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

The aim of this study was to establish a reproducible and quantitative liver metastasis model in mice. The in vitro colon 26 (C-26) cultured cell line was initially taken from an in vivo transplantable C-26 adenocarcinoma tumor mass using the standard enzymatic treatments, collagenase and DNAse. In vitro cultured cells x 10(4) were introduced into the portal vein of syngeneic BALB/c mice to induce liver metastases and, 3 weeks later metastatic foci were found in approximately 50% to 70% of the mice. In contrast, C-26 cells desialylated by neuraminidase (Nase) treatment greatly increased the incidence of hepatic metastases with countable hepatic colonies being found in all mice (100%). This result seems to be related to the liver-characteristic D-galactose receptors, since pre-injection with an excess amount of galactocerebroside completely prevented tumor colonization in the liver. Thus, although we cannot disregard the involvement of other adhesion molecules in this system as yet, our experimental model may become a useful tool for the analysis of hepatic metastases from colon cancer in the future.
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PMID:A successful liver metastasis model in mice with neuraminidase treated colon 26. 821 12

Human breast tumors are often associated with a fibrotic reaction termed desmoplasia. Tumor cells may indirectly modulate the composition of the extracellular matrix by influencing fibroblast properties. They may also directly interact with collagen fibrils leading to retraction of the matrix. We have studied in vitro the influence of various human mammary tumor cells on the proliferation rate of normal human fibroblasts and on their level of collagen synthesis, as well as their release of collagenase activity. Interactions between neoplastic cells and collagen matrix were investigated by incorporation of tumor cells in collagen gels (lattices) and measurement of their retraction. All cells tested (HBL100, SW613, SA52, MDA-MB-231, MCF7, MCF7/6, MCF7 ras, BT20 and T47D) were able to modulate the composition of the extracellular matrix by one or several of the mechanisms investigated. Our results also demonstrate an opposite regulation of collagen and collagenase production. The effects on the collagen metabolism and on fibroblast proliferation are probably mediated by soluble cytokines since they are reproduced by incubating the fibroblasts in the presence of medium conditioned by tumor cells. The desmoplastic reaction may thus result from different mechanisms dependent upon tumor cell types.
Invasion Metastasis 1993
PMID:Different mechanisms of extracellular matrix remodeling by fibroblasts in response to human mammary neoplastic cells. 822 54

The liver is the most common site of hematogenous metastases from colorectal carcinoma. Kupffer cells (KC), which line the hepatic sinusoids, may form the first line of defense against circulating tumor cells. The purpose of this study was to determine the effect of hepatic metastases and intra-abdominal tumor growth on KC binding of human colorectal carcinoma (HCRC) cells. MIP-101, a poorly metastatic cell line, and CX-1, a highly metastatic cell line, were injected intrasplenically into nude mice and KC were isolated by collagenase perfusion at varying intervals after injection. Conditioned media were collected from MIP-101, CCL 188 and CX-1 to determine their in vitro effect on KC function. KC from MIP-101 injected mice (14% liver metastases, 100% splenic tumors) bound a significantly greater number of MIP-101 and clone A cells than CX-1 cells in vitro. KC isolated from mice 5 weeks after CX-1 injection (100% liver metastases) also showed increased binding of MIP-101 and clone A cells compared to CX-1 cells. Similar results were obtained when tumor cell binding to normal human liver KC was compared to binding to KC from human livers from patients with hepatic metastasis from colorectal cancer. In contrast KC obtained from mice 3 weeks after CX-1 injection (44% liver metastases) showed significantly decreased binding of MIP-101 and clone A cells. The conditioned medium from CX-1 cells significantly decreased the in vitro binding of both MIP-101 and CX-1 by KC. These results indicate that the ability of KC to bind HCRC cells (which precedes phagocytosis and tumor cell killing) is a dynamic function and affected by concomitant tumor growth. HCRC cells may alter KC function via the production of specific tumor-derived soluble factors. In order to devise new and more effective therapeutic options in the treatment of liver metastases the nature of this tumor cell-KC interaction must be better understood.
Clin Exp Metastasis 1993 Mar
PMID:Human and murine Kupffer cell function may be altered by both intrahepatic and intrasplenic tumor deposits. 844 9

Using zymography and computer assisted image analysis, we have measured the levels of type IV collagenases in biopsies from normal breast, and benign and malignant breast disease. The 92 kDa form was present in three of 11 cases of normal/benign disease, three of nine grade I tumours, four of 12 grade II tumours, but 11 of 11 grade III tumours. Mean levels were higher in grade III tumours (P < 0.0001). When the levels of 72 kDa collagenase and its active 62 kDa form were considered together, there was no difference between the benign and malignant cases (P = 0.55), but the amount of active enzyme, considered as a proportion of the 62 + 72 kDa forms, was significantly higher in malignant disease (P = 0.003). There was also a trend towards a higher proportion of active enzyme with increasing tumour grade (P < 0.0001). In situ hybridisation and immunohistochemistry studies showed that that mRNA and protein for the 92 kDa enzyme was primarily found in the tumour stroma. mRNA for the 72 kDa enzyme was also found in stromal areas. This study demonstrates a clear relationship between production of Type IV collagenases and malignant breast disease. Inhibitors of these enzymes may be of value in preventing metastatic disease.
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PMID:Activity of type IV collagenases in benign and malignant breast disease. 849 11

Prostatic carcinoma cells have a propensity to metastasize to bone, and we propose that this phenomenon may be promoted by the adhesion of metastatic cells to bone matrix. Bone matrix is produced by osteoblasts, and we have developed an in vitro model of bone matrix by isolating the substratum deposited by human osteoblast-like U2OS cells. The collagenous nature of this matrix was demonstrated by the incorporation of [3H]proline and its subsequent release by purified collagenase. Both U2OS matrix and purified type I collagen stimulated the adhesion of human PC-3 prostatic carcinoma cells. Human laminin supported adhesion to a much lesser extent, and PC-3 cells did not adhere to fibronectin. Adhesion of PC-3 cells to U2OS matrix closely resembled adhesion to purified type I collagen with respect to (a) inhibition by a collagen-derived peptide and by antibodies raised against alpha 2 or beta 1 integrin collagen receptor subunits; (b) lack of inhibition by RGD (Arg-Gly-Asp) peptides; (c) stimulation by Mn2+ and Mg2+ ions but not by Ca2+ ion; and (d) stimulation by the phorbol ester PMA (phorbol 12-myristate 13-acetate). This adhesion was also stimulated (2.3-fold) by transforming growth factor beta (TGF-beta), which is a major bone-derived growth factor. We conclude that human osteoblast-like matrix is an adhesive substrate for PC-3 prostate carcinoma cells. This adhesion appears to be mediated by the interaction of alpha 2 beta 1 integrin on PC-3 cells with matrix-derived collagen. The stimulation of this adhesion by TGF-beta suggests that the co-expression of TGF-beta and type I collagen in bone may synergistically facilitate the adhesion of metastatic cells to bone matrix proteins and thereby increase their localization in the skeleton.
Clin Exp Metastasis 1996 Jan
PMID:Bone cell matrix promotes the adhesion of human prostatic carcinoma cells via the alpha 2 beta 1 integrin. 852 12

We have previously shown that a 78-kDa "invasion stimulating factor" (ISF) triggers collagenase IV (MMP-2) secretion and the invasive behavior of metastatic PC-3 ML subclones in modified Boyden chamber assays [Stearns, M. E.; Stearns, M. Autocrine factors, type IV collagenase secretion and prostatic cancer cell invasion. Cancer Metastasis Rev. 12:39-52; 1993. Wang, M.; Stearns, M.; Stearns, M. E. Identification of the receptor for a novel M(r) 78,000 "invasion stimulating factor" from metastatic human prostatic PC-3 ML clones. Cancer Res. 54:2492-2495; 1994.]. Recently, we have shown that interleukin 10 (IL-10) preferentially stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) production in these cells [Wang, M.; Stearns, M. E. Characterization of a novel TIMP-1 enhancer element. J. Biol. Chem., submitted.]. In this paper, we report that IL-10 (20-40 ng) can inhibit the invasion stimulatory effects of ISF (30-60 ng) on PC-3 ML cells. "Checkerboard analysis" with modified Boyden chambers (precoated with 10 and 100 micrograms collagen IV) shows that IL-10 inhibits the stimulatory effects of ISF on both cell motility and chemoinvasion processes. In support of these data, exogenously supplied TIMP-1 (10 micrograms/ml) and collagenase antibodies (1:200 dilution) both completely blocked invasion. Quantitative ELISAs comparing the molar ratios of TIMP-1:MMP-2 and TIMP-2:MMP-2 further demonstrate that IL-10 (10-40 ng) preferentially activates TIMP-1 secretion to increase the molar ratio of TIMP-1:MMP-2 in the presence of increasing amounts of ISF (0-60 ng). IL-10 did not elevate TIMP-2 secretion or influence the molar ratio of TIMP-2:MMP-2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-10 blocks collagen IV invasion by "invasion stimulating factor" activated PC-3 ML cells: upregulation of TIMP-1 expression. 855 49

We used the Boyden chamber system to investigate the mechanism by which the antimetastatic agent sodium D-glucaro-delta-lactam (ND2001) inhibits tumor cell invasion, and by establishing what ND2001 did not achieve, we were able to pinpoint the areas in which it was successful as an inhibitor. ND2001 did not inhibit cell adhesion of a highly metastatic B16 melanoma variant (the B16 variant) to the reconstituted basal membrane Matrigel, nor did it affect the production or activity of basal membrane-degrading type i.v. collagenase, but, in the Boyden chamber, ND2001 inhibited cell migration of the B16 variant toward a chemoattractant, laminin, on the lower surface of a Matrigel-free filter set (haptotaxis). Lewis lung carcinoma (3LL) cells that had been treated with ND2001 also exhibited hardly any haptotaxis, although the cells showed no alteration in behavior during cell adhesion to Matrigel. Since ND2001 did succeed in inhibiting the pulmonary metastases of the B16 variant and 3LL, we infer that inhibition of the metastases by ND2001 in these tumors is likely to be due to the inhibition of haptotactic migration.
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PMID:Inhibition of tumor cell haptotaxis by sodium D-glucaro-delta-lactam (ND2001). 856

Human giant cell tumor (GCT) consists of multinucleated giant cells and mononuclear stromal cells, and is characterized by frequent vascular invasion without distant metastases. To study the role of matrix metalloproteinases (MMPs) in the vascular invasion, we examined production of MMP-1 (tissue collagenase), -2 (gelatinase A), -3 (stromelysin-1), -9 (gelatinase B), and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in GCT. MMP-9 was highly and predominantly expressed in giant cells by both immunohistochemistry and in situ hybridization. Expression of other MMPs was also observed in some cases but was inconstant. Sandwich enzyme immunoassays demonstrated that MMP-9 is the predominant MMP secreted by GCT. There was a definite imbalance between the amounts of MMP-9 and those of TIMPs in the culture media of GCT, leading to detectable gelatinolytic activity in an assay using 14C-gelatin. Gelatin zymography demonstrated the main activity at about 90 kd, which was identified as the zymogen of MMP-9 by immunoblotting. Immunohistochemistry for type IV collagen and laminin, major basement membrane components, showed that disappearance of the proteins is closely associated with MMP-9-positive giant cells. These results indicate the production of MMP-9 by multinucleated giant cells and suggest that the metalloproteinase may contribute to proteolysis associated with vascular invasion and local bone resorption in human GCT.
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PMID:Matrix metalloproteinase 9 (gelatinase B) is expressed in multinucleated giant cells of human giant cell tumor of bone and is associated with vascular invasion. 857 23

Four potent, synthetic inhibitors of matrix metalloproteinases (MMPs) were assessed as inhibitors of tumor growth and spontaneous metastasis to the lung. Mat Ly Lu rat prostate tumor, LOX human melanoma and M27 murine Lewis lung tumor were implanted subcutaneously (s.c.) in mice and allowed to grow for 3-12 days. The lungs of the tumor-bearing mice were then removed and implanted s.c. into untreated mice, and the outgrowth of secondary tumors from the implanted lungs measured. The incidence and rate of outgrowth of secondary tumors increased with the length of primary tumor growth, validating these measurements as indices of spontaneous metastasis to the lung. Compounds were tested by s.c. implantation of minipumps which delivered compound throughout the period of primary tumor growth and spontaneous metastasis to the lung at steady-state drug concentrations orders of magnitude greater than the concentrations needed to either inhibit collagenase, gelatinase or stromelysin in vitro. Inhibitor treatment slowed the growth of primary s.c. Mat Ly Lu and LOX tumors by 40-60% but had no significant effect on the growth of primary M27 tumors. Surprisingly, inhibitor treatment had no significant effect on the ability of the lung to generate secondary tumors when reimplanted s.c. in untreated mice. Because of the possible importance of cathepsins B, H and L in tumor growth and metastasis, the irreversible inhibitor E-64 was also infused by s.c. minipump. E-64 had no effect on the growth or spontaneous metastasis of Mat Ly Lu or M27 tumors.
Clin Exp Metastasis 1996 Mar
PMID:Effect of matrix metalloproteinase inhibitors on tumor growth and spontaneous metastasis. 860 25

It is now recognised that epithelial-stromal interactions are important in a wide range of disease processes including neoplasia and inflammation. Metalloproteinases are central to matrix degradation and remodelling, which are key events in tumour invasion and metastasis and may also be involved in tissue changes occurring in chronic inflammation. Immunohistochemistry was performed on sections from 50 patients with pancreatic cancer (n = 27), ampullary cancer (n = 12), low bile duct cancer (n = 3), neuroendocrine tumours (n = 3) and chronic pancreatitis (n = 5), using antibodies raised against collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of metalloproteinase (TIMP1) and developed using the avidin-biotin complex method. Abundance of MMP2, MMP3 and TIMP1 was greater in pancreatic and ampullary cancer than any other pathology and immunoreactivity in the malignant epithelial cells in pancreatic and ampullary cancer was greater than in the stromal tissues (in pancreatic cancer: MMP2 100% vs 37%, MMP3 93% vs 15%, TIMP1 93% vs 4%, P < 0.0001). There were strong correlations between the immunoreactivity of the two antibodies for MMP2 (P < 0.0001), between MMP2 and TIMP1 (P < 0.0001) and between MMP3 and TIMP1 (P < 0.0001). The immunoreactivity for TIMP1 in pancreatic and ampullary cancers with lymph node metastases was significantly less compared with those cases without lymph node metastases (P < 0.02) and there was an association between increased immunoreactivity for MMP2 and the degree of tumour differentiation (P < 0.01). The results implicate MMP2, MMP3 and TIMP1 in the invasive phenotype of pancreatic and ampullary cancer.
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PMID:Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease. 861 34


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