Begell House Inc.
Critical Reviews™ in Oncogenesis
CRO
0893-9675
15
1-2
2009
Nuclear Factor-κB Signaling: A Contributor in Leukemogenesis and a Target for Pharmacological Intervention in Human Acute Myelogenous Leukemia
1-41
10.1615/CritRevOncog.v15.i1-2.10
Hakon
Reikvam
Division for Hematology, Institute of Medicine, University of Bergen, Bergen, Norway
Astrid Marta
Olsnes
Division for Hematology, Institute of Medicine, University of Bergen, and Department of Medicine, Haukeland University Hospital, Bergen, Norway
Bjorn Tore
Gjertsen
Division for Hematology, Institute of Medicine, University of Bergen, and Department of Medicine, Haukeland University Hospital, Bergen, Norway
Elisabeth
Ersvar
Division for Hematology, Institute of Medicine, University of Bergen, Bergen, Norway
Oystein
Bruserud
Division for Hematology, Institute of Medicine, University of Bergen; and Department of Medicine, Haukeland University Hospital, Bergen, Norway
acute myelogenous leukemia
nuclear factor-kB
apoptosis
autophagy
angiogenesis
chemotherapy
allogeneic stem cell transplantation
Acute myeloid leukemia (AML) is an aggressive malignancy with only 40%-50% long-term survival even for younger patients who can receive the most aggressive therapy. For elderly patients who only receive palliative treatment, the median survival is only 2-3 months. Inhibition of the nuclear factor-κB (NF-κB) transcription factor family is one of the therapeutic strategies that are considered in AML. NF-κB is an important regulator of several biological processes that are involved in leukemogenesis, including proliferation, differentiation, autophagy, and apoptosis. Constitutive NF-κB activation has been detected in AML cells and NF-κB inhibition is therefore a possible therapeutic strategy in AML. Multiple pharmacological agents have shown inhibitory effects against NF-κB signaling pathways, including proteasome inhibitors as well as the more-specific agents that are directed against various steps of this signaling pathway. Recent studies strongly suggest that primary human AML cells (including AML stem cells) are susceptible to NF-κB inhibition, but this therapeutic approach should possibly be combined with other therapeutic agents to achieve a combined effect both on NF-κB transcriptional activity, tumor suppressor-induced signaling, and stress-induced pathways. The clinical documentation with regard to the efficiency and safety of NF-κB inhibition is still limited, but experimental evidence strongly suggests that NF-κB inhibition should be further investigated in human AML.
Inflammation Versus Adaptive Immunity in Cancer Pathogenesis
43-63
10.1615/CritRevOncog.v15.i1-2.20
Sheraz
Yaqub
The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo; and Department of Gastroenterological Surgery, Akershus University Hospital, N-1478 Lørenskog, Norway
Einar Martin
Aandahl
The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0317 Oslo, Norway
cancer
inflammation
immunoediting
immune surveillance
regulatory T cells
Cancer pathogenesis is initiated and modulated in an interplay between the malignant transformed cells, the surrounding stroma, and the innate and adaptive immune system. These interactions are complex, and components of the immune system act as both defense mechanisms against and contributors to tumor initiation, tumor growth, invasivity, and development of metastases. Inflammatory conditions help to establish a microenvironment promoting cancer development, whereas a malignant tumor feeds the inflammatory response and accelerates tumor growth. However, mouse models and epidemiological and clinical data demonstrate that an intact immune system is associated with a favorable prognosis, although the inflammatory response and the adaptive immune system share many cellular and humoral features. Here, we review the emerging concepts in cancer pathogenesis where the inflammatory and adaptive components of the immune system play an important role in the interaction with the tumor and stromal tissue.
Gain of Antitumor Functions and Induction of Differentiation in Cancer Stem Cells Contribute to Complete Cure and No Relapse
65-90
10.1615/CritRevOncog.v15.i1-2.30
Minal
Garg
Department of Biochemistry, Lucknow University, Lucknow, INDIA
Cancer stem cells
stem cell markers
tumor suppression
apoptosis
differentiation therapy
The progeny of the mutated cell is maintained in a self-renewing tissue stem cell and its immediate progeny or due to cellular components that display stem cell like properties known as cancer stem cells (CSCs) that grow into cancer. Failure to achieve complete and safe eradication of cancer is due to the presence of quiescent population of cancer stem cells. Understanding and interfering with the processes of transformation of normal stem cells into their malignant counterparts, their micro-environmental niche and the mechanisms responsible for therapeutic resistance in CSCs enhance the curative efficacy of clinical elimination of all tumor cells. Functional identification of the molecular targets of CSCs provides useful insights for characterization of their response to particular therapy protocols. This review also focuses on the potential implications of promising novel therapies in suppression of oncogenic pathways specific to CSCs including their self-renewal capacity, property of drug transportation, seeding and oxidative stress, activation of apoptosis through the gain of antitumor molecules, restoration of DNA repair mechanisms and differentiation therapy that allows the terminal differentiation of CSCs thereby depleting their pool, all contribute to long-term disease control and improved patient survival. Significant developments in the optimization of combinational CSC-targeted therapies would lead to the improved outcome with great difference thus substantiating its profound impact in disease free survival with no relapse.
Structural and Expression Changes of Septins in Myeloid Neoplasia
91-115
10.1615/CritRevOncog.v15.i1-2.40
Nuno
Cerveira
Department of Genetics, Portuguese Oncology Institute, Portugal
Joana
Santos
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
Manuel R.
Teixeira
Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; and Abel Salazar Biomedical Sciences Institute (ICBAS), Porto, Portugal
septins
myeloid neoplasia
fusion gene
Septins are an evolutionarily conserved family of GTP-binding proteins that associate with cellular membranes and the actin and microtubule cytoskeletons. Fourteen septin genes have been characterized to date (SEPT1 to SEPT14) in humans. Septins have been reported to be misregulated in various human diseases, including neurological disorders, infection, and neoplasia. In this review, we describe what is known thus far about septin deregulation in myeloid neoplasia. Septin abnormalities in myeloid neoplasia can be divided into two major groups. First, some septins (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been repeatedly identified as in-frame fusion partners of the MLL gene in de novo and therapy-related myeloid neoplasia, in both children and adults. Second, deregulation of the expression of septin family genes in hematological cancers can be observed either with or without the concomitant presence of MLL gene fusions. Although current hypotheses regarding the roles of septins in oncogenesis remain speculative for the most part, the fundamental roles of septins in cytokinesis, membrane remodeling, and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton could be involved in neo-plastic disorders.
New Doctorial Cancer Research:Novel Genetic and Epigenetic Alterations in Colorectal Tumors and Their Potential as Biomarkers
121-123
10.1615/CritRevOncog.v15.i1-2.50
Terje
Ahlquist
Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital— Radiumhospitalet, Oslo, Norway
With the relaunch of Critical Reviews in Oncogenesis, a special section called "New Doctorial Cancer Research" was introduced. Here, we provide new Ph.Ds. with the opportunity to present themselves and their work, preferentially followed by a commentary of a senior scientist with knowledge of the study, and as such, attention is also drawn to the work of the research group. In the current issue of CRO, we present two new Ph.Ds. Keep this opportunity in mind when new Ph.Ds. have fulfilled their dissertations. Instructions for submission to the "New Doctorial Cancer Research" section can be found in the general Instructions to Authors of CRO (www.begellhouse.com).