Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Invasion and extravasation of tumor cells through blood vessels and the capillary bed of different organs provide a major pathway for the dissemination and metastatic spread of neoplastic cells. In order to investigate this process in vitro, cloned lines of the low-metastatic methylcholanthrene-induced DBA/2 T lymphoma Eb and its highly metastatic variant line ESb were compared for their mode of interaction (attachment, invasion and morphological appearance) with a confluent monolayer of cultured vascular endothelial cells and with the subendothelial extracellular matrix (ECM). Both the Eb and ESb lymphoma cells exhibited a much faster and firmer attachment to the subendothelium than to the apical surface of the endothelial cell layer. Whereas the Eb cells mostly retained their spheroidal shape when attached to the subendothelium, the ESb cells adopted within 5-24 h a flatter morphology and 30-40% of the cells exhibited an extension of a long pseudopod. Invasion through the endothelial cell layer was faster and occurred to a higher extent with ESb than with Eb cells and was most frequently seen at the edges of an artificial wound made to locally expose the subendothelial basal lamina. Lymphoma cell invasion was most often initiated by a cytoplasmic process indenting at junctions between adjoining endothelial cells and less often traversing through intact cells. Invasion was followed by regeneration of the endothelium and sealing of the invasive cells from the exterior environment. These findings corroborate and extend previous observations on endothelial cell penetration and basement membrane attachment and degradation by various types of metastatic tumor cells. The major new observation comes from the striking contrast in morphological appearance and dynamic behavior between the high- and low-metastatic cells of this tumor system after contact with endothelial cells or their ECM. This suggests a critical role of pseudopod formation and cell motility in endothelial cell penetration and invasion, and thus in an essential step in cancer metastasis.
Invasion Metastasis 1983
PMID:Lymphoma cell interaction with cultured vascular endothelial cells and with the subendothelial basal lamina: attachment, invasion and morphological appearance. 667 23

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

Properties of Ts, a long-term tissue culture line of T1699 mammary adenocarcinoma of DBA/2 mice, and two of its sublines - TR2 and TLI-1-were comparatively studied. Ts tumors produced no spontaneous metastases, nor did i.v. injection of up to 1 X 10(6) Ts cells produce a lung tumor nodule. Ts cells were susceptible to macrophage cytotoxicity in vitro and i.v. injected cells were rapidly destroyed in the lungs. TLI-1 tumors spontaneously metastasized to the lungs, and i.v. injection of 1 X 10(3) TLI-1 cells produced approximately 15 lung nodules per animal. TLI-1 cells were least susceptible to both macrophage-mediated cytolysis in vitro and in vivo host antitumor mechanisms. TR2 cells were intermediate with respect to all these properties. Differences in their susceptibility to macrophage cytotoxicity were recognized not only by normal peritoneal macrophages but also by murine macrophage lines. On the other hand, all the subpopulations were uniformly resistant to NK activity in vitro. These findings suggest that resistance of tumor cells in vitro to macrophage cytotoxicity corresponds with their in vivo metastatic potential.
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PMID:Heterogeneity of murine mammary adenocarcinoma cell subpopulations. In vitro and in vivo resistance to macrophage cytotoxicity and its association with metastatic capacity. 669 96

Intravenously (i.v.) or subcutaneously (s.c.) injected T1699 tumor cell subpopulations (Ts, and TLI-1) were destroyed more rapidly in BALB/c nu/nu athymic mice than in syngeneic DBA/2J mice. The number of artificial pulmonary metastases of TLI-1 tumors was significantly lower, and the growth rate of s.c. Ts, and TLI-1 tumors was correspondingly slower in the nude mice. No macroscopic outgrowth of pulmonary metastases of Ts tumors was detected in either group of s.c. tumor-bearers, even though the s.c. tumors progressed and killed the hosts. Unexpectedly, however, s.c. implantation in normal DBA/2J mice of lung homogenates not only from DBA/2J but also from s.c. Ts tumor-bearing BALB/c nu/nu mice produced tumors, suggesting that significant numbers of clonogenic Ts cells were present in the lungs of animals without spontaneous outgrowth of pulmonary metastases. Perturbations of s.c. Ts tumor-bearing DBA/2J or BALB/c nu/nu mice with immunosuppressive drugs or with anti-mouse thymocyte serum, respectively, induced rapid outgrowth of pulmonary metastases.
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PMID:Immunological responses to a murine mammary adenocarcinoma. Outgrowth of pulmonary occult metastases induced by immunosuppressive perturbations. 669 97

The effects of the specific active cancer immunotherapy utilizing autologous tumor tissue particles polymerised with ethylchlorformiate, and used in combination with PPD tuberculin, were studied with respect to the growth of mastocytoma (P-815 X 2) in DBA/2 mice. As a control material, animals not immunised or immunised only with the nonspecific reticuloendothelial system stimulator, PPD tuberculin, were used. The frequency of the tumor metastases in the organs surveyed (lymph nodes, spleen, liver, kidney, lung and thymus) was lowest in mice having received the specific immunotherapy regimen. Similarly, the signs of tumor rejection by the host (tumor-associated fibrous scar, lymphocyte and plasma cell infiltration, and disappearance of the tumor tissue totally or subtotally) were found to be most pronounced in this series of mice. The findings were discussed against the background of the successful clinical trials made with this mode of specific cancer immunotherapy during the recent few years in patients whose neoplasia had escaped the reach of conventional cancer therapy. The findings were also discussed in the light of the mechanisms involved in cancer immunity in general, and a conclusion was drawn that this kind of specific active cancer immunotherapy seems to exert beneficial effects on the host's immune system, and thus seems to contribute to tumor rejection by the host.
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PMID:Experimental cancer immunotherapy in DBA/2 mouse-mastocytoma model utilizing autologous tumor tissue polymerised with ethylchlorformiate. 677 79

B10.D2 mice (H-2d) were found to be able to reject more than 10(6) cells of the DBA/2 (H-2d) tumor ESb, while DBA/2 mice could not reject even small (less than 10(1) cells) tumor cell inocula and died within a few weeks from the developing internal metastases. Chimaeric mice and F1 hybrids between DBA/2 and B10.D2 were susceptible to the tumor and its metastases, suggesting that tumor resistance was dependent on the ability of the host to recognize DBA/2 minor alloantigens. About two thirds of the (DBA/2 X B10.D2) F2 generation mice were ESb tumor-resistant. Also, the majority of C57B1/6 X DBA/2 recombinant inbred strains (BXD RI lines) of H-2d type were found to be able to reject ESb tumor cells. There was no apparent linkage of tumor resistance to coat color genes. Mls locus, or immunoglobulin heavy chain genes. It is suggested that tumor resistance in these mice was dependent on the recognition of several DBA/2 minor histocompatibility antigens such as H-1 and H-4. The most resistant of the BXD RI strains, BXD-6, was shown to react to minor DBA/2 antigens by the production in vitro of interferon and of cytotoxic cells. These cellular immune reactions were not observed in one of the less resistant strains, BXD-28, suggesting a close relationship between tumor rejection and the capability to produce interferon and cytotoxic lymphocytes.
Invasion Metastasis 1981
PMID:Immunogenetic studies on the resistance of mice to highly metastatic DBA/2 tumor cell variants. II. Influence of minor histocompatibility antigens on tumor resistance, gamma-interferon induction and cytotoxic response. 682 64

The evolution towards more aggressive and autonomous behaviour of many cancerous tumours, often referred to as tumour progression, is thought to stem from the development of heterogeneity within the tumour cell population, combined with the continuous selection of progressively more malignant cellular phenotypes. During the course of the disease, the tumour cells show multiple phenotypic changes in a stepwise, but apparently random fashion, becoming more anaplastic, increasingly independent of growth controls and more metastatic. Several laboratories, including our own, have analysed aspects of tumour heterogeneity and cancer metastasis by selecting and studying the properties of lectin-resistant (LecR) membrane mutant tumour sublines; in a few cases, such variants have been claimed to be less tumorigenic or metastatic than the parental cells from which they were derived. We have attempted to study the factors involved in the reestablishment of tumour heterogeneity by monitoring the stability in vivo of LecR phenotypes of metastatic tumour cells after injection of cloned LecR tumour cells. We now report that spontaneous metastases arising after a subcutaneous (s.c.) injection of cells from variant tumour lines selected from a highly metastatic DBA/2 mouse tumour known as MDAY-D2, and which are stably resistant in tissue culture to wheat germ agglutinin (WGA), no longer carry the WGA-resistant (WGAR) phenotype. The results demonstrate that WGAR tumour cells do not metastasize, but rather, 'revertants' for the WGAR phenotype, which presumably were generated in vivo after injection, were the cells actually capable of metastatic growth.
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PMID:Apparent reversion of stable in vitro genetic markers detected in tumour cells from spontaneous metastases. 689 84

The MDAY-D2 tumor of DBA/2 origin metastasizes widely and predictably in syngeneic DBA/2 mice, as well as in allogeneic athymic mice. BALB/c mice, which are H-2 compatible with MDAY-D2, reject the tumor based on non-H2 histocompatibility antigens. This rejection corresponds directly with the generation of a "low-level," in vitro, cell-mediated cytotoxic response in ipsilateral peripheral lymph nodes and spleen. Production of cytotoxic antibody also occurs during tumor rejection. Previous work has demonstrated the effectiveness of adoptively transferred, sensitized BALB/c lymphocytes in eliminating preexisting visceral metastases in BALB/c athymic mice. The present study shows that in this model the complete regression of H-2-compatible allografts, in the form of preexisting metastases, correlates directly with the ability of adoptively transferred cells to mediate low-level, cell-mediated cytotoxicity in vitro. Both graft rejection in vivo and cell-mediated cytotoxicity in vitro are mediated by T cells. Enriched sensitized B cells and anti-MDAY-D2 serum are both incapable of mediating this graft rejection in vivo. Based on these findings, we conclude that relatively weak in vitro cell-mediated cytotoxic responses should not be dismissed as biologically insignificant, for they may be indicative of considerable immune potential in vivo.
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PMID:Immune regression of visceral metastases in athymic mice. Correlation of "low-level" in vitro cell-mediated cytotoxic reactions with allograft rejection in vivo. 696 91

The L5178Y-cell tumor dormant state in DBA/2 mice is an excellent model for assessing immunologically mediated tumor-growth restraint mechanisms associated with establishment and control of a tumor dormant state. It has enabled us to relate components of the host's tumor suppressive immune system to the stage of tumor dormancy and the magnitude of the tumor burden. A strong CTL response has been associated with establishment of the tumor dormant state and can be reelicited in vivo or in vitro, after its initial decline, by reexposure to tumor antigen. This reelicitation is mediated via immunologic stimulation of memory CTL. Combined cultures of NAD T-lineage lymphocytes and macrophages from tumor dormant mice produce considerable cytolytic activity where little or no activity can be detected in the individual populations. Based on the similar pattern of tumor target cell specificity of the two responses, it is likely that memory CTL contribute to this synergistic cytolytic activity. The synergistic cytolytic response persists after CTL activity has waned to undetectable levels and is probably the predominant cytolytic activity associated with maintenance of the tumor dormant state. However, this activity may be obscured by proliferation of endogenous tumor cells, which in turn triggers direct macrophage-mediated cytolytic activity. The target cell specificity of this direct macrophage-mediated cytolytic response is also similar to the CTL response suggesting T cell (or memory CTL) involvement in its generation. The L5178Y-cell tumor dormant model is well suited for attempts at cure with immunotherapy. Active specific and nonspecific immunotherapy are each capable of eliminating all tumor cells from approximately 50% of tumor dormant mice. The L5178Y-cell tumor dormant state is one of several animal models of tumor dormancy. The great variety of growth restraint mechanisms that control tumor dormant states in animal systems is strong evidence that tumor dormant states exist in cancer in human beings.
Cancer Metastasis Rev 1982
PMID:Establishment and control of the L5178Y-cell tumor dormant state in DBA/2 mice. 698 47

Antigenic variation in cancer metastasis was observed in a syngeneic murine tumor system consisting of a low metastatic parental tumor line (derived from a methylcholanthrene-induced DBA/2 T lymphoma, Eb), a high metastatic spontaneous variant thereof (ESb), and a low metastatic 'revertant' from ESb (ESb-M). All three lines expressed tumor-associated transplantation antigens (TATA) which elicited specific T cell-mediated antitumor immune reactions in the host. The strongest host response was elicited upon intradermal inoculation. It could be followed by (a) the infiltration of the locally growing tumor by host cells, such as lymphocytes and macrophages, (b) the establishment of specific systemic antitumor immunity, (c) the generation of immune cells capable of transferring protective antitumor immunity into a normal syngeneic recipient, and (d) the generation of tumor specific cytotoxic T lymphocytes (CTL). Anti-TATA CTL were used as typing reagents to investigate the stability or variability in the TATA expression by cloned tumor cell lines. Antigenic variability in the TATA expression was seen under various conditions: (a) clone-dependent variation in the sensitivity to anti-TATA CTL lysis upon prolonged growth in tissue culture, (b) qualitative change in the TATA (TATA1 leads to TATA2) upon successive i.p. transplantation of the parental Eb tumor line and, (c) generation of TATA negative immune escape variants (TATA2 leads to TATA-) during metastasis formation from a s.c. site. The relative inefficiency of specific immunization procedures against ESb was found to be due to the effective generation of TATA negative variants by this highly metastatic tumor. The balance between immune control and immune escape could be influenced to the advantage of the host by some means, for instance optimizing the route of antitumor-immune sensitization or by infusion of allogeneic but H-2 identical antitumor-immune T cells. Such immune cells recognized the tumor via minor histocompatibility antigens and thus circumvented the need of TATA recognition. Finally, manipulations at the cell surface of the highly malignant ESb tumor such as those introduced in the ESb-M variant were found to dramatically effect its metastatic potential.
Cancer Metastasis Rev 1982
PMID:Antigenic variation in cancer metastasis: immune escape versus immune control. 698 48


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