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)

Adhesion to vascular endothelium is a primary step in the colonization of select target organs by blood-borne cancer cells. Previous studies in our laboratory have shown that adhesion is followed by the establishment of fully functional gap junctional channels between the arrested tumor cell and the endothelium and that gap junctional communication might play an important role in extravasation. Here we report on a critical interdependence between endothelial cell adhesion and communication of lung-metastatic cancer cells. Gap junctions are assembled at focal adhesion contacts between tumor cells and endothelial cells where they mediate metabolic coupling between the junction-forming cell pair. The level of coupling depends on sufficient amounts of connexin43 (cx43) protein expression by both cell partners and, in a rate-limiting fashion, on the expression level of the receptor/ligand pair that mediates adhesion between tumor cells and the endothelium. This conclusion is based on our findings that (a) tumor cells with equal cx43 message, yet different adhesion potential for endothelial cells, differ significantly in their level of communication with the endothelium (e.g., R230AC-MET vs. R3230AC-LR), and (b) gap junctional communication between B16-F10 melanoma cells and lung-matrix-modulated endothelium can be effectively blocked by antiadhesive, anti-Lu-ECAM-1 monoclonal antibody 6D3 and by soluble Lu-ECAM-1. Significantly increased adhesion and communication levels in highly lung-metastatic carcinoma cells imply a role of gap junctional coupling in cancer metastasis, presumably by facilitating extravasation.
Invasion Metastasis
PMID:Adhesion-mediated gap junctional communication between lung-metastatatic cancer cells and endothelium. 765 9

Even though the liver is a relevant metastatic site for several human malignant tumors, mechanisms or organ-specific metastasis to the liver remain largely unknown. In the following paper we summarize the results obtained with different murine model systems which have been set up to elucidate the above mechanisms, and describe our own results with two murine models: the F9 teratocarcinoma and the B16 melanoma. While the F9 teratocarcinoma model system underscores the roles of both adhesion and growth stimulation in the target organ, the B16 melanoma model strengthens the relevance of paracrine growth stimulation. Moreover, B16 melanoma cells selected in vivo for increased liver colonization ability appear to depend on cell-to-cell contact with hepatocytes in order to gain efficient growth stimulation. When we next tried to identify the molecule(s) responsible for the growth effect in a liver plasma membrane extract, we found that such activity was mediated by two closely related protein bands. These turned out to be two different forms of transferrin (Tf), one of which is specifically present on the hepatocyte surface. Moreover, when we analyzed the different B16 lines for the expression of c-Met[the receptor for the hepatocyte growth factor-scatter factor (HGF/SF)], we found that liver-specific LS9 had more of this protein than lung-specific F10 or parental F1, suggesting a role for HGF/SF in liver colonization by B16 melanoma cells.
Invasion Metastasis
PMID:Murine models of liver metastasis. 765 28

The results presented here further characterize four murine monoclonal antibodies (mAb) that recognize melanoma-specific antigens (9B6, T97, 2-3-1 and 2-3-3). These melanoma-specific mAbs are of the IgG2b isotype and are significantly therapeutic when administered systemically against established pulmonary melanoma metastases. Here we show a consistent and significant inhibition of the growth of melanoma lung metastases by all four mAbs and the existence of a time 'window' at days 5-8 after tumor inoculation for optimal therapy. Since these mAbs were found not to be cytotoxic or cytolytic in vitro, we looked for host immune response regulation as being responsible for the therapeutic effects. Natural killer (NK) cells were implicated as one arm of the host immune system involved in this response since depletion of NK cells in vivo by alpha asialoGM1 or alpha NK1.1 antibodies partially abrogated the inhibitory effect of the mAbs. The observed antimetastatic effects could also be partially abrogated using antibodies directed against the T-cell subset surface markers, CD4+ and CD8+. Intramuscular melanoma tumor growth was also found to be suppressed by mAb 2-3-1, but only if administered in the area of tumor growth and only if multiple inoculations are administered over a 13-day period. The beneficial effect of mAb antimetastatic therapy was found to be useful against several syngeneic melanomas, including JB/MS, B16 and several sublines of the B16 F10 melanoma.
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PMID:Further studies of the therapeutic effects of murine melanoma-specific monoclonal antibodies. 790 33

The therapeutic efficacy of active immunization with B16-F10.9 melanoma cells transfected with syngeneic major histocompatibility complex (MHC) class-I genes, modified by infection with Newcastle Disease virus (NDV) or modified by both treatments, was compared. B16-F10.9 tumor-bearing mice were treated at various stages of tumor growth and metastasis with irradiated, modified tumor-cell vaccines. Irradiated tumor cells and H-2Db transfectants did not stimulate anti-tumor immunity while H-2Kb transfectants and NDV-modified F10.9 cells showing low and high expression of MHC class-I genes efficiently prevented metastasis of small established tumors. NDV-modified parental-cell vaccines functioned optimally and improved overall survival by about 60%, also at early stages of metastasis establishment. A synergistic effect of H-2Kb expression and virus modification on rejection of micrometastases was observed in mice bearing advanced tumors. Postoperative vaccination of mice carrying multiple metastases with NDV-modified vaccines caused significant, but incomplete, reduction of metastatic tumor load. The therapeutic effect of NDV-modified tumor vaccines was dependent on multiple immune mechanisms. Depletion of CD8, CD4 or NK cells by in vivo treatment with monoclonal antibodies reversed the immunotherapeutic effects of the vaccine. Thus, tumor xenogenization and gene modification may act synergistically to vaccinate against advanced tumors, while single modalities can effectively vaccinate against metastasis at early stages of tumor growth.
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PMID:Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). 798 21

We investigated the respective roles of specific adhesion and paracrine growth stimulation in preferential liver colonization by an in vivo selected B16 murine melanoma cell line (B16-LS9). Comparison of B16-LS9 cells with a lung-specific B16 melanoma cell line (B16-F10) revealed no significant differences between their adhesion properties in vitro, or their immediate organ retention pattern in vivo after tail vein injection. In contrast, B16-LS9 cells grew at slower rates in vitro than B16-F10, unless hepatocytes in coculture, or a liver plasma membrane-extract, were present. In vivo, tumors produced by B16-LS9 cells after subcutaneous or intrafootpad injection also grew at slower rates than those produced by B16-F10, and appeared to progressively lose their liver specificity. However, after intravenous (tail vein) or intrasplenic inoculation, liver colonization was much more pronounced with B16-LS9 than B16-F10 cells. These data indicate that liver colonization by the B16-LS9 cell line depends primarily on the inability of these cells to grow efficiently at sites other than the liver. The liver can indeed provide these cells with a growth-stimulating factor which we found associated with its plasma membrane fraction (i.e. juxtacrine growth stimulation).
Invasion Metastasis 1993
PMID:Paracrine growth response as a major determinant in liver-specific colonization by in vivo selected B16 murine melanoma cells. 803 43

The antitumor efficacy of recombinant murine interleukin-1 alpha (rMuIL-1 alpha) was evaluated either alone or in combination with recombinant human hybrid interferon alpha A/D (IFN-alpha A/D) against the murine B16 F10 malignant melanoma. Treatment of subcutaneous tumor-bearing mice intraperitoneally with rMuIL-1 alpha resulted in a dose-dependent inhibition of tumor growth with the greatest activity obtained with the maximum tolerated dose of rMuIL-1 alpha (10 micrograms per treatment). Augmented tumor inhibition comparable to that seen in mice treated with a high dose of rMuIL-1 alpha was observed in subcutaneous tumor-bearing mice injected with the combination of IFN-alpha A/D and a low dose of rMuIL-1 alpha. Similar inhibition of subcutaneous tumor growth was obtained in T-cell-deficient nude or natural killer cell-deficient beige mice. In contrast, treatment of mice bearing B16F10 experimental pulmonary metastases with rMuIL-1 alpha resulted in no decrease in the number of metastases, and rMuIL-1 alpha did not potentiate the antimetastatic activity of IFN-alpha A/D. A synergistic induction of IL-6 was induced in mice treated with the combination of rMuIL-1 alpha plus IFN-alpha A/D but the level of IL-6 induced was not correlated with inhibition of tumor growth because this elevation of IL-6 was not observed in tumor-bearing nude mice. No direct antiproliferative activity was demonstrable in vitro against B16 F10 cells with rMuIL-1 alpha, IL-6, or rMuIL-1 alpha plus IL-6, and addition of these cytokines did not enhance the antiproliferative activity of IFN-alpha A/D.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced antitumor efficacy in mice by combination treatment with interleukin-1 alpha and interferon-alpha. 806 95

The identification of (gamma-glutamyl)polyamines in proteolytic digest of proteins from the cytosolic and particulate fractions of B16-F10 and B16-F10Lr6 cell lines, originating from a spontaneous tumor in C57BL/6 mice, indicates that polyamines are incorporated into melanoma cell proteins by transglutaminases (TGases-EC 2.3.2.13). The levels of spermidine-derived protein cross-links were found to be inversely related with the metastatic potential of the 2 melanoma lines. Characterization of TGase activity in the 2 tumor cell lines showed 3 types of enzyme. The soluble cellular TGase activity (TGase C) was higher, and increased more, during the growth of the least metastasizing clone B16-F10Lr6 than in the B16-F10 line, which is the most metastasizing. Consistently, N1,N8-bis(gamma-glutamyl) spermidine, which is responsible for protein cross-link formation, was present in greater amount in B16-F10Lr6 cells. The enhancement by theophylline of soluble-TGase activity and spermidine-dependent protein cross-links of B16-F10 cells reduced, with linear dose dependence, the ability of these cells to penetrate through human fibronectin-coated membrane in an in vitro assay of invasiveness. Our data confirm and extend earlier observations indicating that the propensity of a tumor to metastasize can be indirectly related to intracellular levels of TGase activity, and provide the basis for some speculation concerning the role of polyamines as modifiers of murine melanoma cell proteins in metastasis.
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PMID:Differences in the post-translational modification of proteins by polyamines between weakly and highly metastatic B16 melanoma cells. 809 90

B16 melanoma sublines (B16-F10-BL6 and B16-F1) exhibited elevated adenosine 3',5'-cyclic monophosphate (cAMP) levels when cultured in Dulbecco's modified Eagle's medium (DMEM) in comparison to cells in RPMI-1640 medium. In parallel, cells cultured in DMEM had increased tyrosinase activity, melanization and dendrite formation, all markers of melanoma differentiation. Also, the proliferative rates of both cell lines were decreased by 80-85% when cultured in DMEM relative to cells maintained in RPMI-1640 medium. In these studies, elevated levels of the melanin precursors tyrosine (Tyr) and phenylalanine (Phe) found in DMEM were shown not to be solely responsible for the phenotypic changes observed with DMEM. Both BL6 and B16-F1 cell lines formed more experimental pulmonary tumor metastasis in syngeneic C57BL/6 mice when maintained in DMEM vs RPMI-1640 medium. Analysis of metastasis formation in nude mice with normal and depleted natural killer (NK) cell activity revealed that the enhanced lung colonizing capacity of the BL6 cells maintained in DMEM was independent of the function of T-cell or NK-cell-mediated immunity. A close association between metastatic ability of tested lines and the expression of the membrane-associated enzyme gamma-glutamyltranspeptidase (gamma-GTPase, EC 2.3.2.2) was observed. The highly metastatic BL6 cell line had 20-fold higher levels of gamma-GTPase activity than the weakly metastatic B16-F1 cell line. Both cell lines, when grown in DMEM, had elevated gamma-GTPase activity that paralleled augmentation of metastatic ability. The dramatic changes in lung-colonizing capacity of the variant B16 melanoma cells maintained in DMEM in contrast to those grown in RPMI-1640 medium may serve as a useful model in understanding certain steps involved in triggering cell differentiation as well as metastasis development.
Clin Exp Metastasis 1993 May
PMID:Enhancement of pulmonary metastasis formation and gamma-glutamyltranspeptidase activity in B16 melanoma induced by differentiation in vitro. 809 41

The synthetic molecule muramyl tripeptide (CGP 19835A) encapsulated in liposomes is effective in increasing the survival of mice with spontaneous experimental lung metastases induced by the RENCA renal adenocarcinoma and B16 melanoma tumor models. The present study was aimed at extending the effects of CGP 19835A to another highly metastatic carcinoma model and at evaluating the efficacy of combination therapy with standard cytotoxic agents and other immunomodulators. C57BL/6 mice received whole tumor implants of PancO2, a spontaneously metastasizing pancreatic adenocarcinoma, subcutaneously in the hind leg. Therapeutic effects were measured by increased survival which is a direct function of the growth of spontaneous lung metastases in this system. No therapeutic efficacy was observed with CGP 19835A alone or in combination with any of a series of cytotoxic or biological agents, including cis-platinurn (cis-Pt), mitomycin C (MMC), adriamycin (ADR), cyclophosphamide (CP), interferon gamma (IFN gamma), and interleukin 2 (IL-2). In accord with previous studies, when the B16-F10 melanoma was used as an experimental metastatic tumor model, CGP 19835A, alone and in combination with CP, significantly reduced the number of pulmonary metastases. Cis-Pt, however, partially negated the effects of CGP 19835A when a combination of the two agents was used. The results indicate that CGP 19835A is an effective therapeutic agent in some models of spontaneous or experimental lung metastases, but not others, and that the effects of CGP 19835A are not enhanced by the accompanying cytotoxic drugs tested here.
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PMID:Analysis of the antimetastatic effects of synthetic muramyl tripeptide (CGP 19835A) encapsulated in liposomes in combination with other immunomodulatory agents and chemotherapeutic drugs. 819 65

Following intravenous injection of B16 melanoma cells into mice, more than 99.9% of the cells are killed by a combination of rapid and slow processes: however, the F10 line of B16 mouse melanoma cells produces approximately 10 times as many pulmonary colonies as wild-type cells. We have attempted to determine the role of one rapid cancer cell-killing process, namely deformation-driven, loss of surface membrane integrity of the type occurring in capillaries, by the use of an in vitro model in which cells are filtered through 8-microns pores in polycarbonate membranes. In accord with in vivo observations, more wild-type than F10 cells were killed by filtration in vitro. The hypothesis that resistance to mechanical trauma of this type is enhanced by a small cell diameter and a high degree of surface rugosity is supported by measurements of these parameters on viable cells and electron micrographs. Differential resistance in these cells is associated to a major extent with a high degree of utilizable surface membrane excess, and to a minor extent with the smaller mean diameter of the F10 cells. Calculations, which are in accord with previous in vivo observations, indicate that most of the cells delivered to the capillary beds of target organs during hematogenous metastasis can be destroyed by rapid mechanical trauma, which is therefore implicated as one of a number of major contributors to metastatic inefficiency.
Invasion Metastasis 1993
PMID:The differential resistance of B16 wild-type and F10 cells to mechanical trauma in vitro. 822 56


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