Showing papers in "Advances in Cancer Research in 1985"

Plasminogen activators, tissue degradation, and cancer.

Abstract: Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

Down-Regulation of the Antitumor Immune Response

Abstract: Publisher Summary This chapter discusses the immune response to chemically induced, transplantable tumors in syngeneic mice. It deals with those tumors that are immunogenic by virtue of their possession of tumor-specific, transplantation rejection antigens. A framework of evidence has been presented in the chapter that supports the hypothesis of down-regulation of antitumor immune response. Direct evidence for the hypothesis consists of the finding that infusion of suppressor spleen cells from donors with a large tumor can prevent recipient mice from generating a concomitant immune response. Additional direct evidence is being supplied by an ongoing study that shows that complete or partial regression of the Meth A fibrosarcoma that results from appropriately timed exposure to sublethal, whole-body γ-radiation is associated with a prolonged generation of effector T cells and an absence of suppressor T cells. It is suggested that down-regulation of antitumor immunity by suppressor T cells can explain the escape of only of those tumors that are immunogenic enough to evoke the generation of enough effectors T cells to cause tumor regression in the absence of suppressor T cells. This implies that the immunity generated to some tumors is too little too late to cause regression, even in the absence of the negative regulatory influence of suppressor cells. Therefore, successful immunotherapy of some established tumors, besides depending on the employment of agents capable of eliminating suppressor T cells, will also depend on the employment of agents capable of directly augmenting the generation of effectors T cells.

Cancer metastasis: experimental approaches, theoretical concepts, and impacts for treatment strategies.

Abstract: It has been the purpose of this article to describe recent advances in cancer metastasis research. Clinical realities and experimental approaches to the study of underlying basic mechanisms of metastasis formation were discussed. Wherever possible, results were reported which led to the development of theoretical concepts. Such results and concepts were finally evaluated in light of their possible impact for the design of new treatment strategies. Experimental findings from many diverse research fields were summarized with the help of tables, figures, and references. It was concluded that the process of metastasis is a dynamic event that can be described as a sequence of interrelated steps. Experimental results indicated that malignant cells that migrate and disseminate from the primary organ to distant sites and there eventually develop into metastases have to survive a series of potentially lethal interactions. Intimate tumor-host interactions were reported to take place all along the metastatic process. They were elucidated at the steps of angiogenesis, invasion, organ interaction, dormancy, tumor rejection, and tumor immune escape. The outcome of such tumor-host interactions seemed to depend on intrinsic properties of the tumor cells themselves as well as on the responsiveness of the host. Metastasis does not appear as a merely random process. Both clinical and experimental studies revealed that the whole process can be described more appropriately in terms of stochastic, sequential, and selective events, each of which is controlled and influenced by a number of mechanisms. With regard to therapeutic intervention, a selective event offers more possibilities than a random one because it is governed by rules that can be exploited experimentally. Various impacts from experimental studies for the design of antimetastatic cancer treatment strategies were discussed. Sequential steps of the metastatic cascade could become new therapy targets. Conventional empirically derived treatment modalities should become flanked by methods aimed more specifically at critical steps of cancer spread in order to prevent progression of the disease. This is where basic research on mechanisms could make significant contributions to therapy planning in the future. Furthermore, possible negative effects of surgery, radiotherapy, and adjuvant chemotherapy or immunotherapy that could result in enhancement of metastatic progression need to be critically evaluated to limit them as much as possible.(ABSTRACT TRUNCATED AT 400 WORDS)

The canine transmissible venereal tumor: a unique result of tumor progression.

Abstract: Publisher Summary The canine transmissible venereal tumor (TVT) is the only tumor known to be transmitted in nature by the transplantation of cells. Under natural conditions, the TVT is transmitted by coitus and experimentally, the tumor can be induced by the inoculation of living tumor cells to immunocompetent allogeneic dogs. Evidence that the tumor is transmitted by cells is derived from cytogenetic and immunological studies. Cytogenetic studies show that TVT from different geographical origins is characterized by extensive and characteristic chromosomal aberrations. With the characterization of the banding patterns of normal dog chromosomes, the background information for comparative banding pattern analysis of TVT chromosomes is now available. These studies may enable investigators to determine whether this unique tumor has a common origin or it arose repeatedly in the domestic dog. The results of immunological studies also suggest that the TVT is transmitted by the transplantation of cells. Investigations of the immune response against the TVT have clearly demonstrated that the tumor is antigenic in the dog and that immunological mechanisms are involved in the induction of the spontaneous regressions of this neoplasm.

The nude mouse in cancer research

Abstract: Publisher Summary The nude mouse is considered a marvel as a laboratory animal and in many respects is uniquely qualified for in vivo model studies of human cancer. Most human tumors have been transplanted to nude mice and tumor lines are established with varying degrees of ease. It is noted that the additional immunosuppression of the mice or the use of very young animals can increase tumor growth and malignant expression. Other variables that affect tumor transplantation include the health of the mice, site of injection of the transplant, and specific properties or requirements of the human tumor cells. Hormone-dependent human tumors are grown in nude mice, either in special sites or after hormonal supplement. It is observed that the tumor growth rates differ in nude mice and in cancer patient and this tumor heterogeneity occasionally result in the growth of selected tumor components. These differences do not necessarily demean the human tumor-nude mouse model, but is well in line with the changes occurring with time in the human patient tumors. Many tumor characteristics appear to be stable in the nude mouse, and it has been shown that tumor markers and secretion of certain hormones may be maintained in the xenografts.

Genetic suppression of tumor formation.

Abstract: Publisher Summary Genomic changes of all kinds, ranging from base substitutions, deletions, duplications, amplifications, and rearrangements, are characteristic of malignant cells. With respect to genetic suppression of tumor formation, genomic changes can play a crucial role in eliminating or silencing suppressor genes during tumorigenesis. The chapter provides one avenue for the loss of suppression that states that the loss of specific chromosomes from cell hybrids result in the re-emergence of tumor-forming ability that is initially suppressed. Another avenue—namely, the same process of chromosome re-arrangement that generates oncogene activity is also considered as a source of suppressor loss. In this context, cancer can be viewed as a disease of the genome in which chromosome instability lies at the heart of the process, generating the genotypic and phenotypic changes that typify the malignant disease. To assess the potential of tumor suppressor genes and gene products, it is often useful to re-examine the record of past studies as well as consider the application of novel molecular approaches.

Seroepidemiological studies on nasopharyngeal carcinoma in China.

Abstract: Publisher Summary This chapter explores simple and sensitive techniques that can be conveniently applied in the high-nasopharyngeal carcinoma (NPC) risk field for the early detection of NPC. It is noted that early treatment gives a good prognosis and helps to explore the roles of Epstein–Barr (EB) virus, environmental factors, and genetic factors in the development of NPC. The chapter also summarizes serological studies associated with NPC. Serological studies exhibit that the geometric mean titer (GMT) of compliment-fixing antibody to EB virus in healthy individuals over 20 years of age in the high NPC risk areas are significantly higher than that in the low NPC risk areas. The studies also show that the presence of IgA/VCA antibody is closely related to clinical and pathological changes in the nasopharynx. Thus, EB virus plays an important role in the development of NPC and the mortality rate of NPC can be reduced through early detection and treatment.

Retrovirus-induced acquired immunodeficiencies.

Abstract: Publisher Summary This chapter discusses the Retrovirus (RV)-induced acquired immunodeficiency. It deals primarily with the former type of mechanisms, but emphasizes that distinguishing between tumors-unrelated and tumor-dependent immunodepressive events may be exceedingly difficult. RV can adversely affect the functioning of the immune system. In a limited number of infections of lower animals, a multiplicity of phenomena pertaining to the whole organism and to isolated immunocompetent cells has been described. Infected hosts have been shown to mount reduced responses against a variety of immunogens and to present a subnormal resistance to superinfecting agents. Functional tests have established that all classes of immunocytes exhibit potentially important alterations in their effectors, inducer, or immunoregulatory activities, and several pieces of evidence have suggested the centrality of macrophage impairment. Attempts to clarify the underlying mechanisms have indicated that many factors may contribute, but the direct interaction of the infecting virus with immunocompetent cells is of great importance. Even though it seems likely that active infection is a prerequisite for such cells to become grossly or permanently malfunctioning, the mere physical contact with the virion or with virion components has been shown to perturb both lymphocytes and macrophages.

Human Cancer-Associated Antigens: Present Status and Implications for Immunodiagnosis

Abstract: Publisher Summary The successful demonstration of specific antigens in animal tumors essentially provided a major impetus to the search for comparable antigens in human neoplasms. This chapter examines the considerable amount of data that have accumulated in recent years on tumor-associated antigens (TAAs) of human solid tumors to assess their specificity and their possible usefulness for the early diagnosis of cancer. The selection of material included is arbitrary, as there is an absence of a clear-cut and universally accepted definition for TAA. TAAs are an extremely heterogeneous group of molecules and their overlap with normal antigens is so great that it is practically impossible to define TAAs in such a way so as to distinguish them clearly from ordinary cellular components. The chapter considers a molecule as a TAA if its presence renders the cancer cell quantitatively or qualitatively different from its normal counterpart. TAAs appear to be oncofetal or digerentiation antigens and their apparent specificity is due to their generally increased concentration in the tumor cells.

Trichothecenes, zearalenone, and other carcinogenic metabolites of Fusarium and related microfungi.

Abstract: Publisher Summary This chapter presents the epidemiological and experimental evidence showing the importance of secondary metabolites of Fusarium microfungi in the etiologies of the human cancers of sex organs, the digestive tract and the brain. Fusarial secondary metabolites are sporadically present in livestock feeds and have been recognized as the cause of a variety of disorders, “mycotoxicoses,” some of which are fatal. The carcinogenic potentialities of fusarial mycotoxins have yet to be fully evaluated. Though the available experimental data are scanty, epidemiological and circumstantial evidence strongly indicates that the prevention of common human cancers may largely depend on the decrease or elimination of carcinogenic mycotoxins from the environment and food. Large scale disasters caused by mycotoxins occurred in people who were usually undernourished in the form of ergotism among populations consuming rye bread contaminated with ergot alkaloids produced by Claviceps purpurea. The greater efficacy of few large doses of such “natural” carcinogens over that of continuous low dosage tends to induce tolerance. The main hazards of mycotoxins appear related to the occasional exposure to very high levels as a result of unusual weather conditions.

Biological and molecular analysis of p53 cellular-encoded tumor antigen.

Abstract: Publisher Summary p53 was originally observed as a cellular product that formed a stable complex with the viral large T antigen expressed in Simian Virus 40 (SV40)-transformed cells. p53 is found in tumor cells in its phosphorylated form. The addition of radioactive phosphorus yields a phosphorylated p53 that immunoprecipitates with anti-p53 monoclonal antibodies. Under in vivo conditions, p53 phosphorylates onto a serine amino acid. Experiments showed that immunoprecipitation of p53 with a specific anti-p53 monoclonal antibody yields a p53 protein that also autokinases under in vitro conditions. In these experiments, p53 immunoprecipitated with several other anti-p53 monoclonal antibodies apparently did not bind the radioactive phosphate of γ-ATP under in vitro conditions. These conflicting results, concerning autokinase of p53 in vitro after immunoprecipitation with one reagent and not with another could be explained by the assumption that some monoclonal antibodies bind directly to the site of phosphorylation. The assumption that p53 is encoded by the normal cellular genome is based on the observation that it is expressed in several types of nontransformed cells. Several investigations suggest that the basis for the quantitative difference of p53 in transformed and nontransformed cells is due to posttranslational regulatory mechanisms.

Cellular aspects of DNA repair.

Abstract: Publisher Summary This chapter discusses the cellular aspects of DNA repair. It considers both the processes of excision repair and those that involve a more direct interaction with DNA synthesis. The mechanistic details of excision repair have been extensively reviewed in the chapter. It concentrates on the biological implications of the chemical data and considers the interactions of the damage to the DNA and the metabolic systems of the damaged cell. In this context, the major sort of damage to be considered is that in which a block to DNA chain elongation or initiation has been produced as a result of an alteration in a nucleotide so that it becomes noninstructive for Watson–Crick base pairing. DNA synthesis can be studied in vitro by the modification of the Sanger chain termination sequencing technique that permits the determination of the exact nucleotide at which the termination has occurred. To observe excision repair, a cellular system must be subjected to an agent that damages or alters the DNA.

Retroviruses as chromosomal genes in the mouse.

Abstract: Publisher Summary The mouse retroviruses are RNA-containing viruses that replicate through a DNA intermediate. This chapter describes the four major classes of endogenous mouse retroviruses—namely, the type C mouse leukemia viruses (MuLVs), the type B mouse mammary tumor viruses (MMTVs), the intracisternal A particles (IAPs), and the virus-like endogenous sequences (VL30s). It also describes the arrangement and stability of these sequences in the mouse germline, the experimental evidence linking specific germline integrations with various polymorphic chromosomal loci, and the association of specific somatically acquired proviruses with tumor induction and progression. The mouse retroviruses are essentially classified into four groups based on differences in virion morphology— MuLVs, MMTVs, IAPs, and VL30s. The virions have type A, B, or C structure as revealed by electron microscopy. MuLVs and MMTVs are replication-competent viruses with type C and type B structures, respectively. IAPs resemble immature type B virions, but are noninfectious and are found only intracellularly. VL30s are endogenous retrovirus-like sequences that are not known to produce any virion structural components, but can be efficiently packaged and transmitted as pseudotypes of type C viruses.

Monoclonal antibodies reactive with breast tumor-associated antigens.

Abstract: Publisher Summary Monoclonal antibodies (MAbs) led to the identification of novel tumor-associated antigens (TAAs) from various human carcinomas, melanomas, leukemias, and lymphomas There are approximately two dozen characterized monoclonals reactive with human breast tumors Several of these are chosen to elaborate those phenomena that are most relevant for the use of MAbs in the management of human breast cancer as well as in the study of the biology of human mammary carcinoma cell populations This chapter describes numerous MAbs that are reactive with human mammary carcinomas They can be classified into four groups based on the immunogen used to generate the MAb These include using breast tumor cell lines, milk fat globule membrane, and membrane-enriched extracts of breast carcinoma metastases as immunogen, and lymph nodes from mastectomy patients Each of the MAbs, including those prepared by several different groups to milk fat globule membrane, appears to be unique with respect to percentage of reactive mammary tumors, percentage of reactive cells within tumors, location of reactive antigen within the tumor cell, or degree of reactivity with nonmammary tumors as well as normal tissues

The molecular action of platelet-derived growth factor.

Abstract: Publisher Summary This chapter reviews the biology of Platelet-derived growth factor (PDGF) with an emphasis on understanding the relationship between growth factors and cell transformation. It also discusses the regulation of gene expression by PDGF. PDGF has been shown to stimulate the growth of fibroblasts in culture from chickens through humans. In vivo , PDGF is thought to play a role in the maintenance of the vascular lining, though direct evidence is lacking. Through the study of the molecular biology of PDGF, the role of oncogenes in cell transformation and their relationship to growth factors is beginning to be understood. It appears that the deregulation of molecular events that are normally controlled by growth factors can lead to cell transformation. Several known oncogenes can be associated with specific molecular events regulated by growth factors. Some oncogenes, such as the sis gene, may code for a growth factor that is capable of stimulating cell growth through an autocrine-type mechanism. Other oncogenes may code for functions similar to events inside the cell that are regulated by growth factors. It seems quite likely that some oncogenes will either turn out to be growth factor receptors or mimic the functions of them. This may be a likely explanation for the coincidence that a large number of oncogenes as well as growth factor receptors are tyrosine kinases.

The mechanism of action of mAMSA.

Abstract: Publisher Summary This chapter describes the effects and mechanisms of action of 4´-(9-acridinylamino)methanesulfon- m -anisidine (mAMSA) and drugs with related action on cells. It also presents a brief history of AMSA drug development. In specific, mAMSA is a member of the AMSA series of 9-anilinoacridine derivatives. mAMSA was first reported as a dose-potent acridine derivative highly active against L1210 leukemia. It is noted that because of the relative ease with which acridines can be substituted and chemically modified, they essentially provide an excellent series to study the mechanism of action. AMSA exhibit molar potency approximately five to sixfold lower than mAMSA. This illustrates one of the unusual features of the AMSA series that states that extremely wide range of activity and potency is afforded by small changes in structure, and the less active drugs provide useful controls when exploring the interaction of active compounds with putative cellular targets. In addition to its antitumor properties, mAMSA also possess some antiviral activity.

Fusion proteins in retroviral transformation

Abstract: Publisher Summary Retroviral transforming proteins are coded for by oncogenes. The mechanism of the uptake of oncogenes by retroviruses often results in fusion with replicative genes. Fusion of oncogenes to retroviral replicative genes generates protein products that are also fused. These proteins contain viral and oncogene information in a single polypeptide chain. The viral structural portion provides a convenient antigenic marker that allows detection of such oncogene products with antiviral antibodies, which are easily available. In contrast, oncogene products are generally poorly antigenic because they closely resemble cellular proteins. Therefore, oncogene products without viral structural portions are much more difficult to detect. This chapter discusses several known retroviral fusion proteins and the potential role of the viral structural protein portions in the transforming proteins. It summarizes the oncogenes, their viral origin, their gene products, and some of their characteristic properties. The avian retroviruses comprise four groups; three consist of the acute avian leukemia viruses, such as the myelocytomatosis virus family (MC29), the avian erythroblastosis viruses (AEV), and the avian myeloblastosis viruses (AMV). The fourth group is represented by the avian sarcoma viruses.

Application of migration inhibition techniques in tumor immunology.

Abstract: Publisher Summary Macrophage migration inhibition (MMI) and leukocyte migration inhibition (LMI) phenomena are in vitro correlates of delayed hypersensitivity, and migration inhibition assays are used to evaluate cellular immunity to tissue, tumor, and virus antigens. Any nontoxic immunogenic material can be applied as antigen in these assays at proper concentrations, which must be determined in preliminary, pilot experiments. Technically these assays are relatively simple and can be evaluated after 18-96 hrs, depending on whether the direct or indirect technique is applied. The advantage of these assays can be used in allogeneic combinations of cells, because during the short incubation period no apparent sensitization and reactivity to histocompatibility antigens can be found. Another advantage is that tests can be performed with cell extracts and cell fractions. The vast majority of animal and human tumors studied with MMI and LMI appeared to contain tumor-determined (TAA, TSTA) antigen, usually not present in normal adult tissue. The tumor-determined antigens are always immunogenic in autochthonous/autologous and usually in allogeneic tumor-bearing animal/patients.

Cooperation between multiple oncogenes in rodent embryo fibroblasts: an experimental model of tumor progression?

Abstract: Publisher Summary Stepwise progression of tumoral diseases toward increased invasiveness, hormonal independence, and resistance to chemical and physical treatment is an all-too-common phenomenon that has been analyzed in various experimental systems. The stepwise character and apparent irreversibility of these phenotypic changes would be most easily accounted by a sequential accumulation of genetic alterations. Alterations of cellular genes associated with malignancy (oncogenes) are recently identified, first as a result of the natural capacity of retroviruses for gene transduction and subsequently by the transfection of genomic DNA from human tumors into mouse cells. Unlike most retroviruses, oncogenic DNA viruses that have been analyzed so far appear to require more than one gene to establish and maintain neoplastic transformation. This was extensively documented for polyoma viruses and adenoviruses, and more recent observations suggest a similar situation for two herpesviruses— herpes simplex type 2 and Epstein–Barr virus. Experimental evidence summarized in this chapter defines an early stage of the oncogenic transformation process induced by the plt and E1A oncogenes and, at least under some defined conditions of expression, by the rearranged forms of the myc gene.

The Blym oncogenes.

Abstract: Publisher Summary Oncogenes are a set of cellular and viral genes that induce morphologic transformation and/or neoplastic changes in cells in which they are either activated or introduced in activated form. Their oncogenic properties are defined by the particular cells and biological test systems that are used to detect their presence. This chapter focuses on the BLYM oncogenes. These genes are best characterized as a subset of oncogenes that were not initially discovered within the genomes of oncogenic viruses. They were first detected by the use of a transfection assay in which DNA from tumor cells transforms cultured NIH/3T3 mouse fibroblasts. Unlike other oncogenes that also transform NIH/3T3 cells, such as the ras family that has been found in association with tumors in a wide variety of cell lineages, Blym oncogenes have been detected so far only in B cell neoplasms in both animals (chickens) and humans. The chapter discusses the pathogenesis of Bursal Lymphomas induced in chickens by avian leukosis virus (ALV). Determination of the sequence of HyBlym-1 provides further details of the relationship between the human- and chicken-transforming genes.