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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is generally accepted that primary tumors become heterogeneous as a consequence of tumor-cell genetic instability. Clonal dominance has been shown to occur in some experimental models allowing a subpopulation of cells to overgrow the primary heterogeneous tumor and to metastasize. Alternatively, interactions among coexisting tumor subpopulations may contribute to the emergence of a malignant invasive primary solid tumor. We asked the question whether emergence of carcinoma cells producing a growth/dissociating factor within a tumor cell population may be a determinant for tumor progression and for clonal dominance. To mimic such a situation, we have investigated the impact of tumor subpopulation heterogeneity in an in vivo model in which mixtures of carcinoma cells that differ in their ability to produce acidic fibroblast growth factor are injected into nude mice. Our data indicate that a growth-factor-producing cell subpopulation can confer increased tumorigenicity to an entire cell population and subsequently elicit a shorter delay for appearance of metastasis. A community effect via cell interactions may account for a heterogeneous tumor cell population rather than clonal dominance during progression of certain tumor types.
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PMID:A minority of carcinoma cells producing acidic fibroblast growth factor induces a community effect for tumor progression. 750 17

In order to study the clinical usefulness of biological response modifiers (BRMs) in eliminating malignant solid tumors, we have investigated the effect of various combination therapies on the murine Colon26 solid tumor model. When the tumor-bearing mice were treated with chemotherapeutics, G-CSF and OK-432 (streptococcal preparation), the tumors completely disappeared from all of the treated mice. When these survivors were rechallenged with Colon26 tumor cells on Day 120, all of them survived without showing any sign of recurrence or metastases. The results indicate that mice with malignant solid tumors, which can not be cured using chemotherapeutics alone, may be completely healed with a combination immuno-chemotherapy. During the course of this combination therapy, study, it was found that there was a clear positive correlation between immunosuppressive acidic protein (IAP) levels and tumor sizes. Suppressor macrophages (sM phi) which produce IAP were found to be decreased in bone marrow and spleen of treated mice. This suggests that the combination therapy may make the mice recover from a suppressed immune state caused by sM phi. In conclusion, the combination therapy with chemotherapeutics and BRMs could cure the solid tumor-bearing mice very effectively through not only synergistic direct tumor cell destruction but also indirect immunomodulation of the host.
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PMID:Curative treatments of murine Colon26 solid tumors by immunochemotherapy with G-CSF and OK-432. 754 45

In the present study we tested whether T cells retargeted with a bispecific antibody (bsAb) could block the growth of lung metastases of syngeneic mammary adenocarcinoma in immunocompetent mice. BALB/c mice were injected i.v. with tumor and i.p. with a genetically engineered bispecific F(ab')2 [bs(Fab')2] having specificity for murine CD3 epsilon chain and for the gp52 mouse mammary tumor viral glycoprotein, which is expressed on the tumor cells. The bs(Fab')2 was physically stable in blood and serum, was removed from the body with a half-time of 12-15 h, and accumulated in lymphoid tissue where it bound to T cells. We show that treatment of tumor bearing mice with the bs(Fab')2 significantly prolonged their survival relative to untreated controls. Two other genetically engineered bs(Fab')2s having specificity for murine CD3 epsilon chain and irrelevant antigens did not inhibit tumor growth. In addition, survival was not affected by bsAb therapy using a variant tumor cell line that expressed low levels of the gp52 target antigen. Inhibition of tumor growth was even more evident by histologic analysis. Treatment with the relevant bs(Fab')2 resulted in a marked reduction of tumor burden in lung sections taken on days 7, 9 and 11. This is the first report demonstrating that a bsAb can inhibit the growth of syngeneic solid tumor metastases in mice without addition of T cell activators.
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PMID:A bispecific antibody prolongs survival in mice bearing lung metastases of syngeneic mammary adenocarcinoma. 757 3

The past decade has witnessed substantial progress in our understanding of the molecular mechanisms of tumor cell interactions with vascular endothelium and extracellular matrix, important events in the metastatic process. This progress has been made possible by the identification and functional characterization of a large number of adhesion molecules involved in tumor cell-vasculature interactions. Essentially, most of the adhesion receptor families so far reported, including integrins, cadherins, selectins, immunoglobulins, and proteoglycans, have been implicated in various stages of tumor progression and metastasis. Disseminating cancer cells often employ ectopic expression of certain adhesion molecules to facilitate their interaction with the vessel wall and matrix, typical examples being the expression of integrins alpha IIb beta 3 and alpha L beta 2 and immunoglobulin family members PECAM-1, ICAM-1, and N-CAM in solid tumor cells. The expression of adhesion molecules in cancer cells and vascular endothelial cells is spatiotemporally regulated, in a dynamic fashion, by a wide diversity of bioactive molecules such as eicosanoid 12(S)-HETE. Recent data indicate that most adhesion molecules, integrins in particular, participate in various signaling functions such as the induction of calcium fluctuation and protein tyrosine phosphorylation. The importance of adhesion molecules in tumor metastasis is also evidenced by their involvement in other important parameters of metastasis such as angiogenesis. Collectively, the accumulated literature suggests that interference with adhesion and signaling represent a future direction for the development of anticancer and antimetastasis therapeutic protocols.
Invasion Metastasis
PMID:Adhesion molecules and tumor metastasis: an update. 765 6

A metastatic rat bladder carcinoma cell line, M-NBT-II, produces and secretes a dissociating factor called SFL, whereas the tumorigenic parental cell line from which it originated (E-NBT-II) does not. In this work, we report that SFL production is correlated with an invasive phenotype in three-dimensional collagen gels or organotypic cocultures. This invasiveness may be related to the production of gelatinolytic activity. We have also investigated the behavior of SFL-producing cells within an NBT-II solid tumor. Here we report that the presence of 14% of SFL-factor-producing cells are sufficient to increase the tumorigenicity, and subsequently the metastatic behavior, of the entire cell population, indicating that there is no clonal dominance of the SFL-producing cells for tumorigenicity and metastatic spreading, but rather a community effect. SFL factor may contribute to cell-cell cooperativity by paracrine or other indirect mechanisms.
Invasion Metastasis
PMID:SFL production by carcinoma cells induces the aggressive properties of nonproducing cells in vivo via a community effect. 765 25

One of the reasons for the development of cancers and their relentless malignant progression--even in the face of highly toxic anticancer therapies--is an enhanced ability to bypass mechanisms responsible for precipitating cell death. The latter include active cell death mechanisms often referred to as programmed cell death or apoptosis. Active cell death is a genetically controlled, intrinsic suicide process, and evidence is rapidly accumulating that cancers are more resistant to undergoing apoptosis than normal cells. This may be a major factor explaining the ability of small numbers of tumor cells, e.g. tumor emboli, to survive transit in the bloodstream and form distant metastases in ectopic organ sites. In addition, because many therapeutic agents ultimately kill tumor cells by inducing apoptosis, acquisition of an apoptosis-resistant phenotype could be a generic mechanism of drug or radiation resistance in cancer patients. It follows that uncovering the basis of the enhanced survival capacity of tumor cells is fundamental to gaining a better understanding of tumor progression, metastasis formation, and response to therapy. In this respect many of the principles thought to regulate apoptosis in cancers have been established using conventional, two-dimensional monolayer cell cultures of 'liquid' tumors, i.e. unicellular model systems. Suppression of apoptosis in solid tumors, however, may be governed by different cellular and genetic mechanisms. Evidence is presented in support of this hypothesis, and that multicellular architecture may render individual tumor cells within solid tumors less susceptible to apoptosis. This multicellular resistance--which may represent a form of group protection--can also be induced or acquired during cytotoxic drug chemotherapy or cytokine-mediated growth inhibition of solid tumors. It follows that disruption of solid tumor multicellularity may provide a means of enhancing the therapeutic destruction of small solid tumors such as occult micrometastases. Such disruptions may be brought about by a variety of so-called antiadhesive agents.
Invasion Metastasis
PMID:Impact of multicellular resistance on the survival of solid tumors, including micrometastases. 765 32

The production and local release of various proteolytic enzymes, either by tumor cells or tumor-associated stromal cells, is thought to facilitate the malignant behavior of solid tumors. Human cutaneous melanoma offers an excellent clinical model to study the possible contribution of such proteases to solid tumor progression because melanoma goes through a series of well defined stages in its pathogenesis; moreover, permanent cell lines have been established from these various stages. As a first step to analyzing the gelatinolytic enzymes in melanoma pathology, we examined cell lines derived from early stage primary melanomas in which patients were cured of their disease and compared the results to those obtained with cell lines established from advanced stage primary lesions or metastases (i.e., from patients who eventually succumbed to the disease). We found that 80% of cell lines examined from early stage lesions constitutively produced only the 72-kDa gelatinase A but never the 92-kDa gelatinase B. In contrast, the majority of advanced stage cell lines examined produced both the 72-kDa gelatinase A and the 92-kDa gelatinase B. Advanced stage cell lines that did not constitutively produce the 92-kDa gelatinase B could be induced to do so with transforming growth factor beta, interleukin 1 beta or 12-O-tetradecanoyl-phorbol-13-acetate. In total, 0 of 5 early stage cell lines constitutively expressed the 92-kDa gelatinase B, and only 2 of 5 could be induced to produce this activity. In contrast, all advanced stage cell lines that were evaluated either constitutively or inducibly produced the 92-kDa gelatinase B. To analyze the mechanism by which 92-kDa gelatinase B production is switched on in the advanced stage melanoma cell lines, somatic cell hybrids were constructed using an advanced stage melanoma cell line as one partner and either one of two early stage cell lines as the other. Constitutive production of the 92-kDa gelatinase B in such hybrids was lost and could not be induced in such hybrids. Coculture of the early and advanced stage cell lines failed to recapitulate what was seen after somatic hybridization, and zymographic analysis of lysates from hybrid cell lines demonstrated no 92-kDa gelatinase B activity. Reverse transcription-PCR analysis demonstrated that the loss of 92-kDa gelatinase B production occurred at the level of steady-state mRNA for the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The 92-kDa gelatinase B is expressed by advanced stage melanoma cells: suppression by somatic cell hybridization with early stage melanoma cells. 766 94

Arachidonic acid metabolites have been implicated in multiple steps of carcinogenesis. Their role in tumor cell metastasis, the ultimate challenge for the treatment of cancer patients, are however not well-documented. Arachidonic acid is primarily metabolized through three pathways, i.e., cyclooxygenase, lipoxygenase, and P450-dependent monooxygenase. In this review we focus our attention on one specific lipoxygenase, i.e., 12-lipoxygenase, and its potential role in modulating the metastatic process. In mammalian cells there exist three types of 12-lipoxygenases which differ in tissue distribution, preferential substrates, and profile of their metabolites. Most of these 12-lipoxygenases have been cloned and sequenced, and the molecular and biochemical determinants responsible for catalysis of specific substrates characterized. Solid tumor cells express 12-lipoxygenase mRNA, possess 12-lipoxygenase protein, and biosynthesize 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid], as revealed by numerous experimental approaches. The ability of tumor cells to generate 12(S)-HETE is positively correlated to their metastatic potential. A large collection of experimental data suggest that 12(S)-HETE is a crucial intracellular signaling molecule that activates protein kinase C and mediates the biological functions of many growth factors and cytokines such as bFGF, PDGF, EGF, and AMF. 12(S)-HETE plays a pivotal role in multiple steps of the metastatic 'cascade' encompassing tumor cell-vasculature interactions, tumor cell motility, proteolysis, invasion, and angiogenesis. The fact that 12-lipoxygenase is expressed in a wide diversity of tumor cell lines and 12(S)-HETE is a key modulatory molecule in metastasis provides the rationale for targeting these molecules in anti-cancer and anti-metastasis therapeutic protocols.
Cancer Metastasis Rev 1994 Dec
PMID:12-lipoxygenases and 12(S)-HETE: role in cancer metastasis. 771 97

Transplantation of the human ovarian adenocarcinoma cell line, NIH:OVCAR-3 into athymic mice produces two morphologically distinct tumor cell populations (ascites and solid tumors). In the present study, we isolated both tumor cell phenotypes and investigated their relative malignant potential. Since cytoskeletal and morphological changes correlate with metastatic phenotype, expression of the intermediate-filament protein vimentin was compared between ascites and solid tumors. Ascites tumor cells showed a less differentiated epithelial morphology and concurrently expressed higher levels of vimentin. Ascites cells were more efficient in anchorage independent growth when compared with their solid tumor counterpart. Ascites tumor cells were also highly motile compared with the solid tumor cell population (P = 0.006). Migration of ascites tumor cells was further enhanced by type IV collagen, hyaluronic acid, and chondroitin sulfate A. Solid tumor cells removed from the same animal, however, were not significantly affected by these agents. From these studies, we conclude that ovarian cancer cells present in ascites are phenotypic variants which are highly motile compared with solid tumor cells isolated from the same animal. Ascites tumor cells with increased motility may contribute to peritoneal seeding and metastasis.
Clin Exp Metastasis 1995 May
PMID:Phenotypic variations and differential migration of NIH:OVCAR-3 ovarian carcinoma cells isolated from athymic mice. 775 Feb 4

Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis.
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PMID:Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. 785 49


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