Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
20
1
2010
mTOR Signaling in Cancer Cell Motility and Tumor Metastasis
1-16
10.1615/CritRevEukarGeneExpr.v20.i1.10
Hongyu
Zhou
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA
Shile
Huang
Department of Biochemistry and Molecular Biology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, USA
mTOR
rapamycin
S6K1
Akt
cell motility
metastasis
Tumor cell migration is a key step in the formation of cancer metastasis. The mammalian target of rapamycin (mTOR), a highly conserved and ubiquitously expressed serinethreonine kinase, has been intensely studied for over a decade as a central regulator of cell growth, proliferation, differentiation, and survival. Recent data have shown that mTOR also plays a critical role in the regulation of tumor cell motility and cancer metastasis. Here, we briefly review recent advances regarding mTOR signaling in tumor cell motility. We also discuss recent findings about the mechanism by which rapamycin, a specific inhibitor of mTOR, inhibits cell motility in vitro and metastasis in vivo.
Triple Negative Breast Cancer: From Molecular Portrait to Therapeutic Intervention
17-34
10.1615/CritRevEukarGeneExpr.v20.i1.20
Pietro
Carotenuto
Pharmacogenomic Laboratory, CROM - Oncological Research Center Mercogliano, 83013 Avellino, Italy
Cristin
Roma
Pharmacogenomic Laboratory, CROM - Oncological Research Center Mercogliano, 83013 Avellino, Italy
Anna Maria
Rachiglio
Pharmacogenomic Laboratory, CROM - Oncological Research Center Mercogliano, 83013 Avellino, Italy
Gerardo
Botti
Surgical Pathology Unit, INT Fondazione "G. Pascale," 80131 Naples, Italy
Amelia
D'Alessio
Cell Biology and Biotherapy Unit, INT Fondazione "G. Pascale," 80131 Naples, Italy
Nicola
Normanno
Pharmacogenomic Laboratory, CROM - Oncological Research Center Mercogliano, 83013 Avellino, Italy; and Cell Biology and Biotherapy Unit, INT Fondazione "G. Pascale," 80131 Naples, Italy
triple negative
breast cancer
gene expression
molecular portrait
target therapy
Triple negative breast cancer is a subtype of breast cancer that lacks expression of an estrogen receptor (ER), a progesterone receptor (PR), and HER2. It is characterized by its unique molecular profile, aggressive behavior, and distinct pattern of metastasis. Epidemiological studies show a high prevalence of triple negative breast cancer among younger women and those of African descent. Although sensitive to chemotherapy, early relapse is common, and a predilection for visceral metastasis, including brain metastasis, has been described. Gene-expression profiling approaches demonstrated that triple negative breast cancer is a heterogeneous group of diseases composed of different, molecularly distinct subtypes. Although not synonymous, the majority of triple negative breast cancers carry the "basal-like" molecular profile on gene-expression arrays. However, several studies have shown that triple negative breast cancer includes tumors with a non-basal expression profile and, in particular, the "normal-breast," the "multiple marker negative," and the recently identified "claudin-negative" subtypes. Target-based agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly-ADP-ribose polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease.
Strategies for Regeneration of Heart Muscle
35-50
10.1615/CritRevEukarGeneExpr.v20.i1.30
Jacques P.
Guyette
Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA 01609 USA
Ira S.
Cohen
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794 USA
Glenn R.
Gaudette
Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA 01609
regenerative medicine
myocardium
cardiomyocytes
stem cells
Regenerative medicine has emerged to the forefront of cardiac research, marrying discoveries in both basic science and engineering to develop viable therapeutic approaches for treating the diseased heart. Signifi cant advancements in gene therapy, stem cell biology, and cardiomyoplasty provide new optimism for regenerating damaged myocardium. Exciting new strategies for endogenous and exogenous regeneration have been proposed. However, questions remain as to whether these approaches can provide enough new myocyte mass to sufficiently restore mechanical function to the heart. In this article, we consider the mechanisms of endogenous cardiomyocyte regeneration and exogenous cell differentiation (with respect to myoblasts, stem cells, and induced pluripotent cells being researched for cell therapies). We begin by reviewing some of the cues that are being harnessed in strategies of gene/cell therapy for regenerating myocardium. We also consider some of the technical challenges that remain in determining new myocyte generation, tracking delivered cells in vivo, and correlating new myocyte contractility with cardiac function. Strategies for regenerating the heart are being realized as both animal and clinical trials suggest that these new approaches provide short-term improvement of cardiac function. However, a more complete understanding of the underlying mechanisms and applications is necessary to sustain longer-term therapeutic success.
Functional Properties of Human Embryonic Stem Cell−Derived Cardiomyocytes
51-59
10.1615/CritRevEukarGeneExpr.v20.i1.40
Naama
Zeevi-Levin
The Sohnis Family Stem Cells Center, and Ruth & Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
Joseph
Itskovitz-Eldor
The Sohnis Family Stem Cells Center, Ruth & Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology; and Rambam Medical Center, Haifa, Israel
Ofer
Binah
The Sohnis Family Stem Cells Center, The Rappaport Family Institute for Research in the Medical Sciences, Ruth & Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
human embryonic stem cell–derived cardiomyocytes
cell-replacement therapy
functional properties
Cardiovascular diseases are the most frequent cause of death in the industrialized world, with the main contributor being myocardial infarction. Given the high morbidity and mortality rates associated with congestive heart failure, the shortage of donor hearts for transplantation, complications resulting from immunosuppression, and long-term failure of transplanted organs, regeneration of the diseased myocardium by cell transplantation is an attractive therapeutic modality. Because of their remarkable capacity for expansion and unquestioned cardiac potential, pluripotent human embryonic stem cells (hESC) represent an attractive candidate cell source for obtaining cardiomyocytes. Moreover, a number of recent reports have shown that hESC-derived cardiomyocytes (hESC-CM) survive after transplantation into infarcted rodent hearts, form stable cardiac implants, and result in preserved contractile function. Although the latter successes give good reason for optimism, considerable challenges remain in the successful application of hESC-CM to cardiac repair. Because it is desired that the transplanted cells fully integrate within the diseased myocardium, contribute to its contractile performance, and respond appropriately to various physiological stimuli, it is of crucial importance to be familiar with their functional properties. Therefore, this review describes the characteristics of hESC-CM, including their transcriptional profile, structural and electrophysiological properties, ion channel expression, excitation-contraction coupling, and neurohumoral responsiveness.
Mutational Status of Myeloproliferative Neoplasms
61-76
10.1615/CritRevEukarGeneExpr.v20.i1.50
Elisa
Rumi
Department of Oncology and Hematology, Division of Hematology, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy 27100
Chiara
Elena
Department of Oncology and Hematology, Division of Hematology, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy 27100
Francesco
Passamonti
Department of Hematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 27100
polycythemia
thrombocythemia
myelofibrosis
JAK2
MPL
CBL
TET2
Philadelphia negative myeloproliferative neoplasms include essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Altered signaling is a hallmark of myeloproliferative neoplasms, as demonstrated by the presence of activating JAK2 (V617F) mutation in about 70% of patients (95% of polycythemia vera, 50%−60% of essential thrombocythemia, and 50%−60% of primary myelofibrosis). How a unique point mutation can cause three different phenotypes remains to be clarified. The oncogenic potential of this mutation has been documented by mouse models, and different clinical studies have demonstrated an effect of mutant allele burden on phenotype. Mutant allele burden, in fact, directly correlates with hemoglobin value, leukocyte count, and, inversely, with platelet count. The molecular basis of JAK2 (V617F)-negative myeloproliferative neoplasms remains largely unexplained. Additional mutations in MPL, TET2, and CBL genes have been found in a small proportion of these patients. Implications of these mutations in the understanding of the pathogenesis of myeloproliferative neoplasms and in the clinical phenotype are discussed in this review.
Regulation of the p53 Tumor Suppressor Pathway: The Problems and Promises of Studying Mdm2's E3 Ligase Function
77-86
10.1615/CritRevEukarGeneExpr.v20.i1.60
Hilary V.
Clegg
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Yanping
Zhang
Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Mdm2
Hdm2
p53
RING domain
ubiquitin
knock-in mouse model
Mdm2 is a major negative regulator of the tumor suppressor p53 and has long been thought to inhibit p53 in two ways: by ubiquitinating p53 to signal for its degradation, and by binding to p53, masking its transactivation domain. Mdm2 is also believed to control its own levels by autoubiquitination. Despite the widespread acceptance of these hypotheses, the supporting data were drawn primarily from in vitro and ectopic expression studies, which have not always been corroborated when tested in the more physiologically relevant setting of a knock-in or knock-out mouse model. Recently, a mouse model was generated in which a single point mutation (C462A) in Mdm2’s RING domain abrogated Mdm2’s E3 activity while leaving Mdm2-p53 binding intact. This study called into question two major dogmas about Mdm2 by suggesting that when endogenously expressed, (1) Mdm2 cannot inhibit p53 sufficiently by binding without ubiquitination, and (2) Mdm2 may not be regulated by autoubiquitination. Two years later, we are still without definitive answers for why these results conflict with previous findings, but we have gained new insights from subsequent studies. Here, we discuss potential reasons for the discrepancies concerning Mdm2’s functions and how they might be resolved, taking into account new research in the field.