UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Class I antigens encoded in the major histocompatibility complex (MHC) (HLA in man, H-2 in the mouse) play a key role in the recognition of target cells by cytolytic T lymphocytes. Tumor cells frequently do not express class I MHC molecules, which strongly suggests that down-regulation of the latter facilitates escape of tumor cells from immune surveillance. The expression of class I MHC genes is tightly regulated. An enhancer element, conserved in the promoters of mouse and human MHC genes, has been shown to be important for mouse class I MHC gene expression. At least two related regulatory factors (KBF1 and NF-kappa B) bind to this regulatory element. We have analyzed the binding of these factors in cellular extracts of 23 human tumor cell lines displaying various levels of class I mRNA and surface expression. In this panel, combined deficiency of KBF1- and NF-kappa B-like DNA-binding activities was frequent among the class I-negative cell lines and correlated with the absence of class I mRNA. A few cell lines that lack KBF1 binding activity still display NF-kappa B-like activity and express normal levels of MHC class I mRNA. These results suggest (i) that, in the absence of KBF1, NF-kappa B or a related factor promotes MHC class I gene transcription; and (ii) that a combined defect in KBF1/NF-kappa B DNA-binding activity can cause a pleiotropic defect in class I gene expression, which may facilitate tumor progression.
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PMID:Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression. 156 43

Class I major histocompatibility complex (MHC) antigen expression in neuroblastoma may play a role in the oncogenicity of this embryonal tumor of childhood. Since N-myc amplification in neuroblastoma tumors is associated with rapid tumor progression (33) and N-myc decreases Class I MHC antigen expression in rat neuroblastoma cells (21), we quantitated levels of N-myc mRNA and Class I MHC cell surface antigens in a panel of 24 human neuroblastoma cell lines. We found that N-myc expression is not invariably associated with low levels of beta 2-microglobulin (B2M) and Class I MHC antigen expression. As we considered that Class I MHC antigens may be regulated in association with the differentiation stage of the neuroblastoma tumor, we examined the expression of B2M during development of the human adrenal medulla, the tissue of origin of most neuroblastomas. We found that B2M is a marker of differentiated adrenal medullary cells, expressed late during the third trimester of development. Moreover, using morphological and immunological criteria, we found that B2M is expressed in differentiated tumor cells. These data suggest that the expression of B2M in neuroblastoma is associated with the stage of differentiation of the tumor cell and not N-myc expression. Furthermore, these findings suggest that neuroblastomas may correspond to the arrested differentiation of adrenal neuroblasts at different stages of development.
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PMID:Beta 2-microglobulin expression in human embryonal neuroblastoma reflects its developmental regulation. 218

A study was undertaken to determine the ability of the DNA hypomethylating drug 5-aza-2'-deoxycytidine (5-azadCyd) to induce antigen expression in a high proportion of treated tumor cells and to evaluate if this effect could be mimicked by the drug hydroxyurea (HU) which is a genomic DNA hypermethylating agent. Induction of heritable changes in gene expression by 5-azacytidine or the 2'-deoxy analogue (5-azadCyd), at least in some cases, may not be necessarily due to their hypomethylating properties, but to some other induced high frequency genetic change which occurs when DNA synthesis or repair is perturbed. A comparison of 5-azadCyd and HU effects on human and murine tumors was chosen for this study. The phenotypic properties examined with the above treatments were (a) induction of a Mr 110,000 antigen, detected with M111 antibody, in a variant subpopulation (SMeLus7) of human melanoma cells which fail to maximally express this antigen (M111). The parent cell line, MeWo, and other MeWo-derived variant cell cell lines do not demonstrate a similarly inducible phenotype; and (b) induction of class I major histocompatibility complex antigens in a population of mouse mammary adenocarcinoma cells which normally fail to express these antigens. The results showed that 5-azadCyd was effective in inducing antigen expression in both systems whereas HU was effective (and equally so) only in the human melanoma cell line system. In these treatments 5-azadCyd was demonstrated to transiently hypomethylate the same human melanoma cell line whereas HU hypermethylated genomic cytosines. The results suggest that some of the reported effects of 5-azacytidine or 5-azadCyd in inducing very high frequency heritable phenotypic alterations may not necessarily be related to the drugs' ability to cause DNA hypomethylation. The implications of these results are discussed in terms of the use of 5-azacytidine or 5-azadCyd and the effects of chemotherapy on tumor progression and metastasis.
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PMID:Heritable high frequency modulation of antigen expression in neoplastic cells exposed to 5-aza-2'-deoxycytidine or hydroxyurea: analysis and implications. 245 61

Three independent variants with a profound reduction of cell surface H-2 have been selected from the C57BL/6 mouse-derived RBL-5 and EL-4 T lymphomas. After subcutaneous inoculation of low cell doses in syngeneic mice, the H-2- variants failed to grow out, whereas the H-2+ control lines showed progressive growth. No difference in growth rate or cloning efficiency was detectable in tissue culture. The in vivo difference in tumor outgrowth was analyzed in detail for one of the H-2-low lines. The outgrowth difference remained after the H-2-low variant and the control line had been injected subcutaneously in opposite flanks of the same mouse, and it was not dependent upon activity of mature T cells, since the same result was seen in athymic nude mice. The difference was partially sensitive to irradiation of the hosts. When mice were pretreated with anti-asialo GM1 antiserum, known to depress natural killer (NK) cell activity, the difference in outgrowth was abolished, and both the control line and the H-2- variant showed progressive growth in vivo. Experiments comparing the distribution and survival of isotope-prelabeled variant and wild type cells indicated that a rapid elimination of the former took place within 24 h after intravenous injection. These differences in tumor elimination were not seen in mice treated with anti-asialo GM1 antiserum. We conclude that the reduced tumorigenicity of sublines with impaired H-2 expression is largely, if not exclusively due to rapid elimination by NK cells. These findings may reflect an inverse, indirect relation between factors controlling H-2 expression and NK sensitivity. Another possible explanation is that major histocompatibility complex (MHC)-encoded gene products are directly involved in a regulatory signal in the NK cell system. According to this interpretation, immunological selectivity in the NK cell system would be achieved by the failure to recognize self-MHC, irrespective of the presence of foreign antigens, i.e. by detection of no-self rather than of nonself. This may also explain previous observations on H-2-linked hybrid resistance against lymphoid grafts and changes in H-2 phenotypes associated with tumor progression.
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PMID:Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. 387 76

Avian-leukosis-free females from Regional Poultry Research Laboratory (RPRL) inbred lines 6(1) and 7(2) were inseminated with pooled semen from RPRL line 15I5 males. The progeny resulting from the two crosses 15I5 X 6(1) and 15I5 X 7(2) were of the B2/B15 major histocompatibility complex (MHC) genotype, the B2 haplotypes from lines 6(1) and 7(2) being indistinguishable. When challenged with Rous sarcoma virus (RSV) at 6 weeks of age, 30 out of 31 progeny of cross 15I5 X 6(1) developed tumors that rapidly regressed, whereas 26 of 29 progeny of cross 15I5 X 7(2) died with progressive tumor growth. On the other hand, 15 of 18 B2/B15 segregants from the three-way cross (15I5 X 6(3]F1 X 7(2), identical in source to the MHC of the (15I5 X 7(2]F1 progressors, were characterized by tumor regression. Thus influences associated with non-MHC background genes from lines 6(1), 6(3), and 7(2) appeared to be critical to host response to RSV-induced sarcomas. Similar findings suggesting a strong non-MHC influence on anti-sarcoma response were obtained using 107 F2 and 77 backcross progeny of RPRL line 100 and noninbred University of New Hampshire (UNH) line 105. The B2 haplotype of line 100 was associated with tumor regression when combined with the line 105 background and with tumor progression when expressed on the line 100 background. Suppression of the anti-tumor response associated with line 100 appeared to be fairly generalized, since a poor response to tumor was observed regardless of which of three subgroups of RSV was used to induce tumor.
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PMID:A non-MHC genetic influence on response to Rous sarcoma virus-induced tumors in chickens. 609 53

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.
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PMID:Spontaneous fusion in vivo between normal host and tumor cells: possible contribution to tumor progression and metastasis studied with a lectin-resistant mutant tumor. 668 20

Intrafootpad inoculation of syngeneic mice with Lewis lung carcinoma (3LL) cells led to the growth of a solid tumor at the site of transplantation, followed by development of metastases in the lungs. Surgical excision of the primary tumor resulted in an accelerated growth and increased incidence of pulmonary metastases. Inasmuch as 3LL tumor cells isolated from the local tumor differed antigenically from the cells isolated from the metastases, the genetic control of the local 3LL tumor growth and that of its lung metastases were tested. The local tumor grew in allogeneic mice, yet its growth rate was higher in syngeneic and semiallogeneic F1 hybrids than in allogeneic recipients. However, lung metastases did not appear in allogeneic animals. By analysis of the rate of growth of the local tumor in congenic mouse strains, the tumor progression appeared to be linked to the host's genetic background rather than to the H-2 region. The generation of lung metastases required compatibility at both background and H-2 haplotype. Tests of the development of metastases in mice of congenic resistant recombinant strains revealed that metastases developed only in animals that shared with the tumor the gene products of the D-end of the major histocompatibility complex. Thus metastasis formation was controlled by both a non-H-2 gene(s) and a gene(s) linked to the H-2D region or another nearby region to the right of H-2D.
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PMID:Control of progression of local tumor and pulmonary metastasis of the 3LL Lewis lung carcinoma by different histocompatibility requirements in mice. 693 34

The major histocompatibility complex (MHC) class II genes encode surface molecules that are required for presentation of antigenic peptides to helper T-cells. The concentration of these proteins on the surface of effector cells (antigen-presenting cells such as B-cells and macrophage) is one of the parameters affecting the intensity of the immune response. Many studies have thus focused their attention on the mechanisms that control the expression of class II genes, particularly in B-cells. The anatomy of MHC class II promoters has been dissected in detail, and many trans-acting factors and their cognate DNA regulatory elements have been identified and characterized, thus helping to elucidate the molecular circuitry which determines tissue-specific, coordinate expression of these genes. In most cases, regulation has been investigated at the level of mRNA transcription. MHC class II gene expression has been observed as well, under physiological conditions, in many other tissues and organs such as brain, thyroid, thymus, and intestine, thus implying that class II molecules may be involved, whether directly or indirectly, in the modulation of other important biological responses in addition to the control of the immune reaction against soluble antigens. Spurious MHC class II activity is also detected in tumor cells and in other pathological conditions such as those found in autoimmune, inflammatory, and infectious diseases. In autoimmunity, cells that express class II molecules may present tissue-specific antigens, thus triggering a mechanism of self-destruction. In tumors, instead, unscheduled MHC class II expression may be part of a mechanism that prevents tumor progression. Comprehension of the regulatory functions operating in pathological conditions as compared to those active in B-cells and in macrophages is still rudimentary. Because of the possible pathogenetic importance of aberrant class II expression, knowledge of the cis- and trans-acting elements controlling gene expression at either the transcriptional or posttranscriptional level may allow the development of strategies for immunointervention against these diseases.
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PMID:Control of MHC class II gene expression in autoimmune, infectious, and neoplastic diseases. 811 Mar 78

Tumorigenesis in mice of the rat insulin promoter [RIP]-simian virus 40 tumor antigen [SV40 Tag] transgenic lineages, RIP1-Tag2 and RIP1-Tag4, is a process initiated by expression of SV40 Tag in pancreatic beta cells, evolution of islet cell hyperplasia and insulinoma appearance. Analysis of major histocompatibility complex [MHC] class I gene expression during this process revealed a normal level of MHC class I molecules at the surface of pancreatic islet cells of RIP1-Tag4 mice, while hyperplastic islets from the same mice contained cells expressing a normal level and cells expressing a low level of MHC class I antigen. Insulinomas themselves expressed very low levels or no MHC class I gene product. Thus, down-regulation of MHC class I gene appears to accompany tumor progression of SV40 Tag-transformed beta islet cells. MHC class I antigen expression in a series of clonally derived cell lines of beta cell origin from different SV40 Tag-induced insulinomas ranged from quite low to undetectable, although expression was inducible by interferon-gamma. Nuclear run-on and transient transfection analyses indicated that expression of the MHC class I gene in these cells in controlled at the transcriptional level, and that the decreased expression is paralleled by reduced binding of transcription factors to the R1 element of the H-2 enhancer.
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PMID:Down-regulation of MHC class I antigen in insulinoma cells controlled by the R1 element of the H-2 enhancer. 813 22

Many human as well as experimental tumours, including melanoma, express reduced levels of major histocompatibility complex (MHC) Class I antigens. Decreased MHC Class I antigen expression may be selected during neoplastic progression because it allows tumour cells to escape killing by cytotoxic T lymphocytes. Furthermore, the regulatory role of MHC Class I antigens in the proliferation of T cells suggests that abnormalities in MHC Class I antigen expression may play a role in the disordered proliferation of malignant cells and in their metastatic potential by non-immunological mechanisms. This paper reviews some of the available evidence supporting the concept of non-immune functions of MHC Class I antigens in the biology of malignant cells, with emphasis on experimental models for metastatic melanoma.
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PMID:Modulation by MHC class I antigens of the biology of melanoma cells. Non-immunological mechanisms. 821 62

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