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BBA - Reviews on Cancer (v.1805, #2)
Letter to the Editor: Efficacy and safety of anti-Trop antibodies, R. Cubas, M. Li, C. Chen and Q. Yao, Biochim Biophys Acta 1796 (2009) 309–1 by Marco Trerotola; Emanuela Guerra; Saverio Alberti (pp. 119-120).
Still little information is available on the efficacy and toxicity of anti-Trop-2 antibodies in man. Findings on antibodies anti-Trop-1/Ep-CAM, a paralog molecule of Trop-2, may provide preliminary indications, and a low-affinity anti-Trop-1/Ep-CAM monoclonal antibody, failed to show any benefit in colon cancer patients. Other anti-Trop-1 antibodies, e.g. MT201, may bear more promise, as may more advanced molecular forms, e.g. a BiTE design (MT110) or trifunctional antibodies (catumaxomab). However, the efficacy of these reagents in cancer patients still needs to be proven in randomized clinical trials.As for toxicity, the administration of ING-1, a high-affinity, human-engineered anti-Trop-1/Ep-CAM monoclonal antibody, caused cases of acute pancreatitis. The exocrine pancreas also expresses Trop-2. Hence, similar concerns should apply to the administration of anti-Trop-2 monoclonal antibodies to patients. More in general, contrary to the statements by Cubas et al., Trop-2/T-16/Mov-16 is expressed by several normal tissues in man, e.g. epidermis, exocervix, esophagus, tongue, urothelium, kidney, pancreas, trophoblast and breast. Hence, additional effort is required to develop Trop-2 into a useful immunotherapeutic target, by increasing anti-Trop-2 antibody efficacy, while keeping under control toxicity on expressing normal tissues.
Keywords: Cancer; Trop-2; Monoclonal antibody; Immunotherapy
Response to: Letter to the Editor: R. Cubas, M. Li, C. Chen and Q. Yao, Biochim Biophys Acta 1796 (2009) 309–1 by Rafael Cubas; Changyi Chen; Qizhi Yao (pp. 121-122).
Trop2; Active immunotherapy; Passive immunotherapy
Playing the DISC: Turning on TRAIL death receptor-mediated apoptosis in cancer by Bodvaël Pennarun; Annemieke Meijer; Elisabeth G.E. de Vries; Jan H. Kleibeuker; Frank Kruyt; Steven de Jong (pp. 123-140).
Formation of the pro-apoptotic death-inducing signaling complex (DISC) can be initiated in cancer cells via binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to its two pro-apoptotic receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2. Primary components of the DISC are trimerized TRAIL-R1/-R2, FADD, caspase 8 and caspase 10. The anti-apoptotic protein FLIP can also be recruited to the DISC to replace caspase 8 and form an inactive complex. Caspase 8/10 processing at the DISC triggers the caspase cascade, which eventually leads to apoptotic cell death. Besides TRAIL, TRAIL-R1- or TRAIL-R2-selective variants of TRAIL and agonistic antibodies have been designed. These ligands are of interest as anti-cancer agents since they selectively kill tumor cells. To increase tumor sensitivity to TRAIL death receptor-mediated apoptosis and to overcome drug resistance, TRAIL receptor ligands have already been combined with various therapies in preclinical models. In this review, we discuss factors influencing the initial steps of the TRAIL apoptosis signaling pathway, focusing on mechanisms modulating DISC assembly and caspase activation at the DISC. These insights will direct rational design of drug combinations with TRAIL receptor ligands to maximize DISC signaling.
Keywords: TRAIL-R1; TRAIL-R2; TRAIL; DISC; Apoptosis; Cancer
Metabolic genes in cancer: Their roles in tumor progression and clinical implications by Eiji Furuta; Hiroshi Okuda; Aya Kobayashi; Kounosuke Watabe (pp. 141-152).
Re-programming of metabolic pathways is a hallmark of physiological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis are drastically altered at different stages of tumor progression. These alterations are generally considered as an adaptation of tumor cells; however, they also contribute to the progression of tumor cells to become more aggressive phenotypes. This review summarizes the recent information about the mechanistic link of these genes to oncogenesis and their potential utility as diagnostic markers as well as for therapeutic targets. We particularly focus on three groups of genes; GLUT1, G6PD, TKTL1 and PGI/AMF in glycolytic pathway, ACLY, ACC1 and FAS in lipogenesis and RRM2, p53R2 and TYMS for nucleotide synthesis. All these genes are highly up-regulated in a variety of tumor cells in cancer patients, and they play active roles in tumor progression rather than expressing merely as a consequence of phenotypic change of the cancer cells. Molecular dissection of their orchestrated networks and understanding the exact mechanism of their expression will provide a window of opportunity to target these genes for specific cancer therapy. We also reviewed existing database of gene microarray to validate the utility of these genes for cancer diagnosis.
Keywords: Metabolism; Oncogenesis; Diagnostic marker
The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer by Mary-Clare Cathcart; John V. Reynolds; Kenneth J. O'Byrne; Graham P. Pidgeon (pp. 153-166).
Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development.In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer.
Keywords: Abbreviations; AA; arachidonic acid; COX; cyclooxygenase; PGIS; prostacyclin synthase; PGI; 2; prostacyclin; IP; prostacyclin receptor; PPAR; peroxisome-proliferator-activated receptor; TXS; thromboxane synthase; TXA; 2; thromboxane A; 2; TP; thromboxane receptor; LMWH; low-molecular weight heparinCancer; Prostacyclin synthase; Prostacyclin; Thromboxane synthase; Thromboxane A; 2
Targeting transcription factor NF-κB to overcome chemoresistance and radioresistance in cancer therapy by Feng Li; Gautam Sethi (pp. 167-180).
Activation of transcription factor NF-κB is frequently encountered in tumor cells and contributes to aggressive tumor growth and resistance to chemotherapy and ionizing radiation during cancer treatment. Accumulating evidence over the last few years indicate that most chemotherapeutic agents and radiation therapy activate NF-κB in vitro and in vivo. Moreover, induction of chemoresistance and radioresistance is mediated through several genes regulated by NF-κB and inhibition of this transcription factor increases sensitivity of cancer cells to the apoptotic action of chemotherapeutic agents and to radiation exposure. This review explores the role of NF-κB and its regulated genes in resistance of tumor cells to chemotherapeutic agents and radiation and evaluates the importance of targeting NF-κB as a potential therapeutic approach to overcome chemoresistance and radioresistance for cancer treatment.
Keywords: NF-κB; Cancer; Chemoresistance; Radioresistance; Apoptosis
Hedgehog beyond medulloblastoma and basal cell carcinoma by Stephan Teglund; Toftgard Rune Toftgård (pp. 181-208).
The Hedgehog (Hh) signaling pathway is of central importance during embryo development in metazoans and governs a diverse array of processes including cell proliferation, differentiation, and tissue patterning. In normal adult physiology, the pathway is implicated in stem cell maintenance, tissue repair and regeneration. However, the pathway's darker side is its involvement in several types of human cancer, to which it confers growth promoting and/or survival capabilities to the cancer cell to varying degrees, and by different mechanisms. The Hh pathway is firmly linked to the etiology of basal cell carcinoma and to at least a subset of medulloblastoma. There is increasing evidence that other sporadic cancers, including those in pancreas, prostate, lung, and breast, could also be dependent on Hh pathway activity. In this review, we provide an overview of the pathway's role in various tumor types, where much of the framework for Hh-dependent malignancies has been elucidated in experimental mouse models. We discuss three different signal transduction models for the pathway's involvement in cancer: i) ligand-independent signaling, ii) ligand-dependent autocrine/juxtacrine signaling, and iii) ligand-dependent paracrine signaling. These different modes of signaling may have implications for future therapeutic interventions aimed at inhibiting the pathway during disease. In addition, crosstalk with other pathways, and indications of non-canonical Hh signaling in cancer cells may further cause complications, or perhaps possibilities, in the treatment regimen. Finally, we review the rapid progress and promising results in the development of small-molecule inhibitors of the Hh pathway.
Keywords: Hedgehog pathway; Medulloblastoma; Basal cell carcinoma; Pancreatic cancer; Mouse cancer models; Small-molecule inhibitors
MicroRNAs in cancer — from research to therapy by William C.S. Cho (pp. 209-217).
MicroRNAs (miRNAs) regulate target gene expression through translation repression or mRNA degradation. These non-coding RNAs are emerging as important modulators in cellular pathways, and they appear to play a key role in tumorigenesis. With increasing understanding of the miRNA target genes and the cellular behaviors influenced by them, modulating the miRNA activities may provide exciting opportunities for cancer therapy. Here the latest findings of which genes are targeted by each miRNA are reviewed, with particular emphasis on the deciphering of their possible mechanisms and the potential of miRNA-based cancer therapeutics.
Keywords: Cancer; Locked nucleic acid; MicroRNA; Target gene; Therapy
Helpers of the cellular gatekeeper—miRNAs dance in P53 network by Ming Shi; Dan Liu; Beifen Shen; Ning Guo (pp. 218-225).
Recent findings position microRNA (miRNAs) as novel key players in regulating expression of protein-coding genes by interfering with the stability and/or translation of specific target mRNAs and in controlling cell proliferation and differentiation by actively functioning in the p53 tumor suppression network. Accumulating evidence reveal the intimate relationship between p53 and miRNAs. P53 regulates the expression of miRNAs at multiple levels. miRNAs influence the post-transcriptional regulation and activities of p53 by invoking a myriad of mechanisms. These findings are unveiling the unknown mechanisms of the p53-mediated biological effects.
Keywords: p53; MicroRNA; Apoptosis; Cell proliferation; Tumor suppresser; Oncogene