Showing papers in "Advances in Cancer Research in 1996"

Proteins of the Myc Network: Essential Regulators of Cell Growth and Differentiation

Abstract: Publisher Summary This chapter focuses on the proteins of the Myc network that are essential regulators of cell growth and differentiation. The identification of the Myc partner, Max, in 1991 and the subsequent realization that this protein is the essential dimeric partner for all known c-Myc functions was a major boost to the field and led to a number of very interesting observations and findings. The chapter focuses on c-Myc's role as a transcription factor in the regulation of cell growth, apoptosis, and transformation. The most exciting recent findings suggest that the Myc network not only includes proto-oncoproteins (c-, N-, and L-Myc) but, with the Mad family proteins, also potential tumor suppressors. This together with the fact that Myc proteins as well as Max are essential, as deduced from homozygous disruption of the genes in mice, places the Myc network in a central position in the regulation of cell growth and homeostasis. Genes that have been generated by the duplication of and divergence from an ancestral gene(s) are grouped into families. The myc family of protooncogenes has most likely arisen through such duplications. It currently consists of three well-characterized members; c-myc, N-myc, and L-myc. Two additional genes, B-myc and S-myc, have been identified only in rodents. The c-, N-, and L-myc genes share similar genomic organization and the corresponding proteins contain several regions of high sequence homology. The identification of the Myc dimerization partner Max has significantly advanced our understanding of the molecular function of c-Myc.

Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer.

Abstract: Publisher Summary This chapter focuses on the genetic alterations of cyclins, cyclin dependent kinases (Cdk), and Cdk inhibitors in human cancer. Contemporary research into the molecular basis of cancer has two central tenets. The first is that cancer arises through alterations in the genetic make-up of the tumor cell. The second is that these changes are manifested in the breakdown of the processes that regulate cell growth and differentiation. In simplistic terms, cancer cells proliferate uncontrollably and fail to differentiate. The large numbers of tumors that show perturbations in the D cyclins themselves, their upstream regulators, or their downstream targets suggest that this pathway is extremely important in human cancer and holds great promise for therapeutic intervention. The conventional view of the cell division cycle is as a series of checkpoints or transitions at which certain criteria must be met before the cell proceeds to the next phase. The cyclin D1 gene, now given the locus designation CCNDI, maps to band q13 on the long arm of chromosome 11. The chapter also discusses the amplification of cyclin D1 in human tumors. When the gene for Cdk4 was located on chromosome 12q13, it was quickly realized that it too lies within a tumor-specific amplicon, which had been previously observed in human sarcomas of various types and in tumors of the central nervous system, particularly gliomas. There has been a great deal of interest in the cyclin-dependent kinase inhibitors that have been identified in mammalian cells. The chapter describes cyclin D1-p16-pRb pathway.

How tumors become angiogenic

Abstract: Publisher Summary As normal cells progress to tumorigenicity, they must develop two distinct new characteristics not possessed by the normal cells from which they arise: they must become able to multiply without restraint and they must be able to create in vivo an environment where this newly acquired growth potential can be realized. Normal cells are antiangiogenic, because they secrete only low levels of inducers of angiogenesis and high levels of molecules that inhibit neovascularization. These cells develop into successful tumors that are potently angiogenic and secrete high levels of a cocktail of molecules that induce neovascularization. It is possible to halt the production and/or release of angiogenic activity by tumor cells themselves using retinoic acid and similar compounds. Endothelial cells that form the vessels that support tumor growth can be disabled in two distinct ways. Antiangiogenic agents have distinct advantages over conventional cytotoxic cancer therapies. Although the importance of angiogenesis to the growth of tumors is now well established, the mechanism by which tumor cells develop this crucial ability to attract new blood vessels is just beginning to be explored. Available data suggest that the angiogenic phenotype develops gradually as a result of many of the same genetic changes in oncogenes and tumor suppressor genes that are also responsible for the deregulation of cell growth. The inhibitors of angiogenesis offer a new and promising avenue for tumor therapy.

The Role of the Insulin-like Growth Factor System in Human Cancer

Abstract: Publisher Summary This chapter focuses on the role of the insulin-like growth factor system in human cancer. The normal process of growth and differentiation results from the genetically programmed action of a number of different cellular and extracellular factors. Derangement in the function of one or more of those agents can result in a pathologic phenotype, including neoplastic growth. A family of growth factors shown to be intimately involved in the regulation of cell growth as well as in cellular transformation is the insulin-like growth factor (IGF) family. IGF-I and IGF-II are mitogenic polypeptides produced in the largest amounts by the liver and secreted into the circulation, where they mediate the effects of growth hormone (GH) on longitudinal growth. In addition to ligands and receptors, the IGF system comprises a third category of molecules, which bind IGFs in the circulation and in extracellular compartments. Six IGF-binding proteins (IGFBPs) have been characterized to date. Binding of IGFs to the IGF-I receptor induces receptor autophosphorylation. The cell cycle consists of four major phases: (1) the presynthetic phase, G; (2) the phase of DNA synthesis, S; (3) the premitotic phase, G; and (4) mitosis, M. IGF-I, IGF-II, and insulin are chemotactic agents for the human melanoma cell line A2058, as assayed in a modified Boyden chamber. The chapter also gives selected examples of IGF involvement in human cancer. The wealth of information generated in the IGF field, as well as continued research efforts, both basic and clinic, promise to produce rational therapeutic approaches for those cancers in which the IGF system is involved.

c-Myc in the control of cell proliferation and embryonic development.

Abstract: Publisher Summary This chapter reviews recent knowledge on the cell cycle regulation of c-Myc expression and c-Myc activity, as well as the structural features of the c-Myc protein that give new insights into the understanding of c-Myc function during the cell cycle and embryonic development. C-myc was the first nuclear proto-oncogene discovered and has been the subject of intense investigation during the past 16 years. The initial property attributed to c-Myc was its ability to transform normal cultured cells, but a great deal of evidence since then has indicated that this proto-oncogene is involved in a variety of different cellular processes—such as proliferation, differentiation, and apoptosis. The current focus of investigation into c-Myc is, therefore, primarily concerned with deciphering the way one gene can both participate in and discriminate between these seemingly divergent activities. Embryonic development requires cellular multiplication coupled to diversification of the genetic program, and therefore additional levels of control are required to provide a tight coordination between proliferation and differentiation. The biochemical analysis of c-Myc activity has been hampered by the extreme difficulty in obtaining a soluble form of the purified full-length protein. The chapter also discusses cell proliferation and c-Myc as a transcription factor. The majority of studies concerning c-Myc expression in adult tissues or embryos are related to the production of mRNA, although gene expression does not always strictly correlate with the temporal pattern and level of protein expression during development. While proliferating cells exhibit stable c-Myc RNA levels and abrupt changes in c-Myc expression are often observed during exit from the cell cycle, because cells undergo terminal differentiation. During the past decade it has become increasingly apparent that programmed cell death, or apoptosis, is a fundamental process affecting both growth and development.

Identification of the Genes Encoding Cancer Antigens: Implications for Cancer Immunotherapy

Abstract: Publisher Summary This chapter focuses on the identification of the genes encoding cancer antigens. The development of new cancer therapies based on stimulating the immune response of the host against a growing malignancy is based on the hypothesis that cancers contain, on their surface, unique antigens that can serve as targets for immune destruction. The validity of this hypothesis was bolstered by the development of immune manipulations that could mediate the rejection of growing cancers in humans and by the identification of T lymphocytes that could specifically recognize cancer cells in vitro . A variety of techniques have been developed that enable the identification of T lymphocytes that selectively recognize tumor antigens. A variety of methods have been used to identify human melanoma antigens recognized by T cells. Approaches to cancer immunotherapy can be divided into active or passive categories. Active immunotherapy involves the direct immunization of cancer patients with cancer antigens in an attempt to boost immune responses against the tumor. Passive immunotherapy refers to the administration of immune reagents, such as immune cells or antibodies with antitumor reactivity, with the goal of directly mediating antitumor responses. The most effective forms of immunization involve the incorporation of genes encoding immunogenic molecules into recombinant bacteria—such as bacillus Calmette-Guerin, Salmonella, or Listeria—or into recombinant viruses—such as vaccinia, fowlpox,or adenovirus. The genes encoding cancer antigens can be expressed either alone or in combination with genes encoding cytokines, costimulatory molecules, or other genes that can enhance the immune response following infection. Many of these approaches to active immunization are being pursued in experimental animal models using model tumor antigens. The availability of the genes encoding human tumor antigens has led to the development of clinical trials in humans with cancer.

Signaling by the cytokine receptor superfamily in normal and transformed hematopoietic cells.

Abstract: Publisher Summary This chapter focuses on the structure and function of the cytokine receptor superfamily and the alterations in function that have been associated with leukemias. The malignant transformation of hematopoietic cells is associated with alterations in specific phenotypic properties of the cells. These alterations can involve changes in the ability of the cells to terminally differentiate, the increased rates of cell cycle progression, the reduction or elimination of apoptosis, and the abrogation of the requirements for normal growth factors. Hematopoiesis is normally controlled, in part, through the regulated availability of a variety of hematopoietic growth factors. The majority of hematopoietic growth factors utilizes a novel family of receptors termed the “cytokine receptor superfamily”. The cytokine receptor superfamily was initially identified by comparison of the structure of the first hematopoietic growth factor receptors that were cloned. Growth-factor independence in leukemias can be conferred by the activation of growth-factor production in an autocrine model of transformation. Vav was initially identified as a novel human gene whose transforming activity was activated by a vector insertion in transfection studies to identify new human oncogenes. In addition to tyrosine kinases, protein tyrosine phosphatases play a critical role in cytokine signaling. Studies dealing with the biochemical events in interferon (IFN)-induced gene transcription identified a novel family of transcriptional factors. Although Statl and Stat2 were initially identified and characterized within the context of the interferon system, a variety of studies support the hypothesis that Stat family members may play a very general role in cytokine signaling. The diversity of Stats that can be activated in response to cytokines is illustrated by the responses of T cells.

Genetic basis and clonal evolution of human prostate cancer.

Abstract: Publisher Summary This chapter focuses on the genetic basis and clonal evolution of human prostate cancer. Prostate cancer is now receiving attention among cancer researchers, urologists, as well as in the media because of a number of reasons. First and foremost, prostate cancer is now the most common cancer of men in many regions of the developed world. Despite this high incidence, etiology, and risk factors for prostate cancer have remained largely unknown. Studies suggest that although hereditary factors are involved in a fraction of the cases, currently unknown environmental and lifestyle factors are likely to be the most important causative factors. The diagnosis of prostate carcinoma at a very early stage is attractive as it enables curative treatment of the disease. An underlying problem in studies of the epidemiological and clinical aspects of prostate cancer is the fact that the biology and natural history of human prostate cancer are so poorly understood. Studies on the genetic basis of cancer progression should be based on the detailed understanding of the histological and clinical characteristics of tumor progression. Several genetic aberrations that are found in primary prostate carcinomas have been reported to predict the likelihood of metastasis. The failure of endocrine therapy is one of the most important problems in the management of prostate cancer patients. Studies on the genetic basis of prostate cancer have provided new information on the biological behavior and natural history of this increasingly common disease, whose molecular basis was previously very poorly understood. A genetic test to diagnose an inherited predisposition to prostate cancer may become available in the near future. The further understanding of genetic mechanisms is likely to be instrumental in developing targeted therapies for the advanced stages of prostate cancer.

The Men II Syndromes and the Role of the ret Proto-oncogene

Abstract: Publisher Summary This chapter focuses on genetic and biological aspects of the multiple endocrine neoplasia type II (MEN II) syndromes and of ret mutations. The discussion of clinical and pathological aspects is limited for providing the background to the biological problem and indicating the application of the genetic results. The MEN II syndromes are dominantly inherited syndromes of tumor formation and disordered development that involve principally four tissues: the “C” cells of the thyroid, the adrenal medulla, the parathyroid, and the intestinal autonomic nerve plexuses. There are distinct clinical subtypes of the syndromes, depending on the combination of tissues affected and the presence or absence of specific developmental abnormalities. The chapter discusses the ret proto-oncogene, the development of the tissues involved in Men II, and the patterns of ret expression. At least two sets of observations must be accounted for in any scheme of inherited and sporadic tumorigenesis in C cells. These are (1) the comparative rarity of cysteine codon mutations, compared with the MEN IIB codon 918 mutation, in sporadic tumors and (2) the apparently contradictory reports that differentiation of C cells and related neuroectodermal cells is induced by yet overexpression or is accompanied by silencing of yet expression. There is still little information about the molecular events in tumor progression in MEN II-related tumors. Studies using X chromosome markers show that the established tumors are clonal. Thyroid C cell tumors and pheochromocytomas have been reported in certain Wistar-derived and other strains of rat.

Strategies involved in developing an effective vaccine for EBV-associated diseases.

Abstract: Publisher Summary This chapter first considers EBV host–virus relationships and then proceeds to discuss the immune control of EBV infection. Epstein–Barr virus (EBV) is encoded by a linear, double-stranded DNA genome of 172 kb that includes almost 100 identified open reading frames. The virus maintains a lifelong latent association with B lymphocytes and a permissive association with stratified epithelium in the oropharynx. Two major subtypes of EBV have been identified, A type and B type (also known as EBV-1 and EBV-2). It is possible to characterize three distinct forms of EBV latency (latency I, latency II, and latency III) that are distinguished on the basis of expression of EBV latent genes and promoter usage. These latency patterns or programs form a convenient means of classifying EBV-associated diseases and are the basis for vaccine development. The humoral response to EBV infection is defined in terms of a set of immunofluorescence assays that quantitatively assessed the antibody response to virus capsid antigen (VCA), membrane antigen (MA), early antigen-restricted (EA-R), early antigen-diffuse (EA-D), and EBV-induced nuclear antigens (EBNA). Significantly increased shedding of EBV in the oropharynx of immunosuppressed individuals provides evidence in support of an important role for T cells in controlling EBV infection. It is unlikely that a single vaccine that is applicable to all EBV-associated diseases will be developed in the near future. Given the variety of potential EBV targets in latency III diseases and the problems of immune recognition of latency II and latency I diseases, vaccines against infectious mononucleosis (IM) and posttransplantation lymphoproliferative disorders (PTLD) would seem to offer the best opportunity for early development. Vaccine trials against other EBV-associated diseases may need to proceed with more caution and may be dependent on the emergence of novel vaccine strategies derived from either animal models or related viruses.

The step-by-step development of epithelial cancer: from phenotype to genotype.

Abstract: Publisher Summary This chapter focuses on the step-by-step development of epithelial cancer from phenotype to genotype. Cancer research has at least two major objectives: (1) the understanding of the cancer phenotype and the way it develops and evolves as the immediate basis for the diagnosis and treatment of cancer and (2) the elucidation of the fundamental molecular-biochemical-biological modulations that underlie the development of the cancer phenotype, and its continual evolution to increasingly malignant behavior. The second objective is to add an important facet to the current concepts of basic biology, both “normal” and in disease. In many research enterprises that fall under the rubric of cancer research, both of these major objectives are important and relevant, even though the therapeutic aspects may dominate. Because epithelial cancers and their preceding and precursor epithelial changes are known only by their phenotypes, it is important to delineate these in a scientifically meaningful way. The major objective of this area of cancer research is to delineate the phenotype of the cells of each major step on the path to cancer and to change the phenotype as to prevent or even delay its evolution to carcinoma. Although the knowledge of altered genotypes may ultimately prove to be necessary for us to understand the way cancer develops, it is axiomatic that knowledge of altered phenotypes is a necessary prerequisite. There are at least three major patterns for epithelial cancer development in humans and animals. Patterns I and II are commonly seen and studied in humans. Pattern III appears to be rare, if it occurs at all, in humans.

Cytogenetics and Molecular Genetics of Bone and Soft Tissue Tumors

Abstract: Publisher Summary This chapter focuses on the cytogenetic and molecular genetics of bone and soft tissue tumors. The majority of cytogenetic data stem from the hematological malignancies, and only slightly more than 25% of the more than 22,000 cases reported with chromosome aberrations identified by chromosome banding techniques represent solid tumors. Among these, the bone and soft tissue tumors (BSTT) belong to one of the cytogenetically best characterized groups of tumors. The first reports on consistent tumor-associated chromosome aberrations in BSTT are on Ewing sarcomas. Characteristic chromosome changes have been described in benign and malignant BSTT as well as in some lesions whose true neoplastic nature is uncertain and debated. The finding of specific chromosome aberrations in a number of BSTT has provided molecular geneticists with important information in their efforts to investigate the underlying gene rearrangements. The introduction of new techniques (“molecular cytogenetics”), such as various types of fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH), bridges the gap between cytogenetics and molecular genetics and has also opened up new possibilities to investigate genomic rearrangements and has already yielded interesting results. The genetic analysis of BSTT has become increasingly important in diagnostic work, whereas its role in prognostication is still limited. In the chapter, some mesenchymal tumors that are not literally BSTT, such as uterine leiomyomas and chondroid hamartomas of the lung, are dealt with, but other types—such as meningiomas and mesotheliomas—are not addressed. The chapter also discusses aberrations shared by several tumor types. In the diagnostic situation, cytogenetic and/or molecular genetic analysis adds important, sometimes decisive, information to the cytological, histopathological, and electron microscopic examinations of BSTT.

Immunity to human papillomavirus-associated cervical neoplasia.

Abstract: Publisher Summary This chapter focuses on immunity to human papillomavirus (HPV)-associated cervical neoplasia. Cervical cancer is the fifth most common cancer, with approximately 500,000 new cases diagnosed each year, and is the second most common cause of cancer-related death in women. It is now widely accepted that certain types of HPV are involved in the etiology of cervical cancer. Most cervical carcinomas and preinvasive lesions contain HPV DNA sequences indeed, it has been estimated that over 95% of cervical cancers are associated with HPV infection. The HPV type most commonly associated with cervical cancer and higher grades of cervical intraepithelial neoplasia (CIN) is HPV-16, whereas other genitomucosal HPV types (such as HPV-6 and HPV-11) are associated with lower grades of CIN and condylomata acuminata (genital warts). The association of HPV throughout the pathological spectrum of the disease, and advances in our understanding of viral immunity, has encouraged approaches aimed at immunological intervention for prevention and treatment of this disease. It is apparent that the immune system is often not educated in natural HPV infection of the cervix. High-risk HPV types may have evolved additional strategies for persistence and immune evasion. The prevention of an infectious disease with a vaccine is easier than therapy of the established disease. This suggests that adjuvant vaccination against CIN and early-stage cancer will be more successful than the immunization of patients with advanced disease.

Cell cycle control in fission yeast and mammals: identification of new regulatory mechanisms.

Abstract: Publisher Summary This chapter discusses the recent rapid progress in understanding of the molecular mechanisms controlling the G1 and G2 phases of the cell cycle in fission yeast and mammals, focusing on the newly identified control genes and highly conserved control mechanisms between these two apparently remote organisms The cells of the fission yeast, Schizosaccharomyces pombe, are rod shaped, grow in the longitudinal direction, and divide by septation and medial fission The chapter describes the cell cycle starts control of fission yeast and mammals The mitotic start control of fission yeast and mammals have also been described in the chapter Cell cycle control is one of the most complex and fundamental cellular regulatory processes that eukaryotes possess Cell cycle control is one of the most complex and fundamental cellular regulatory processes that eukaryotes possess Once cells have committed to start the cell cycle, they are unable to differentiate until they return to G1 The next few years will be the period during which rapid progress continues to be made and will witness the discovery of new factors and new mechanisms and the resolution of some of these questions

Transforming growth factor-beta system and its regulation by members of the steroid-thyroid hormone superfamily

Abstract: Publisher Summary This chapter focuses on the transforming growth factor-β system and its regulation by members of the steroid-thyroid hormone superfamily. Transforming growth factor-βs (TGF- β s) are potent regulators of cellular proliferation, differentiation, and morphogenesis as well as extracellular matrix formation, extracellular proteolysis, and inflammation. A major effect of TGF-β is its ability to inhibit cell proliferation. Three different mammalian TGF-β isoforms and many related peptides have been identified. The diverse activities of the members of the TGF-β family are regulated at the levels of TGF-β expression, secretion, and activity; TGF-β receptor expression; and cellular responsiveness. At later stages of tumor development, cells often become refractory to the antiproliferative action of TGF-β. A role for TGF-β in the progression and escape from hormone dependence has also been suggested. The mechanisms of the regulation of TGF-β expression and activation, in addition to TGF- β signaling pathways, are important in understanding neoplastic transformation and escape from normal growth control. TGF- β participates in a variety of cell differentiation processes. Members of the steroid hormone superfamily are potent regulators of the expression of TGF-β isoforms. TGF-βs might have a role as local mediators of the various actions of steroid hormones. Plasmin is a wide-spectrum serine protease that can dissolve fibrin clots and cleave various extracellular and basement membrane proteins. In addition, plasmin activates metalloproteinases and latent elastase, which further contribute to the degradation of matrices. TGF-βs and their receptors are expressed ubiquitously, and they act as key regulators of many aspects of cell growth, differentiation, and function. Steroid action on target tissues is often associated with increase in TGF-β isoforms. Regulation of TGF-β expression and activation is crucial for normal development and growth control.

Viruses In Human Tumors–Reminiscences And Perspectives

Abstract: Publisher Summary This chapter presents the researcher's own experience in the research related to the role of viruses in human tumors. He had initiated some studies on Epstein–Barr virus (EBV) and, in a joint effort with the Henle, was able to demonstrate that those Burkitt lymphoma tissue culture cells that were reactive in a newly developed immunofluorescence assay were indeed the ones that were producing the herpes-type particles identical to EBV. In the years following the initial enthusiasm of regularly demonstrating a suspected human tumor virus in specific human tumors by molecular biological techniques, the difficulties in causally linking EBV to Burkitt's tumor development became increasingly evident. In view of the epidemiological pattern of cancer of the cervix, he decided in 1972, concomitant with his move to Erlangen, to look for other candidate viruses—such as papillomaviruses. With effective collaboration with the University Hospital of Dermatology in Erlangen and the devoted participation of an Erlangen dermatologist, he soon collected a few hundred warts from individual patients. All cervical cancer biopsies were found negative, and although typical human papillomavirus particles in some of the genital warts were detected electronmicroscopically, he failed to detect viral DNA in these tumors.

Plasminogen Activation on Tumor Cell Surface and its Involvement in Human Leukemia

Abstract: Publisher Summary This chapter focuses on the plasminogen activation on tumor cell surface and its involvement in human leukemia. The function of plasminogen activators (PAS) and plasmin in the adult organism has been mainly related to fibrinolysis, tissue remodeling, cell migration, and tissue destruction. Associated with plasmin activity is the dissolution of blood clots, inflammation, tumor cell dissemination, wound healing, angiogenesis, and trophoblast invasion. In addition to directly cleaving components of the extracellular matrix, plasmin is able to regulate various functions through the activation of prohormones and latent growth factors. The invasive capacity of tumor cells requires proteolytic activity; therefore, plasmin, together with other tissue-destructive enzymes, has been implicated in the property of tumor cells to metastasize. Both plasminogen and PAS bind to cell surfaces, and this allows plasmin generation at restricted areas of the cell surface and the cell-matrix interface. High levels of urokinase plasminogen activator (uPA) and/or its inhibitor plasminogen activator inhibitor type 1, in tumor tissue seem to indicate an adverse prognosis for patients with cancer, as was first shown in the case of breast cancer. The components of plasminogen activation described in the chapter include plasminogen, urokinase-type plasminogen activator, and tissue-type plasminogen activator. Plasminogen activation is regulated both by inhibitors of PAS and by inhibitors of plasmin. Plasminogen activator inhibitors (PAIs) are specific, fast-acting inhibitors of PAS. Four inhibitors are known, PAI-1, PAI-2, PAI-3, and PAI-4 (protease nexin). The α 2 MR, which is identical to the low-density lipoprotein receptor related protein (LRP), has been reported to mediate the internalization and degradation of tPA, tPA-PAI-1 complexes, uPA-PAL1 complexes, and uPA-protease nexin complexes. Although plasminogen activation is needed in the process of matrix destruction, it is still unknown whether the activity of uPA or merely the uPA antigen and/or uPAR is involved in the process of cell migration.

Genetics of the nevoid basal cell carcinoma syndrome.

Abstract: Publisher Summary This chapter focuses on the genetics of the nevoid basal cell carcinoma syndrome. The nevoid basal cell carcinoma syndrome (NBCCS), also known as “Gorlin syndrome,” is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), odontogenic kerarocysts, pits of the palms and soles, and a spectrum of skeletal and developmental abnormalities. It is a complex hamartoneoplastic-malformation syndrome with over 100 signs and symptoms primarily involving the skin, central nervous system, and skeletal system. One of the most striking and consistent features of this syndrome is the number and distribution of BCCs in NBCCS patients in contrast to that observed in the general population. The phenotypic manifestation and spectrum of associated defects also provide valuable clues as to possible candidate loci that may be involved in the syndrome. The clinical features of NBCCS and the wide phenotypic spectrum of these features indicate that the gene for this syndrome must be involved in the normal course of embryogenesis and in addition be involved in cellular regulatory processes, such as cell division and differentiation. Malformations involving the skeletal and nervous system and facial dysmorphology indicate that defects in this gene affect early embryonic processes. The spectrum of developmental anomalies associated with the mes mutation makes it an interesting candidate for a mouse model for NBCCS.

The Pastorian: a legacy of Louis Pasteur.

Abstract: Publisher Summary This chapter focuses on the researches carried out by Andre Lwoff in the field of lysogeny and describes the way his work inspired Howard Temin and other scientists to understand retroviruses, and thus prepared the world to identify the cause of acquired immunodeficiency syndrome (AIDS). It mentions two experiments undertaken by Lwoff to extend the Wollmans' hypothesis—bacteriophages contained genetic instructions and—such instructions were inherited by lysogenic bacteria. The findings, coupled with the growing recognition that genetic information resides in DNA, permitted Lwoff to propose a simple and prophetic explanation of lysogeny. According to him, viral infection can either result in the massive production of new viruses and destruction of the bacterium or can lead to the perpetuation of the bacteriophage's genes inserted into the chromosome of the bacterium in an inactive form called a “prophage.” Howard Temin proposed ways in which the infection of an animal cell by a retrovirus resembled the establishment of the lysogenic state in bacteria. His highly unorthodox proposal that viral genes are converted from RNA to DNA during infection, stimulated him to seek and to find an enzyme capable of copying RNA to make DNA. This enzyme, now known as reverse transcriptase, is a distinctive component of all retroviruses and of a few other viruses; an important factor in current views of early evolution; an essential tool in the biotechnology industry; a sign by which human immunodeficiency virus (HIV), the AIDS virus, was detected and recognized as a retrovirus; and the target for the only drugs widely used against HIV.

Fundamentals of Cancer Cell Biology

Abstract: Publisher Summary This chapter focuses on the fundamentals of cancer cell biology. Cell biology can be described as the study of individual cells—in contrast to tissues—individual molecules, and individual genes. Much of cell biology has been cancer cell biology, because in the early days, cancer cells were easier to study than normal cells. One of the most important advances in an understanding of cancer has been the realization that cancer does not arise as an abnormality of an individual or even a tissue. Nearly all cancers originate from one single abnormal cell—that is, they are clonal. The author's slow path toward cell biology was influenced both by local events in Cambridge and distant developments overseas. The chapter also discusses about foundations of cell culture. One of the most active and exciting fields of research in cell biology has been concerned with the adhesion of cells to one another and to the extracellular substrate. This is now known to be because of the families of cell adhesion molecules (CAMs) and substrate adhesion molecules (SAMs) that bind specifically, either homotypically to one another or hetereotypically to a receptor molecule. A great deal of cancer research is at present centered on the protooncogenes and tumor suppressor genes, and the way in which their perturbation as oncogenes, for example, gives rise to cancer itself.