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)

Human colonic carcinoma cell lines, KM12C, KM12SM and KM12L4, were previously established and their in vivo metastatic potentials have been well evaluated. The highly metastatic cell lines KM12SM and KM12L4 were derived from the parental low metastatic cell line KM12C in vivo. To evaluate the metastatic behavior of these cell lines in vitro, we examined colony formation on monolayers of the pulmonary arterial endothelial (CPAE) cells. On day 4, the highly metastatic cell lines showed an approximately 2-fold increase in number of colonies on CPAE cell monolayers relative to the parental KM12C cell line. To investigate what evidence is correlated with their metastatic and invasive abilities, Northern blot analysis and flow cytometry were performed in all cell lines. According to the results of Northern blot analysis, the levels of matrix metalloproteinase (MMP)-2 and c-met mRNA expression were increased in highly metastatic cell lines as compared with the parental cell line. We also examined the cell-surface expression of several adhesion molecules by flow cytometry. The levels of expression of sialyl Lewisa antigen (sLe(a)) in KM12SM and KM12L4 were twice higher than that in KM12C. However, the levels of expression of E-cadherin in KM12SM and KM12L4 were decreased to half that in KM12C. The alterative expression of the collagenase and adhesion molecules might contribute to their metastatic/invasive abilities of these cell lines both in vivo and in vitro.
Clin Exp Metastasis 1998 Jul
PMID:Alterative expression of the collagenase and adhesion molecules in the highly metastatic clones of human colonic cancer cell lines. 1009 41

Experimental evidence has directly implicated matrix metalloproteinases (MMPs) in the remodeling of the stromal tissue surrounding tumors. Thus, MMP inhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a tumor. Much of the work on the role of MMP inhibitors has concentrated on their inhibitory effects on tumor cell invasion. We have examined the effects of a new MMP inhibitor, KB-R7785 (acting on MMP-1, MMP-3, and MMP-9), on tumor angiogenesis and metastasis of murine colon adenocarcinoma (C-26) in two tumor models in BALB/c mice (transparent chamber model and lung colonization model). KB-R7785 has not shown inhibitory effects on in vitro growth of either C-26 or KOP2.16 murine endothelial cells. In vivo, KB-R7785 administrated twice daily for 15 days (100 mg/kg, i.p.), starting the day of tumor inoculation (5 x 10(5) C26 cells) in transparent chamber, has resulted in 88.2% suppression of tumor growth, compared with that in vehicle-administered mice (controls). Tumors grown in controls have doubled their area in 3.3 days, whereas those treated by KB-R7785 progressed almost four times slower (tumor area doubling time, 12 days). KB-R7785 rendered centrally avascular tumors with only a rim of peripheral neovasculature, which had significant lower functional vascular density and vascular area than the corresponding parameters in control tumors 10 days after inoculation [79.9+/-6.7 cm/cm2 versus 164.1+/-10.1 cm/cm2 (P < 0.01) and 19.8+/-1.5% versus 42.6+/-2.7% (P < 0.01), respectively]. In the lung colonization model (tail vein inoculation of 5 x 10(5) C-26 cells), administration of KB-R7785 (100 mg/kg, i.p.) twice daily for 20 days has reduced the number of surface metastasis by 85.8% and abolished the tumor burden, as compared with controls. The few metastatic colonies found in the lungs of KB-R7785 treated mice appeared to be dormant (i.e., staining with von Willebrand factor antibody revealed few, if any, positive cells within the metastatic foci from MMP inhibitor-treated lungs, whereas terminal deoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold increase in the rate of tumor cell apoptosis compared with controls. The fact that KB-R7785 interferes with early steps of angiogenesis and cancer spread suggests that MMP inhibitors may control both primary and secondary tumor growths by limiting the expansion of endothelial cells, as well as cancer cells, composing the tumors.
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PMID:Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models. 1009 56

The demonstration that matrix metalloproteinases [MMPs] play an active role in the invasion and metastasis stages of tumor progression has led to the development of a new class of anti-metastatic chemotherapeutic agent, the matrix metalloproteinase inhibitors [MMPIs]. We present evidence to suggest that the MMP matrilysin, in particular, plays an essential role in much earlier stages of intestinal tumorigenesis. Matrilysin is detected in a high percentage of pre-invasive lesions, in contrast to its absence in most normal tissues, and is expressed by the epithelial-derived tumor cells. Manipulating levels of this enzyme in vitro results in cell lines with enhanced tumorigenic potential, while ablating the gene in vivo leads to a significant reduction in tumor number in two different animal models of intestinal tumorigenesis. Additionally, regulation of matrilysin gene expression appears to be under the control of genetic pathways which are activated very early in the tumor development sequence. Although the precise mechanism by which matrilysin activity contributes to tumor formation is not yet clear, we propose that MMPIs may be of benefit as chemopreventative agents in addition to their therapeutic potential for metastatic disease.
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PMID:Matrilysin in early stage intestinal tumorigenesis. 1019 Feb 86

Development of metastases distant to the primary site of solid tumors marks late stages of tumor progression. Almost all malignant mammary tumors are carcinomas arising from the breast epithelium, but the morphological and molecular alterations in the mammary stroma surrounding the premalignant and the growing tumor contribute to its conversion into neoplastic tissue. Two parameters are critical for initiation of the metastatic process and access of tumor cells to the circulation. These are the ability of tumor cells to invade the basement membrane and the stroma, and the neovascularization of breast tumor tissue. A major site for development of distant metastases is the skeleton. After colonizing the bone, tumor cells promote a cascade of events leading to recruitment of osteoclasts and subsequent osteolytic bone destruction. A ubiquitous theme of neoplastic progression of breast tumors is the overproduction of matrix metalloproteinases. In this review, we summarize the recent insights into the functional consequences of matrix metalloproteinase expression and activation during malignant conversion in the breast, and after bone colonization. The current literature supports the hypothesis that matrix metalloproteinases play a key role in the metastatic expansion of most, if not all, mammary tumors and in the ensuing bone loss.
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PMID:An odyssey from breast to bone: multi-step control of mammary metastases and osteolysis by matrix metalloproteinases. 1019 Feb 89

Functional and immunochemical approaches were used to assess matrix metalloproteinase (MMP) inhibitors, e.g., tissue inhibitor of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2), in organ cultures of normal human skin maintained under growth factor free conditions or in medium supplemented with a combination of growth factors including epidermal growth factor, insulin, and pituitary extract. It has previously been shown that under growth factor free conditions, normal skin structure and function are maintained for several days, while in the presence of these exogenous growth factors, the epithelial cells invade the stroma [Invasion and Metastasis 1993;13:225-233]. TIMP-1 was detected in equivalent amounts in organ culture fluids under both conditions. TIMP-2 was not detected under either condition. Normal epidermal keratinocytes, normal dermal fibroblasts, and three different epithelial tumor cell lines were also examined for MMP inhibitor expression. Keratinocytes and fibroblasts produced high levels of both TIMP-1 and TIMP-2, but in neither cell type was there a significant difference between growth factor free and growth factor containing conditions. In contrast, the three epithelial tumor cell lines produced low to undetectable levels of both TIMP-1 and TIMP-2. These data suggest that acquisition of local invasive capacity is not dependent on a reduction in MMP inhibitor expression. A reduction in MMP inhibitors may accompany the transition from invasive to metastatic tumors.
Invasion Metastasis 1998
PMID:Elaboration of matrix metalloproteinase inhibitors by human skin in organ culture and by skin cells in monolayer culture: relationship to invasion. 1020 48

We have previously shown that alendronate, a potent bisphosphonate compound, can prevent human PC-3 ML tumor cell metastasis to the bone (Stearns and Stearns, 1996, Oncol Res, 8, 69-75). In this paper, tumor cells were injected into the bone medullary cavity of SCID mice femurs both in vivo and following isolation in vitro. ELISAs showed that the amount of collagen I released in the bone marrow (i.e. in in vitro experiments) and the blood plasma (i.e. in in vivo experiments) was a function of the time of incubation or the number of cells injected in the femurs. ELISAs also showed that the levels of matrix metalloproteinase (MMP-2 and MMP-9) secreted in the bone medullary cavity of the femurs directly correlated with the extent of collagen 1 release. In vitro experiments carried out with 'live' and 'devitalized bone' yielded similar results suggesting that the tumor cells (not the osteoclasts) were primarily responsible for the bone solubilization observed. Alendronate pretreatment of the SCID mice (0.1 mg/kg biweekly for 3 weeks) (or the tumor cells) blocked both MMP production by the tumor cells (and the osteoclasts) and collagen I release, providing direct evidence that alendronate might be utilized to prevent bone destruction by metastatic tumor cells. Zymography indicated that MMP-2 activation might be responsible for bone solubilization. In addition, the data suggest that the plasma levels of collagen I might be a marker of bone metastasis and osteolysis.
Clin Exp Metastasis 1998 Nov
PMID:Alendronate blocks metalloproteinase secretion and bone collagen I release by PC-3 ML cells in SCID mice. 1021 82

Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in patients with malignant gliomas.
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PMID:Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340. 1021 21

Breakdown of basement membrane (BM) is believed to be an essential step for tumor invasion and metastases. We have previously demonstrated that matrix metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with metastases in human colorectal cancer (CRC). This study explores the relationship between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and pattern of type IV collagen expression during human colorectal tumorigenesis. Thirty-four CRC patients, including four synchronous adenomas and one synchronous liver metastases, were involved in this study. By immunohistochemical staining, type IV collagen expression was noted to be continuous in the BM of normal mucosa, adenoma and in two cases of carcinoma in situ. Limited or absent type IV collagen staining pattern was seen in 100 (19/19) and 23% (3/13) of CRC with and without metastases, respectively. By double immunostaining, MMP-9 protein expression was noted to localize within areas of limited type IV collagen staining. Similarly, type IV collagen staining was noted to be greatest in areas devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa proenzyme forms in all CRC and normal mucosa extracts examined. The mean tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6+/-0.1 (mean +/- SE) and 2.4+/-0.5 in adenomas, and 2.1+/-0.2 and 4.1+/-0.7 in CRC, respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19) of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC without metastases, respectively. These differences were significant (P = 0.045 and P = 0.030, respectively). Our results demonstrate that loss of BM type IV collagen along with elevations in MMP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis. Our data suggest that control of type IV collagenase activation may be beneficial in preventing human colorectal tumor progression.
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PMID:Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. 1033 90

Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as "state-of-the art" treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLCD-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials.
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PMID:Update on the management of advanced breast cancer. 1035 85

As clinical oncologists, our ultimate goal in treating patients with cancer is to be able to cure their disease with a combination of treatment modalities directed at the primary tumor (surgery or radiation), and potential metastases (chemotherapy). The validity of this multimodality approach to treating cancer was initially demonstrated with the successful treatment and cure of highly chemosensitive childhood cancers, such as Wilms' tumor, and these cures were only realized when adjuvant chemotherapy was included with local control measures. We attribute our treatment successes in childhood cancers to the use of cytotoxic chemotherapy, and we attribute our inability to cure many adults with more common forms of solid tumors to the ineffectiveness of chemotherapy in these diseases. Curing disease is not the goal of most pharmacological interventions in nonmalignant diseases. With the exception of antimicrobial and anticancer chemotherapy, most of the common classes of drugs are administered with the intent of controlling the disease or the symptoms caused by disease. We administer antihypertensive agents to control blood pressure, but the underlying cause of the hypertension is not cured by this therapy. If the hypertension recurs after antihypertensive therapy is stopped, we would conclude that the therapy was successful at controlling the disease. However, if a patient's tumor relapses after completing anticancer chemotherapy, the anticancer therapy would be considered to be unsuccessful. By setting lofty goals for our therapy, we increase the probability that the treatment will not meet our own and our patient's expectations. Schipper et al. [J Clin Oncol 1995;13:801-805] proposed that we abandon the "killing paradigm," which dictates that the treatment of cancer is directed toward eradication of all cancer cells, and that we adopt a "regulatory model" of cancer. This model views cancer as a maladaptive, constantly evolving process in which cancer cells differ only slightly from normal cells as a result of a few critical genetic changes that lead to dysregulation of growth. The treatment approach under this new paradigm is debulking of tumor burden with standard multimodality therapy followed by control of residual disease by "reregulation" of the remaining cancer cells. Controlling growth and spread of this residual disease would be accomplished with non-cytotoxic agents which target pathways that are responsible for the dysregulation in cancer cells. We are now on the verge of having the capacity to test this new paradigm of cancer. Advances in our understanding of the pathogenesis of many common forms of cancer at a molecular level have led to a revolution in anticancer drug development. A number of new agents that target a variety of critical molecular targets, such as the farnesyl transferase inhibitors that block ras oncogene activation, the matrix metalloproteinase inhibitors that block the enzymes involved in tissue invasion and metastasis [Editor's note: please see "New Drugs on the Horizon, page 271], and the angiogenesis inhibitors that block new vessel formation in growing tumors, are now being clinically tested. These new classes of anticancer drugs are aimed at regulating or controlling cancers rather than killing them. The potential utility of targeting the critical molecular lesion in tumor cells is illustrated by the efficacy of all-trans-retinoic acid in acute promyelocytic leukemia (APL). Although the capacity of all-trans-retinoic acid to induce complete remissions by inducing terminal differentiation of leukemic blasts was discovered empirically, the subsequent demonstration that the pathognomonic 15:17 translocation that is present in up to 90% of cases of APL results in the production of a dysfunctional retinoid receptor appears to explain the specificity and high level of activity of retinoid therapy in this disease. This is the first example of a cancer that can be treated by specifically targeting therapy to a pathogenetic molecular lesion. Retinoids are now being used in combination with standard chemotherapy for the treatment of APL, an example of the successful application of combining a molecularly targeted agent with conventional cytotoxic chemotherapy. The development and use of molecularly targeted agents for the treatment of cancer may require us to view cancer in a new light and to adjust our goals and expectations of its treatment as well as the endpoints of our clinical trials. However, pharmacologically controlling cancer may result in an equally acceptable outcome for our patients if it leads to what Schipper et al. termed a "functional cure."
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PMID:The Goal of Cancer Treatment. 1038 18


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