Begell House Inc.
Critical Reviews™ in Oncogenesis
CRO
0893-9675
5
2-3
1994
Regulation of Normal and Transformed Tracheobronchial Epithelial Cell Proliferation by Autocrine Growth Factors
107-120
10.1615/CritRevOncog.v5.i2-3.10
Patrice C.
Ferriola
Epithelial Carcinogenesis Group, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
Paul
Nettesheim
Epithelial Carcinogenesis Group, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
neoplastic progression
lung
carcinogenesis
autocrine growth factors
Several peptide growth factors have been identified as autocrine regulators of normal tracheobronchial epithelial cells, including the transforming growth factors alpha and beta. Using in vitro tissue culture models of multistep neoplastic transformation as well as cell lines derived from human bronchogenic tumors, a significant number of growth factors have been found to function as autocrine factors for neoplastic tracheobronchial cells as well. In several instances, the regulation of the autocrine pathway is disrupted in neoplastic tracheobroncial cells compared with their normal counterparts. These results indicate that there are multiple aberrations in growth factor pathways occurring in tracheobronchial epithelial cells during progression to the neoplastic phenotype.
Chromosome Fragility and Instability in Human Cancer
121-140
10.1615/CritRevOncog.v5.i2-3.20
Nicholas C.
Popescu
Laboratory of Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
fragile site
translocation
deletion
proto-oncogene
tumor suppressor gene
virus integration
chemical carcinogens.
The development of cancer is a multistep process triggered by physical, chemical, or biological carcinogenic factors, with the progression to an invasive phenotype requiring cumulative genetic alterations. Not all cellular genomic sequences are equally susceptible to carcinogenic factors or involved in pathologically relevant genetic alterations. Because of structural chromatin organization and DNA replication, certain genomic regions exhibit an increased fragility and tendency to recombination. At these regions, called fragile sites, there is a convergence of specific deletions, translocations, chemically induced lesions, and virus integrations. Isolation and cloning of sequences at fragile sites are important to a better understanding of the carcinogenesis process and to development of preventive measures.
Steel Factor and c-kit Protooncogene: Genetic Lessons in Signal Transduction
141-168
10.1615/CritRevOncog.v5.i2-3.30
Sima
Lev
Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
Janna M.
Blechman
Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
David
Givol
Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
Yosef
Yarden
Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
growth regulation
tyrosine kinase
stem cell factor
mast cell growth factor
hematopoiesis
white spotting
Despite extensive research on the molecular mechanisms of signal transduction by growth factors and their oncogenic receptor tyrosine kinases, the physiological relevance of these pathways, especially in mammals, remains largely unknown. A unique exception is the Steel factor (SLF) and its c-kit-encoded receptor, because many natural germ line mutations of both the ligand and the receptor exist in mice. The protooncogene c-kit encodes a cell surface receptor that belongs to the immunoglobulin gene family and carries an intrinsic tyrosine kinase activity in its cytoplasmic portion. The precursor of the Kit ligand, SLF, is also a transmembrane protein that exists as a soluble factor as well as a cell surface protein. The interaction of Kit with SLF leads to receptor dimerization, kinase activation, and tyrosine phosphorylation of cytoplasmic proteins that contain Src homology 2 motifs. Various mutations in Kit and SLF result in a defective signaling pathway and underly the complex phenotypes of W and Sl mice, respectively. The early development of at least four cell lineages is affected. These are erythrocytes, melanocytes, germ cells, and mast cells. Correlation between the behavior of these lineages and specific mutations uncovered interesting physiological aspects of the mechanism of signal transduction by a polypeptide growth factor. These include the different degrees of severity of affected lineages, indications for distinct functions during early embryonic development and at late phases, the significance of synergy between a growth factor and lymphokines, the interaction between mutant and wild-type proteins in heterozygous animals, and the possibility that a surface-anchored ligand may act differently than a soluble factor. Predictably, the lessons learned with Kit and Sl mice will be widely relevant to other pairs of ligands and receptors that control the function of different cell lineages and physiological processes.
Retroviral Determinants of Leukemogenesis
169-199
10.1615/CritRevOncog.v5.i2-3.40
Grace B.
Athas
Department of Microbiology and Immunology SL-38; Tulane Cancer Center SL-68, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112
Cindi R.
Starkey
Tulane Cancer Center SL-68; and Program in Molecular and Cellular Biology SL-79, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112
Laura S.
Levy
Department of Microbiology and Immunology SL-38; Tulane Cancer Center SL-68; and Program in Molecular and Cellular Biology SL-79, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112
murine leukemia virus (MuLV)
feline leukemia virus (FeLV)
human T-cell leukemia virus (HTLV)
long terminal repeat (LTR)
transcription
protooncogene
The slowly transforming, leukemogenic retroviruses of humans and other mammals induce malignant disease after prolonged latency but lack an oncogene to which their malignant potential can be attributed directly. The leukemogenic activity of these retroviruses can be attributed to at least three factors, including (1) transcriptional regulatory sequences in the long terminal repeat; (2) the insertional mutagenesis of cellular protooncogenes, thus activating their malignant potential; and (3) the actions of structural and regulatory proteins encoded by viral genes. The goal of this review is to summarize recent findings regarding the roles of these factors in retroviral leukemogenesis. The focus of the review is on the slowly transforming, leukemogenic retroviruses of mammals, including humans and experimental animals.
The CD44 Adhesion Molecule and Metastasis
201-212
10.1615/CritRevOncog.v5.i2-3.50
Kenneth K.
Tanabe
Departments of Surgical Oncology and Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Hideyuki
Saya
Departments of Surgical Oncology and Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
neoplastic progression
lung
carcinogenesis
autocrine growth factors
The family of related cell surface adhesion molecules designated CD44 are multifunctional proteins displayed by a wide variety of normal and malignant tissues. CD44 properties in vitro include hyaluronate-mediated adhesion, motility, hyaluronate degradation, self-aggregation, and adhesion to lymphoid tissue. These properties are among several that are required by invasive and metastatic tumor cells. Several in vivo experiments indicate that tumor cells transfected to overexpress specific CD44 isoforms display an enhancement in metastatic potential. Numerous CD44 isoforms exist as a result of alternative splicing, and specific isoforms enhance tumor cell metastasis more efficiently than others. This suggests that regulation of CD44 alternative splicing is an important determinant of metastatic potential. Several human tumors display specific alterations in CD44 isoform expression, and the extent of clinical disease in specific tumors correlates with the CD44 isoform expression pattern. In this review we analyze these data that suggest that CD44 plays an important role in tumor metastasis.
The Nature of Reed-Sternberg Cells: Phenotype, Genotype, and Other Properties
213-245
10.1615/CritRevOncog.v5.i2-3.60
Su-Ming
Hsu
Department of Pathology, University of Arkansas for Medical Sciences, Arkansas Cancer Research Center, and John L. McClellan Veterans Memorial Hospital, Little Rock, Arkansas
Pei-Ling
Hsu
Department of Pathology, University of Arkansas for Medical Sciences, Arkansas Cancer Research Center, and John L. McClellan Veterans Memorial Hospital, Little Rock, Arkansas
Hodgkin's disease
cytokine
oncogenes
review
The most recent sophisticated investigations have provided new and revealing but also contradictory and controversial information on the biological nature and the cellular origin of Hodgkin and Reed-Sternberg (H-RS) cells. Immunophenotypic analyses have shown consistent expression of CD 15, CD30, CD74, and HLA-Dr antigens, but generally lack of T- or B cell-associated markers in H-RS cells. The H-RS cells are also devoid of many monocyte/macrophage-associated antigens. Molecular genetic studies have demonstrated heterogeneous findings with respect to rearrangements of T-cell receptor and immunoglobulin genes. Only a small percentage of the cases have rearrangements; this cannot always be attributed to the threshold of sensitivity of the method and/ or the scarcity of the malignant cells in tissues examined. The H-RS cells do not express transcription factors such as BSAP, TCF-1, and GATA-3, known to be associated with lymphoid cells. It appears that evidence to support a lymphoid origin for H-RS cells is still lacking. On the contrary, the mechanism responsible for the unique clinical and histopathologic alterations associated with this disease has become clear. The H-RS cells have been shown to secrete IL-1, IL-5, IL-6, IL-9, TNF-a, M-CSF, and TGF-b, and, less frequently, IL-4 and G-CSF. These cytokines are likely to be responsible for the increased cellular reaction and fibrosis observed in tissues involved by HD and for the immunosuppression in patients with HD. Like most lymphomas, the etiology or pathogenesis of HD remains unknown. The Epstein-Barr virus (EBV) genomes are clonally integrated in the H-RS cells of about half the cases. The significance of these findings, whether EBV is a causative agent or an epiphenomenon, remains to be elucidated.
Recent Developments in the Molecular Genetic Understanding of Breast Cancer
247-270
10.1615/CritRevOncog.v5.i2-3.70
P.
Devilee
Department of Pathology, University of Leiden, Leiden, The Netherlands
E.
Schuuring
Department of Pathology, University of Leiden, Leiden, The Netherlands
M. J.
van de Vijver
Department of Pathology, University of Leiden, Leiden, The Netherlands
C. J.
Cornelisse
Department of Pathology, University of Leiden, Leiden, The Netherlands
breast cancer
oncogenes
tumor suppressor genes
genetic predisposition.
The molecular genetic characterization of breast cancer has implicated or identified the involvement of at least 10 distinct gene alterations in the genesis or progression of this disease. The genes involved fall into three distinct classes, possibly reflecting their particular function in the tumorigenic process. First, there is a class of genes that is being amplified to various levels in clinically manifest breast cancer, most conspicuously c-neu, c-myc, and cyclin D1. Second, an as-yet unknown number of genes are targets for loss of heterozygosity or allelic imbalance events on a number of different chromosomes. Presumably, this reflects the presence of tumor suppressor genes located on chromosomes 3p, 6q, 16q, 17, and possibly a few additional chromosomes. Finally, at least three genes are implicated to confer heritable predisposition to breast cancer. These include the p53 oncogene on 17p, an as yet unknown gene on 17q, and at least one locus outside these regions. While a number of presently unknown genes will soon be identified and cloned, it is becoming evident from genetic mapping studies that the complexity of gene involvement in breast cancer has not yet seen its very limits. A comprehensive multidisciplinary molecular profiling of a large series of tumors of various histological subtypes may aid in understanding how the different genes may cooperate to cause breast cancer.
Rat Tumor Cytogenetics: A Critical Evaluation of the Literature
271-295
10.1615/CritRevOncog.v5.i2-3.80
Rosi
Kerler
Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
Hartmut M.
Rabes
Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
cytogenetics
karyotype
chromosome
rat
oncogene
review
Cancer cytogenetics is a valuable tool for the analysis of cellular and molecular aberrations during malignant transformation and tumor progression. The rat has served as an important experimental model to investigate various steps in oncogenesis. An attempt was made to compile data on rat tumor cytogenetics from previously published data in order to provide a basis for further research, especially when combining classic and molecular cytogenetics, a yet underdeveloped area of research in rat tumorigenesis. The wealth of data presented here provides a contrast to its impact on biological specificity. Because of the different experimental procedures involved with tumor induction and the application of carcinogens at relatively high dosages, as well as occasional less than careful histological documentation, a delineation of unambiguous chromosome alterations, critical in the process of carcinogenesis, is rare in the rat. Future studies should be performed with spontaneously arising rat tumors and/or tumors after low, single-dose carcinogen exposure in order to reduce unspecific karyotype alterations not intrinsically related to tumor initiation and progression. Short-term culture or early passages in vitro should be methods of choice, especially for solid tumors, to avoid erroneous karyotype analyses because of contaminating normal cells. The combined karyological and molecular genetic approach to an analysis of tumor-specific changes, still hindered by an almost complete lack of cell type-, chromosome-, or gene-specific molecular probes for the rat, should become a focus of research in order to continue having the advantages this species offers for stage-specific analysis of tumorigenesis.
The Tumor-Promoting Effect of Wounding: A Possible Role for TGF-β-lnduced Stromal Alterations
297-311
10.1615/CritRevOncog.v5.i2-3.90
Michael H.
Sieweke
Division of Life Sciences, Cell and Molecular Biology Department, LBL, University of California, Berkeley, CA 94720
Mina J.
Bissell
Division of Life Sciences, Cell and Molecular Biology Department, LBL, University of California, Berkeley, CA 94720
tumor promotion
wound healing
TGF-beta
stroma
fibrosis
microenvironment
From clinical, chemical carcinogenesis and transgenic animal studies, it is evident that wounding has a tumor-promoting effect. We discuss the role of TGF-β (with special emphasis on TGF-β 1) in this process and suggest that stromal alterations during wound healing, induced by TGF-β, can be an important determinant of tumor growth. A tumor and a wound both require similar stromal microenvironments. Thus, a chemically initiated or an oncogene-expressing cell could be complemented to grow into a tumor if it finds itself in a hospitable wound-healing stroma.
The c-erbB-2 Protein in Oncogenesis: Molecular Structure to Molecular Epidemiology
313-329
10.1615/CritRevOncog.v5.i2-3.100
Paul W.
Brandt-Rauf
Division of Environmental Sciences, Department of Medicine and Comprehensive Cancer Center, Columbia University, 60 Haven Avenue, New York, N.Y. 10032
Matthew R.
Pincus
Department of Pathology, SUNY Health Sciences Center, 750 East Adams Street, Syracuse, N.Y. 13210
Walter P.
Carney
Oncogene Sciences/ Applied Biotechnology, 80 Rogers Street, Cambridge, MA 01242
p185 oncoprotein
transmembrane domain
extracellular domain
serum biomarker
cancer risk
The c-erbB-2 (HER-2, neu) oncogene has been implicated frequently in many human tumors. This oncogene codes for a 185-kDa protein that functions as a transmembrane growth factor receptor. Overexpression of the normal protein or point mutations in the transmembrane domain of the protein have been shown to have a transforming effect. Molecular structure studies of the transmembrane domain provide a plausible explanation for this transforming effect in both cases and relate this to the process of receptor dimerization in the membrane, degradation of the protein with release of the extracellular domain (ECD) into the extracellular environment, and aberrant signal transduction. The release of the ECD into the extracellular environment provides a potential biomarker for the study of signal transduction at the molecular level in vivo. The ECD can be quantitated immunologically in the serum of individuals with cancers associated with p185 overexpression and in individuals at risk for the development of such cancers and can be used to distinguish these individuals from normal, healthy controls. Identification of such individuals by their serum ECD levels combined with specific chemotherapeutic/ chemoprophylactic interventions could allow for improvement treatment and prevention of c-erbB-2-related cancers.