transcriptase; LT/st; large T/small t antigen of simian virus SV40; PP2A; protein phosphatase 2A; ECM; extracellular matrix; IGF; insulin-like growth factor; RTK; receptor tyrosine kinase; MAPK; mitogen-activated protein kinase; PI3K; phosphatidyl inositol 3 kinase; PTEN; phosphatase and tensin homologue; TOR; target of rapamycin; Ras*; oncogenic RasCell cycle; Cell growth; Nucleolus; Anchorage; Homeostasis; Cancer


CtIP, a candidate tumor susceptibility gene is a team player with luminaries by G. Chinnadurai (pp. 67-73).
CtIP is a nuclear protein conserved among vertebrates that was discovered as a cofactor of the transcriptional corepressor CtBP. CtIP also interacts with the tumor suppressors such as BRCA1 and the pRb family members through binding sites that are frequently mutated in human cancers. CtIP is a target for BRCA1-dependent phosphorylation by the ATM kinase induced by DNA double strand breakage. CtIP plays a role in DNA-damage-induced cell cycle checkpoint control at the G2/M transition. Homozygous inactivation of the Ctip gene causes very early embryonic lethality during mouse development. The Ctip−/− embryo cells are arrested in G1 and do not enter S phase. Depletion of Ctip in established mouse embryo fibroblasts arrests cells in G1 and results in an accumulation of hypophosphorylated Rb and the Cdk inhibitor p21, suggesting that CtIP is also a critical regulator of G1/S transition of the cell cycle. The Ctip gene contains a mononucleotide (A9) repeat and one of the alleles is mutated at a high frequency in colon cancers with microsatellite instability. The Ctip+/− mice develop multiple types of tumors suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Among the various tumor types observed in Ctip+/− heterozygous mice, large lymphomas are prevalent. Recent studies raise the possibility that Ctip may itself be a tumor susceptibility gene and suggest that it might be important for the activities of tumor suppressors BRCA1, pRb family proteins and Ikaros family members.

Keywords: CtIP; BRCA1; pRb; DNA repair


Identifying and defusing weapons of mass inflammation in carcinogenesis by Lorne J. Hofseth; Lei Ying (pp. 74-84).
The continued cancer risks associated with chronic inflammation necessitate the identification of inflammatory molecules and the cancer pathways they affect. Evidence indicates that there are multiple mechanisms linking inflammation to cancer and that there are multiple targets for chemoprevention. Here, we review some of the key factors and the cancer pathways they disturb as a necessary prerequisite to the identification of targets for chemoprevention.

Keywords: Inflammation; Cancer; Chemoprevention; COX-2; NF-kappa B; iNOS; Cytokine; Interleukin; Colitis; Crohn's; Hepatitis; Gastritis; Esophagitis; Barrett's; Pancreatitis; p53; Retinoblastoma; NSAID; Free radical
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