Showing papers on "Tumor progression published in 1983"

The 5-methylcytosine content of DNA from human tumors

Abstract: The over-all 5-methylcytosine (m5C) content of DNA from normal tissues varies considerably in a tissue-specific manner. By high-performance liquid chromatography, we have examined the m5C contents of enzymatic digests of DNA from 103 human tumors including benign, primary malignant and secondary malignant neoplasms. The diversity and large number of these tumor samples allowed us to compare the range of DNA methylation levels from neoplastic tissues to that of normal tissues from humans. Most of the metastatic neoplasms had significantly lower genomic m5C contents than did most of the benign neoplasms or normal tissues. The percentage of primary malignancies with hypomethylated DNA was intermediate between those of metastases and benign neoplasms. These findings might reflect an involvement of extensive demethylation of DNA in tumor progression. Such demethylation could be a source of the continually generated cellular diversity associated with cancer.

Tumor heterogeneity: biological implications and therapeutic consequences

Abstract: It is now appreciated that cancers can be composed of multiple clonal subpopulations of cancer cells which differ among themselves in many properties, including karyotype, growth rate, ability to metastasize, immunological characteristics, production and expression of markers, and sensitivity to therapeutic modalities. Such tumor heterogeneity has been demonstrated in a wide variety of animal tumors of differing etiology, tissue and cellular origin, and species. It has been shown in autochthonous, as well as transplanted, tumors. Similar results have been reported for human cancers, although much of the evidence that heterogeneity of human cancers, also reflects, at least in part, the existence of clonal subpopulations, is still indirect. Heterogeneity is not a unique property of malignancy. Preneoplastic tumors, as well as normal tissues, are also composed of cellular subpopulations. Proposed mechanisms for the origin of tumor heterogeneity include coalescence of multiple foci of cancer clones and the generation of diverse subpopulations from a single clone. This latter process could be due to genetic errors arising from classical genetic mechanisms or to the production of cellular variants as in normal tissue differentiation. Indeed, certain tumor subpopulations have been shown to produce variants at high frequency. In some cases this frequency can be modified by environmental circumstances. Nontumor cells may also contribute to production of cancer cell variants, perhaps, in the case of infiltrating phagocytic cells, by producing mutagens or by somatic hybridization with cancer cells. Production of tumor cell variants is a dynamic process which can occur at any time. Although tumors are mixed populations of cells, knowledge of the characteristics of individual components is not sufficient to predict the behavior of the whole. Individual cancer subpopulations can interact to affect each other's growth, immunogenicity, ability to metastasize, sensitivity to drugs, and clonal stability. The existence of multiple, interactive subpopulations provides a basis for the well-known phenomenon of ‘tumor progression’ in which tumors undergo qualitative changes in characteristics over the course of time. Selection of subpopulations better able to survive changing environmental circumstances allows for such changes as autonomy in regard to endogenous growth regulation, more ‘malignant’ behavior, and loss of response to therapy. Tumor subpopulation interactions may play a regulatory role in this process. Tumor heterogeneity has obvious consequences to the design of effective therapy. It provides one rationale for combination therapies and suggests that initial treatment should be early and comprehensive. The continuing emergence of new clones suggests that treatment which is unsuccessful at one point might be effective later. Assays to predict effective therapy for individual patients need to address the multiplicity of tumor subpopulations and the ability of these subpopulations to influence each other. Subpopulation interactions may also be useful in therapy design, as may be efforts to control the extent of tumor heterogeneity by agents which effect cellular differentiation. Thus, tumor heterogeneity presents both problems and, perhaps, new solutions for control of cancer.

Spontaneous fusion in vivo between normal host and tumor cells: possible contribution to tumor progression and metastasis studied with a lectin-resistant mutant tumor.

Abstract: Previous studies demonstrated that growth in DBA/2 mice of MDW4, a wheat germ agglutinin-resistant (WGAr) mutant of the highly metastatic MDAY-D2 DBA/2 mouse tumor, led to the emergence of WGA-sensitive (WGAs) revertants having higher ploidy levels at the site of inoculation as well as at distant visceral metastases. The results implied that MDW4 was nonmetastatic but progressed to become metastatic in vivo only after a cellular change took place which was accompanied by extinction of the WGAr phenotype and acquisition of a higher number of chromosomes. Results presented here provide strong and direct evidence for the underlying mechanism being spontaneous cell fusion in vivo between the MDW4 (WGAr) tumor cells and normal host cells, at least some of which are of bone marrow origin. Thus, growth of the H-2d MDW4 tumor cells in (C3H X DBA/2)F1 (H-2k X H-2d) or (C57BL/6 X DBA/2)F1 (H-2b X H-2d) mice led to the appearance of WGAs revertants bearing the H-2k or H-2b major histocompatibility complex antigens associated with the C3H or C57BL/6 parental strains, respectively. Similarly, WGAs revertants of MDW4 were found to express H-2k antigens after growth in CBA/HT6T6 (H-2k) leads to DBA/2 bone marrow radiation chimeras. Attempts to mimic the in vivo hybridization process were successful in that in vitro somatic cell fusion between an ouabain-resistant (OuaR), 6-thioguanine-resistant (Thgr) derivative of the MDW4 mutant and either normal bone marrow or spleen cells resulted in loss of the WGAr phenotype in the hybrids (thus showing its recessive character) and increased malignant properties in vivo. An analysis of spontaneous frequencies of re-expression of various drug resistance genetic markers in several hybrid metastatic cells was also consistent with chromosome segregation of the sensitive alleles. The results show that tumor progression and the emergence of metastatic cell variants could arise as a consequence of tumor X host cell fusion followed by chromosome segregation. We also discuss the possibility that this type of event may normally be a very rare one during the growth of tumors, the frequency of which can be artificially amplified by the use of certain classes of lectin-resistant mutants carrying particular cell surface alterations.

Karyotypic progression in human tumors

Abstract: Karyotypic progression may be viewed in at least two ways. One approach seeks evidence for increasing and progressive deviation from the normal chromosome pattern in tumors. The clearest examples, found in some leukemias, are those in which successive karyotypic changes are superimposed on an already aberrant cell population. Evidence of chromosomal progression within solid tumors is far less frequent, possibly because the tumors themselves are at a relatively late stage in their evolution. An alternative approach, therefore, attempts to correlate the extent of karyotypic deviation with other aspects of tumor progression. Recent data, based on classical cytogenetic analyses and flow cytometry, are presented to determine relationships between karyotype and specific origin and morphology of tumors. The predominant theme which emerges, not surprisingly, is that the more deviant chromosome patterns are associated with other measures of increased biologic malignancy. What is surprising is the degree to which these properties are expressed in primary tumors and the relative lack of evidence for further karyotypic evolution with recurrence or metastasis. Examples of genetic instability, evolution through polyploidy, gene amplification, and selection for specific chromosomal rearrangement are found in populations of premalignant and malignant human cells. There is increasing recognition of the importance of tumor-specific chromosome aberrations in the stepwise progression from the normal to the fully neoplastic cell.

Prognostic significance of tumor grade and stage in the patient with carcinoma of the prostate

Abstract: Available English language articles relating the grade, stage, and grade-stage of carcinoma of the prostate to evidence of tumor progression and survival in untreated and treated patients have been reviewed. Observations of the extremes of the spectrum of biological behavior of carcinoma of the prostate have been emphasized; for example, tumor progression, never or always; survival, never or always. The reported experiences indicated the following; namely, 1) reproducible biologically meaningful grading is achievable; however, grade cannot be utilized as a reliable indicator of stage; 2) accurate staging provides information that correlates with tumor progression and survival in groups of patients. However, unexpectedly prolonged or abbreviated progression-free survivals occur frequently enough in every stage, except perhaps patients with clinically unsuspected focal carcinoma, to indicate that the natural history and treatment response of individuals grouped by stage is far from homogeneous; 3) appropriate use of carefully obtained grade and stage information together maximizes the accuracy of prognostic attempts and is necessary to evaluate treatment results. At the present time, assessment and consideration of the grade and stage of carcinoma of the prostate is essential to formulate prognosis and advise and evaluate treatment in patients with this disease.

The Ernst W. Bertner Memorial Award lecture: the evolution of biological heterogeneity in metastatic neoplasms.

Abstract: The complexity of the processes of tumor progression and metastasis makes it difficult to provide generalized rules. Results and hypotheses that are based upon a single tumor system or a simple experimental technique are likely to be revised as more data become available. However, bearing these limitations in mind and ignoring the above warnings, I wish to conclude the following: By the time of diagnosis, many malignant neoplasms are heterogeneous, i.e., they contain subpopulations of cells with different biological characteristics. The process of metastasis involves a sequence of complex events whose outcome depends on tumor cell properties and host factors. The metastatic process selects variants from a heterogeneous starting population. The diversity for the metastatic phenotype may be a consequence of the multicellular origin of a neoplasm or it may be the result of continuous evolution and progression in tumors of unicellular origin. Metastatic clones appear, in general, to be less stable than nonmetastatic clones. Metastatic clones exhibit an increased rate of spontaneous mutation compared with nonmetastatic clones. Some metastases may be clonal in their origin, and multiple metastases can originate from different progenitor cells. Biological diversity can rapidly develop within individual metastases. The acquisition of phenotypic heterogeneity by populations of tumor cells imposes a degree of stability on the tumor as a whole. The generation of biological diversity in malignant neoplasms and within and among metastases has profound implications both for studies on the pathogenesis of cancer metastasis and for the design of any successful approach to the treatment of this disease.

Intensive chemoradiotherapy with autologous marrow transplantation for small cell carcinoma of the lung.

Abstract: Ten patients with small cell carcinoma of the lung (seven with extensive and three with limited disease) underwent several courses of conventional therapy. The patients were then referred for autologous marrow transplantation, three during a complete response, six during a partial response, and one following no response. The pretransplantation regimen consisted of 120 mg/kg of cyclophosphamide followed by 800-1000 rad of total-body irradiation. In addition, six of the seven patients with extensive disease received high-dose nitrosourea. Following the infusion of cryopreserved autologous marrow, all patients achieved engraftment. Of the three patients without detectable tumor at the time of transplant, two died with tumor present and one survives without recurrence 27 months after transplantation. Of the other seven patients, two had a complete tumor response; both died of interstitial pneumonitis, one without detectable tumor and one with microscopic tumor at autopsy. One of the other five patients had a partial response, but all died of tumor progression. The median survival from initial therapy in patients with extensive disease was 9 months and with limited disease was 18.5 months.

Treatment of metastatic carcinoid tumor with dactinomycin or dacarbazine.

Abstract: We studied the effect of two single drugs on patients with metastatic carcinoid tumors. All patients had symptomatic and measurable disease and all had elevations of urinary 5-hydroxy indole acetic acid excretion. Seventeen patients were treated with dactinomycin at a dose of 12-15 micrograms/kg/day for 5 days repeated every 4-5 weeks. One partial response was achieved. Fifteen patients were treated with dacarbazine (DTIC) at a dose of 250 mg/m2/day for 5 days every 4-5 weeks. Two partial responses were achieved. The median times to tumor progression were 10 weeks with dactinomycin and 18 weeks with DTIC. Median survival times were 28 and 47 weeks, respectively. Dactinomycin given by this schedule appears to have only limited activity as a single-agent treatment in malignant carcinoid tumor. DTIC, although showing only a slightly better response rate, perhaps warrants further investigation in view of our more favorable interval to tumor progression and survival experience and in view of this drug's more established activity in the closely related islet cell carcinoma.

Simultaneous Appearance of Keratin Modifications and γ-Glutamyltransferase Activity as Indicators of Tumor Progression in Mouse Skin Papillomas

Abstract: gamma-Glutamyltransferase (GGT), an enzyme not found in normal adult epidermis, was detected in most skin papillomas larger than 13 mm in diameter and in all squamous carcinomas induced by 7,12-dimethylbenz[a]anthracene initiation and 12-O-tetradecanoylphorbol 13-acetate promotion in noninbred Sencar mice. Furthermore, these GGT-positive lesions were also characterized by a marked decrease or absence of high-molecular-weight components of epidermal keratin. Since these characteristics are common to both carcinomas and large papillomas but are practically undetectable in normal epidermis and small papillomas, GGT activity and lack of high-molecular-weight keratin components seem to be good indicators of tumor progression, i.e., from papilloma to squamous carcinoma.

Thymosin alpha 1 restores NK-cell activity and prevents tumor progression in mice immunosuppressed by cytostatics or X-rays.

Abstract: The effect of thymosin against tumor progression was examined in mice immunosuppressed by cytostatics or X-ray irradiation. When pretreated with cytostatic agents, such as 5-fluorouracil (5-FU) or BCNU, or by X-ray, and then inoculated with P388 or L1210 leukemias, mice died rapidly within a few days. In these systems, thymosin α1 given concomitantly with the cytostatic agents or after X-irradiation prevented rapid death and extended survival, although the mice eventually died with leukemia like normal mice inoculated with cells of the same tumor. Rapid death in the 5-FU-treated mice was also prevented by adoptive transfer of spleen cells from the donor mice if these had been treated with 5-FU plus thymosin α1, but not if they had received 5-FU alone. However, the restorative activity of the donor spleen cells was abrogated by treatment with anti-asialo GM1, but not by treatment with anti-Thy 1 or anti-mouse Ig serum, suggesting that the effector cells in the spleen are NK cells. In fact, thymosin α1, when given concomitantly with 5-FU or after X-irradiation, maintained the NK activity of spleen, which was damaged by treatment with 5-FU or X-irradiation alone. The present study indicates that thymosin α1 exerts a preventive activity against progression of leukemias at least in part through an effect on NK cells or their progenitor cells.

Tumor Progression Studied by Analysis of Cellular Features of Serial Ascitic Ovarian Carcinoma Tumors

Abstract: Seven consecutive ascitic tumors were obtained over a 9-month period from a patient with serous adenocarcinoma of the ovary The tumor cell populations were analyzed for cellular proliferation (labeling index, agar clonogenicity, and self-renewal capacity), for cell differentiation (cell surface expression of carcinoembryonic antigen and histochemical stain for fat accumulation), and for karyotypic changes Evidence is presented of increased aggressiveness of proliferative features together with a decreasing proportion of cells with differentiated features Parallel temporal changes were documented in density-volume characteristics of the tumor cell population, from small, high-density to large, low-density cells The only karyotypic change identified over this period was the loss of one X-chromosome and the increased frequency of cells containing double minute bodies The progressive characteristics described in this human tumor are not, therefore, associated with gross chromosomal changes The accumulation of double minute chromosome bodies may be associated with a low-dose methotrexate exposure or with the tumor progression

Immunology of metastasis. Can the immune response cope with disseminated tumor

Abstract: The application of immunologic methods to the treatment of neoplasia has been a goal of research in tumor immunology. Unfortunately, no clearly defined success for such therapy has been achieved. However, the most recent advances in tumor biology have provided for a more valid conceptual framework upon which to plan further research in this area. The more general awareness of tumor progression and heterogeneity, particularly in the context of tumor metastasis, while imposing a sense of gloom regarding all therapeutic modalities, shifted immunologic thinking toward the development of nonspecific modalities. We herein propose that this ‘shift’ may be premature and that immunotherapy using cytolygic T cells could still be feasible. Our views are based on newer approaches for selecting immunogenic variants of malignant tumors and a better understanding of the relationship of the immune response to metastases.

Fibronectin and its proteolytic fragments. Potential as cancer markers.

Abstract: Since the discovery of fibronectin as a transformation-sensitive 'cell surface' protein, it has been the focus of intensive studies. Fibronectin has multiple interactions and functions and is composed of distinguishing properties of malignant cells, properties. Invasiveness and metastasis, distinguishing properties of malignant cells, involve penetration through components of the extracellular matrix. Enzymatic degradation of matrix components is involved in these phenomena. Proteolytic targets of the pericellular matrices of cells in culture include fibronectin that has been found to be even selectively susceptible to proteinases. Defined fragments of fibronectin have transformation-promoting activity in experimental conditions and such fragments, detected in tumor patient body fluids, may serve as markers for tumor progression.

Histologic characterization of renal tumors (nephroblastomas) induced transplacentally in IIIVO/J and WH/J rabbits by N-ethylnitrosourea

Abstract: The histologic features of 63 renal tumors induced in 39 rabbits of two partially inbred strains, IIIVO/J and WH/J, by transplacental exposure to N-ethylnitrosourea (ENU) were analyzed. All tumors in the series conformed to nephroblastoma, permitting the establishment of histologic standards for this neoplasm in the rabbit as well as observations on tumor progression. Essentially, nephroblastoma proved to be predominantly an epithelial tumor identifying with metanephrogenic blastema, which was presumed to be the tissue of origin during fetal development. The outstanding features comprised clusters or sheets of undifferentiated blastemalike tissue and differentiation along the epithelial pathway into tubular profiles and structures suggestive of primitive, nonvascularized glomeruli. The latter were frequently of a complex nature, with a papillary configuration. On the other hand, no definitive evidence of bipotential differentiation into malignant secondary mesenchyme was found, there being no recognizable areas of fibrosarcomatous elements or specialized connective tissue such as smooth or striated muscle, adipose tissue, cartilage, or osteoid. Mesenchymelike fascicular disposition of neoplastic cells between blastemal clusters was an acquired feature seen in advanced tumors but not in small early lesions. By light microscopy alone it was not possible to determine whether this represented a conformational change of tumor cells or true bipotential differentiation into neoplastic secondary mesenchyme. However, the reticulin pattern was not characteristic of sarcoma. A conspicuous feature accompanying the growth and development of tumors was the magnitude of host fibrous reaction discernible only as a simple ramifying stroma in the earliest lesions but attaining impressive proportions both within and around the tumor with advancing age. Increasing collagen formation appeared to be associated with ischemic necrosis of tumor tissue. Other features of advanced tumors were the presence of discrete foci of differentiated tubular structures suggestive of mature medullary elements and small islands of squamoid differentiation. Metastases occurred only in rabbits of strain IIIVO/J, which had been subjected to a single dose of the carcinogen, representing an incidence in this subgroup of 25%. Nephroblastomas resulting from transplacental induction in IIIVO/J rabbits, particularly by single, high doses of ENU, appear to provide a suitable model for the predominant histologic form of the Wilms' tumor complex in man.

Combination chemotherapy of hepatocellular carcinoma with doxorubicin and streptozotocin.

Abstract: Twenty-three patients with unresectable hepatocellular carcinoma were given doxorubicin 60 mg/m2 I.V. day 1 and streptozotocin 0.5 g/m2 I.V. days 1-5 every 3 weeks. This regimen was chosen because of the activity of doxorubicin and nitrosoureas in hepatocellular carcinoma and the ability to administer both drugs in full doses. Twelve patients were fully ambulatory, 14 had normal serum bilirubin, 11 had pathologic proof of cirrhosis, and 11 had no known extrahepatic tumor dissemination. Partial responses lasting 10 and 14 months occurred in two patients (9%), one had stable disease for 15 months, 12 had documented tumor progression within 4 months, and eight died within 6 weeks of the start of chemotherapy. Median survival of all patients was only 3 months (range 0.3-27), but eight (35%) lived more than 1 year. Of these eight, two responded to doxorubicin and streptozotocin, another two to subsequent chemotherapy, and four had no tumor response whatever. More than 90% of the intended doses of doxorubicin and streptozotocin was administered, with severe leukopenia in three patients, moderate thrombocytopenia in one, and moderate proteinuria in nine. There were no drug-related deaths. Various physical, radiologic, and biochemical parameters were employed in detecting tumor response and progression. Initially abnormal physical examination of the liver, hepatic radionuclide and computed tomographic (CT) scans, and serum alpha-fetoprotein levels improved in both responding patients. Tumor progression was detected by physical examination (7/12), radionuclide (10/12) and CT liver scan (3/7), rising alpha-fetoprotein (5/12), and rising carcinoembryonic antigen (3/8). Physical examination and radionuclide liver scan together documented all tumor response and progression. The combination of doxorubicin and streptozotocin has only modest activity in hepatocellular carcinoma and appears no more active than doxorubicin alone.

Suppressor and reactive lymphocytes in radiation leukemia virus (RadLV)-induced leukemogenesis

Abstract: Suppressor cells capable of enhancing tumor growth in vivo and of abrogating a potential anti-tumor immunity in vitro are generated in C57BL/6 mice inoculated with the high-leukemogenic A-RadLV. Mice inoculated with low-leukemogenic D-RadLV do not develop suppressor cells but contain anti-tumor reactive lymphocytes that can inhibit in vivo tumor growth. Cyclophosphamide (CyF) treatment of mice inoculated with A-RadLV hampered suppressor cell function and rendered the animals' lymphocytes responsive to A-RadLV induced tumor cells in vitro. Administration of CyF also reduced leukemia incidence in mice inoculated with A-RadLV, but had no effect on leukemia induction by D-RadLV in irradiated mice. It is suggested that the high leukemogenic activity of A-RadLV depends on the virus' ability to recruit CyF-sensitive suppressor cells early in latency and that tumor progression in mice inoculated with D-RadLV is arrested due to the host immune response.

In vivo generation and selection of variants with altered sensitivity to natural resistance (NR): A model of tumor progression

Abstract: The stability of a cloned murine tumor for sensitivity to NR was examined following growth in vivo in order to test the hypothesis that tumor progression proceeds through the generation and selection of variants. Clonal sensitivity to the [131I]-dUrd elimination assay of NR was assessed for the L5178Y-F9 tumor grown in syngeneic DBA/2 mice or maintained solely in tissue culture. Subclones derived from a tumor obtained from the injection site 3 1/2 weeks after the s.c. inoculation of 25 cells were less sensitive to NR in comparison with subclones derived from cells grown only in vitro. Subclones from the cells grown in vivo exhibited increased heterogeneity in sensitivity to NR in addition to their expanded range of susceptibility to complement-mediated lysis by CBA serum natural antibodies. The extent of the heterogeneity argues against tumor "adaptation" forming the basis for the phenotypic alteration while chromosomal studies eliminate the possibility that a new tumor was induced. These data support the hypothesis that tumor progression proceeds through the random generation of variants and host-mediated selection for the proliferation of clones with an increased ability to survive.

Antitumor studies of 2-amino-2-thiazoline and other tumor-modifying agents.

Abstract: 2--amino-2-thiazoline (AT) and 1-thiazolidine-4-carboxylate (TC, thioproline), which have been previously proposed as agents of reverse transformation, have been examined as antitumor agents in several rodent tumor systems. AT administration reduced tumor incidence in sym-dimethylhydrazine treated outbred ICR Swiss female mice and doubled the survival of DBA/2Ha female mice infected with polycythemic Friend leukemia virus. Indomethacin, pentoxyphylline, RA233 and diethyldithiocarbamate (DTC), with potential for altering host or tumor prostaglandin levels, platelet aggregation and host immunity, respectively, ranged from marginally effective to ineffective against Friend virus infection. AT was, however, ineffective against 4 other induced and transplanted mouse tumors and did not notably increase differentiation or decrease transformation in any of several tumor cell systems. No in vitro or in vivo tumor system was found to be more than marginally affected by TC. Thus, AT alone was of significant antitumor activity in inhibiting late stages of viral- or carcinogen induced tumor progression, but could not be demonstrated as an agent of reverse transformation.

Spontaneous Phenotypic Shifts from Low to High Metastatic Capacity

Abstract: Tumor progression from low to high malignancy is believed to occur in multiple steps (1). Analogous to mutation/selection the process of tumor progression is thought to have its basis in the continuous emergence of successive clones of tumor cell variants, one gradually replacing another, through the intervention of natural or artificial selection pressures (2). Highly malignant metastasizing tumor cells have been shown to differ from low malignant non-metastasizing ones in a number of properties such as plasma membrane enzyme activities (3), cell surface antigen shedding (4), tumor antigenicity and immunogenicity (5). A critical question is whether all these specific properties have been accumulated in the metastatic cell in a stepwise fashion. Is each new property the result of a process of random variation and host selection? How can a random process result in the generation of cells endowed with not just one but a number of very specific properties that enable them to cross the various biological barriers of the host, to survive and grow in different microenvironments?

Phenotypic and genotypic differences between high- and low-metastatic related tumor lines and the problem of tumor progression and variant generation.

Abstract: We have described a number of phenotypic and genotypic differences between defined tumor sublines from the Eb/ESb model system that differ greatly in metastatic capacity. Some of these differences are summarized in Figure 5. It can be seen that the differences are both structural and functional. They include differences in the glycosylation of membrane glycoproteins as well as differences in total membrane protein composition. The functional differences refer particularly to enzymatic activities, cell motility, and invasive capacity. In addition, a change in membrane fluidity and membrane dynamics was seen when we investigated membrane vesicles shed spontaneously from these tumor lines. ESb type cells were found to shed about three times as much membrane material as the low-metastatic, Eb cells. Since such vesicles carried degradative enzyme activity, they could play a role in the invasion process. The vesicles also carried TATA and thus could also play a role in preventing immunological attack against these tumor cells. Another immunological escape mechanism was found to be based on the ability of the high-metastatic cells to generate immunoresistant variants that no longer expressed the respective TATA. A cytogenetic comparison of such immunoresistant variants with the TATA+ line revealed several chromosomal changes. The contribution of chromosomal rearrangements to the ability of malignant cells to generate variants was discussed.

Protective Activity of Thymosin α1 Against Tumor Progression in Immunosuppressed Mice

Abstract: Thymus gland has been shown to play an important role in the development, growth and function of lymphoid systems through a hormonal mechanism. One of the thymic hormones, thymosin (1), stimulates T cell development and corrects some immunodeficiency diseases resulting from lack of thymus functions. Considering the importance of T cells in immunoregulatory systems, thymosin is expected to be useful as a pharmaceutical agent for a variety of diseases which are caused by or which accompany the aberration of these systems.

Isolation, characterization, and culture of human mammary epithelial cells.

Abstract: Publisher Summary This chapter discusses the isolation, characterization, and culture of human mammary epithelial cells. Mammary cancer develops as a progressive series of changes from normal through various degrees of premalignant changes to frankly carcinomatous lesions. Even after the development of invasive potential, tumor progression continues as the tumor cells become more dedifferentiated and capable of rapid proliferation at various metastatic sites. A fundamental prerequisite for understanding the progression to malignancy of the human mammary gland is the ability to isolate, culture, and identify the mammary epithelial cells regardless of stage in malignant progression. Because there may be different pathways by which a mammary cell becomes malignant, it will be necessary to culture every specimen reproducibly. It is difficult to obtain specimens of premalignant lesions because these lesions are usually small and required by the pathologist to rule out possible areas of frank malignancy. However, it is known that breast tissue peripheral to a carcinoma contains numerous atypias and hyperplasias. The properties used to identify the cultured cells as mammary epithelial in origin are presented in the chapter. In a study described in the chapter, when the primary cultures were allowed to remain confluent for several weeks, they formed dome-like structures.

The spectrum of human lung cancer cells in culture: a potential model for studying molecular determinants of tumor progression and metastasis.

Abstract: We have reviewed the behavior of human lung cancer cells in culture. We have considered the implications of cell biology and biochemistry studies of the cultured cells for the in vivo behavior of lung neoplasms, including the metastatic potential of the different tumor types. Among the human lung cancers, SCC, which grows in culture as suspended aggregates of adherent cells, metastasizes earlier in the life cycle of the tumor and more widely than the major types of non-SCC lung cancers. These latter tumors grow as anchorage-dependent cells in culture. We have pointed out that ultrastructural studies of cultured human lung cancer cells reveal dramatic changes in cell surface membrane morphology coincident with progressive loss of SCC features and intercellular adhesion. We have stressed the potential value of these cultures of human lung cancer cells for studying the molecular determinants of intercellular adhesion and their importance to the process of metastasis. In this context, we have stressed that a different cell surface protein phenotype exists between SCC and non-SCC lung cancer cells in culture and that some of these proteins could be intimately involved in the different growth behavior patterns of these tumor cells. Finally, we have pointed out the need to construct models in which the growth characteristics and biochemical properties of cultured lung cancer cells can be directly compared in vivo with their metastatic potential.

Immunoprophylaxis of an Ocular Solid Malignant Tumor in Cattle

Abstract: Individual Hereford cows bearing benign precursor lesions of ocular squamous cell carcinoma were treated by intralesional injection of mycobacterial cell walls in an oil-in-water emulsion in an attempt to interrupt neoplastic progression. Thirty-one months after treatment, statistical analysis of data indicated that intralesional BCG cell wall vaccine can interrupt this process and provides effective immunoprophylactic prevention of malignant disease.