Current Molecular Medicine

ISSN: 1566-5240

Current Molecular Medicine
Volume 8, Number 1, February 2008

Contents


Editorial Pp. 1


Combating Protein Misfolding and Aggregation by Intracellular Antibodies Pp. 2-11
Alessio Cardinale and Silvia Biocca
[Abstract]


New Aspects of Regulatory Signaling Pathways and Novel Therapies in Pancreatic Cancer Pp. 12-37
Michael Diamantidis, Georgios Tsapournas, Jannis Kountouras and Christos Zavos
[Abstract]


The Role of LEF/TCF Factors in Neoplastic Transformation Pp. 38-50
Amod Ravindranath, Angeline O’ Connell, Patrick G. Johnston and Mohamed K. El-Tanani
[Abstract]


Notch Signaling in Leukemias and Lymphomas Pp. 51-59
Franziska Jundt, Rolf Schwarzer and Bernd Dörken
[Abstract]


Hypoxic Regulation of Metastasis via Hypoxia-Inducible Factors Pp. 60-67
Eelke H. Gort, Arjan J. Groot, Elsken van der Wall, Paul J. van Diest and Marc A. Vooijs
[Abstract]


Overcoming Immune Evasion in T Cell Therapy of Cancer: Lessons from Animal Models Pp. 68-75
Jin-Qing Liu and Xue-Feng Ba
[Abstract]




Abstracts


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Editorial

This year marks the eight year in the publication of Current Molecular Medicine, and the successful culmination of the first year under a new Editor-in-Chief. When I took over this position from Dr. Anil Mukherjee, it was with considerable trepidation. Dr. Mukherjee had established this fledge-ling journal from the ground up with his pain staking efforts, and the new Editorial Board had to step into fairly big shoes. Looking back at the past year, I think we can confidently say that the state of the journal is stronger than it has ever been, with continuing increase in readership and high quality submissions. I want to take this opportunity to sincerely thank the members of the Editorial Board, the Guest Editors who have shepherded Special issues, and of course, numerous colleagues who have taken time out of their valuable schedules to provide expert peer review. I can say without hesitation that finding qualified reviewers who are willing to provide their valuable time and effort for peer review is both the most challenging and the most rewarding task as an Editor-in-Chief. I take my hat off to the scores of anonymous reviewers who provide this service simply out of a sense of citizenship to the scientific community, and without whose acceptance of this non-remunerative responsibility, scientific publications such as ours would always be held askance by its readership.

As in the preceding years, I have tried to maintain a balance between “general” issues and special issues dedicated to a narrowly defined topic of interest in molecular medicine. For example, in 2007, we began with a special issue on Cancer Genetics, and interspersed the year with additional dedicated issues on Tuberculosis, Disorders of Glycosylation, culminating with an issue on Receptor for Advanced Glycation Endproducts (RAGE) in December. I am astounded at the panorama of scientific landscape we have covered in a single year, and look forward to continuing in the same vein for 2008. I am sure the readership of the journal will be delighted to learn that we have lined up a plethora of Special issues for the coming year, in topics as diverse as autophagy and apoptosis, inflammatory airway diseases, hypoxia, and angiogenesis. At the same time, we continue to receive, and following rigorous peer review, publish a broad compendium of manuscripts in the “general” issues. As a glance at the table of contents will confirm, these reviews are at the cutting edge of molecular medicine, featuring aspects of Notch signaling, hypoxia-inducible factors (HIFs), immune evasion in cancers, and the use of therapeutic intracellular antibodies for combating protein misfolding. It is a small wonder that, despite being in the “early childhood” of its life, CMM has a ranking of 8th out of 76 journals in the area of research and experimental medicine. This Editorial is also my pean to the readership of this journal, which continues to make a wise choice in depending on the contents of CMM for staying up-to-date in this fast changing era of molecular medicine. My promise to you, dear reader, is never to compromise the high quality you have come to rely on over the years.


Anirban Maitra
(Editor-in-Chief)
Associate Professor of Pathology and Oncology
Affiliate, McKusick-Nathans Institute of Genetic Medicine
The Sol Goldman Pancreatic Cancer Research Center
CRB-2, Suite 345
Johns Hopkins University School of Medicine
1550 Orleans Street, Baltimore, MD 21231
USA
Tel: (410) 502 8191 (Direct)/(410) 955 3511
Fax: (410) 614 0671
E-mail: amaitra1@jhmi.edu


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Combating Protein Misfolding and Aggregation by Intracellular Antibodies
Alessio Cardinale and Silvia Biocca

Conformational or misfolding diseases are a large class of devastating human disorders associated with protein misfolding and aggregation. Most conformational diseases are caused by a combination of genetic and environmental factors, suggesting that spontaneous events can destabilize the protein involved in the pathology or impair the clearance mechanisms of misfolded aggregates. Aging is one of the risk factors associated to these events, and the clinical relevance of conformational disorders is growing dramatically, as they begin to reach epidemic proportions due to increases in mean lifespan. Currently, there are no effective strategies to slow or prevent these diseases. Intrabodies are promising therapeutic agents for the treatment of misfolding diseases, because of their virtually infinite ability to specifically recognize the different conformations of a protein, including pathological isoforms, and because they can be targeted to the potential sites of aggregation (both intra- and extracellular sites). These molecules can work as neutralizing agents against amyloidogenic proteins by preventing their aggregation, and/or as molecular shunters of intracellular traffic by re-routing the protein from its potential aggregation site. The fast-developing field of recombinant antibody technology provides intrabodies with enhanced binding specificity and stability, together with lower immunogenicity, for use in a clinical setting. This review provides an update on the applications of intrabodies in misfolding diseases, with particular emphasis on an evaluation of their multiple and feasible modes of action.


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New Aspects of Regulatory Signaling Pathways and Novel Therapies in Pancreatic Cancer
Michael Diamantidis, Georgios Tsapournas, Jannis Kountouras and Christos Zavos

Pancreatic cancer is an exceptionally devastating and incurable disease, the treatment of which has largely been unsuccessful due to higher resistance of pancreatic tumor cells to conventional approaches including surgery, radiation and/or chemotherapy. Therefore, there is a need for development of new and effective chemotherapeutic agents which can target multiple signaling pathways to induce responsiveness of pancreatic cancer cells to death signals. Although crucial advances in our understanding of the molecular pathogenesis of the disease have been made, the exceptional aggressiveness of pancreatic cancer remains largely unexplained. Investigators have actively investigated to elucidate molecular mechanisms involved in the onco-genesis, growth, invasion and metastasis of this malignancy. Pancreatic tumor cells have developed remarkable defense mechanisms to evade apoptosis and to increase their resistance to several drugs. All the typical signs of apoptosis are the final results of a complex biochemical cascade of events, whose proper function is regulated by growth and transcriptional factors, hormones and other molecules affecting the intracellular signal transduction. Understanding these complex mechanisms has created new hopes concerning pancreatic cancer in the last years and has evoked new therapeutic approaches, many of which undergo clinical trials with promising results to date. The present review provides a comprehensive description of the molecular signaling mainly of the apoptotic pathways implicated in the pathogenesis of pancreatic cancer, an incentive on the potential pathogenetic role of Helicobacter pylori infection and an appraisal of the most recent therapeutic strategies aiming at the repair of molecular lesions and applied at a cell biochemical level.


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The Role of LEF/TCF Factors in Neoplastic Transformation
Amod Ravindranath, Angeline O’ Connell, Patrick G. Johnston and Mohamed K. El-Tanani

The T cell factor 4 (Tcf-4) interacts with β-catenin in the Wnt signalling pathway and coactivates downstream target genes in diverse systems including the breast. This activity is important during normal development but its deregulation plays a pivotal role in cancer progression. In a rat model for breast cancer it has been shown that metastasis-inducing DNA (Met-DNA) sequesters the endogenous inhibitory Tcf-4 and thereby promotes transcription of the secreted extracellular matrix glycophosphoprotein, osteopontin, the direct effector of metastasis in this model system. Permanent transfection of the benign rat mammary cell line with a fragment from the Met-DNA containing the Tcf recognition sequence CAAAG induces the cells to metastasize in syngeneic rats in vivo. Tcf-4 expression in human breast carcinomas is inversely associated with osteopontin protein levels. High Tcf-4 expression impedes both OPN promoter activity and protein expression in rat mammary carcinoma cells. Understanding the role of Tcf-4 in cancer development and its transcription regulation should lay the foundation for novel therapeutic approaches in the future.


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Notch Signaling in Leukemias and Lymphomas
Franziska Jundt, Rolf Schwarzer and Bernd Dörken

Aberrant Notch activation is linked to cancer since 1991 when mammalian Notch1 was first identified as part of the translocation t(7;9) in a subset of human T-cell acute lymphoblastic leukemias (T-ALL). Since then oncogenic Notch signaling has been found in many solid and hematopoietic neoplasms. Depending on tumor type Notch interferes with differentiation, proliferation, survival, cell-cycle progression, angiogenesis, and possibly self-renewal. In hematopoietic neoplasms, recent findings indicate an important role of Notch for T-ALL induction and progression and the pathogenesis of human T- and B-cell-derived lymphomas. Notch signaling has been identified as a potential new therapeutic target in these hematopoietic neoplasms. This review will focus on the most recent findings on Notch signaling in leukemias and lymphomas and its potential role in the maintenance of malignant stem cells.


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Hypoxic Regulation of Metastasis via Hypoxia-Inducible Factors
Eelke H. Gort, Arjan J. Groot, Elsken van der Wall, Paul J. van Diest and Marc A. Vooijs

Metastases formation is a major factor in disease progression and accounts for the majority of cancer deaths. The molecular mechanisms controlling invasion, dissemination to blood or lymphatic systems and spread of tumor cells to distant organs are still poorly understood. Recent observations indicate that the metastatic phenotype may already be present during the angiogenic switch of tumors. Intratumoral hypoxia correlates with poor prognosis and enhanced metastases formation. The Hypoxia Inducible Factors (HIFs) are key molecules in the hypoxic response and play critical roles during tumor cell expansion by regulating energy metabolism and the induction of angiogenesis. Increasing evidence implicates HIF function in metastatic cell characteristics, like epithelial to mesenchymal transition, cell detachment, invasion and tumor cell seeding. Here, we review the link between tumor cell hypoxia and the acquisition of metastatic behavior. We hypothesize that polyclonal tumor selection by hypoxia enhances metastatic capacity by transcriptional control of key regulators of metastasis. This polyclonal hypoxic gene profile potentially develops into a metastatic profile, driving metastasis formation. The hypoxic gene profile in primary tumors may therefore provide a prognostic indicator in clinical decision-making.


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Overcoming Immune Evasion in T Cell Therapy of Cancer: Lessons from Animal Models
Jin-Qing Liu and Xue-Feng Ba

Cancer antigen-specific cytotoxic T lymphocytes (CTL) are the major effectors against cancer cells. However, large established tumors are usually not fully controlled by CTL for at least two reasons. First, large established tumors have immune suppressive networks that not only suppress CTL effector function but also permit tumor progression. Second, the genetic instability of cancer cells often results in the selection of antigenic variants by CTL, which allow cancer cells to escape destruction. Simply enhancing T cell capacity may not fully control large established tumors. Other measures, such as enhancing local costimulation, inhibiting angiogenesis and down-regulating functions of tumor associated myeloid cells should also be considered. In this paper we will review some of the progress from animal studies.