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

Studies of metastasis can be accelerated and provide more mechanistic information using cell lines which reproducibly and aggressively metastasize, and which are accurately and easily detected in tissues at all stages of the metastatic process. Although reporter proteins such as green fluorescent protein (GFP) and beta-galactosidase have improved the tracking of tumor cells in vivo, their measurement has often been limited to visual observation and manual counting. In this study, we exploited the highly sensitive and objective quantitation provided by flow cytometry to characterize, in detail, the sequence of events associated with orthotopic metastasis in a highly aggressive mouse model. Following stable transfection of the MDA-MB-435 breast carcinoma cell line with GFP, we utilized an in vivo selection process to isolate a variant exhibiting increased primary tumor growth and metastasis. As few as one fluorescent tumor cell per 200,000 host cells could be accurately detected in dissociated tissues by flow cytometry, allowing us to demonstrate that metastatic cells migrate to the lungs of SCID mice very early after orthotopic implantation. Tumor burden in lungs increased in a smooth continuous manner, until death approximately eight weeks later. Levels of circulating tumor cells in blood were also detectable at an early timepoint, but remained relatively low throughout the course of secondary tumor development in the lungs. Surgical removal of the primary tumor at various times after inoculation significantly affected lung tumor burden, supporting the concept that circulating tumor cells in blood inefficiently initiate distal metastases. Furthermore, the continuing contribution to metastasis by the primary tumor was independent of tumor mass. The combined characteristics of enhanced orthotopic metastasis and quantitative detection in blood and tissues will make this a useful new model for the characterization of the multi-stage progression of cancer, and the preclinical evaluation of anti-neoplastic therapies.
Clin Exp Metastasis 1999
PMID:Characterization of spontaneous metastasis in an aggressive breast carcinoma model using flow cytometry. 1076 21

An animal model of metastasis with features similar to those of lung cancer metastasis in humans is required for an understanding of the cellular and molecular mechanisms of human lung cancer metastasis. Ma-44 cell lines derived from human squamous cell lung cancer were percutaneously injected (2-3 x 10(4)) into the left lung of SCID mice. After orthotopic implantation, Ma-44 cell lines formed tumors in the left lung at a high rate (17/25, 68%), and many of those metastasized to mediastinal lymph nodes (13/17, 76%) by the 14th day, but not to other organs. After the ectopic implantation, the Ma-44 cell line inoculated subcutaneously (2-3 x 10(5)) formed a tumor at the inoculation site by the 28th day (all mice), but did not metastasize to any organs. The Ma-44 cell line inoculated intravenously (2-3 x 10(5)) formed metastases in the lungs (37/50, 74%), and these pulmonary metastases metastasized to the mediastinal lymph nodes at low rate (3/37, 8%) by the 14th day. The orthotopic sites of implantation are critical for the metastatic ability of transplanted tumors in SCID mice. Since non-small cell lung cancer (NSCLC) grows at the primary site in humans, lymphogenous metastasis occurs frequently, and blood-born metastasis occurs at moderate rate, our orthotopic SCID mice model was similar to the metastatic behavior of NSCLC in humans. Thus, this model may be useful for elucidating the mechanism of lymphogenous metastasis in human lung cancer, and testing the anti-metastatic efficacy of therapeutic agents in vivo.
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PMID:SCID mouse lymphogenous metastatic model of human lung cancer constructed using orthotopic inoculation of cancer cells. 1076 49

The number of spontaneous lung metastases of the human colon cancer cell line HT29 transplanted into SCID mice was quantified. The lungs were sliced, randomly distributed in agar blocks and the number of lung metastases was counted for each of 39 animals. A nearly exponential increase of metastases with weight of the tumor at the implantation site was observed. This suggests that a critical tumor weight for the initiation of metastatic spread exists. Calculating the data, a simplified quantitative assessment of the metastatic load by counting ten histological sections only for the estimation of the total number of lung metastases is proposed.
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PMID:Quantitative assessment of spontaneous lung metastases of human HT29 colon cancer cells transplanted into SCID mice. 1077 6

GAP31 (Gelonium protein of 31 kDa) and MAP30 (Momordica protein of 30 kDa) are agents isolated from the medicinal plants Gelonium multiflorum and Momordica charantia, respectively. The current study was conducted to investigate the efficacy of GAP31 and MAP30 on estrogen-independent and highly metastatic human breast tumor MDA-MB-231 both in vitro and in vivo. The effect of these agents on the expression of breast tumor antigen HER2 (also known as neu or as c-erbB 2) was also examined. Treatment of MDA-MB-231 breast cancer cells with GAP31 and MAP30 resulted in inhibition of cancer cell proliferation as well as inhibition of the expression of HER2 gene in vitro. When MDA-MB-231 human breast cancer cells were transferred into SCID mice, the mice developed extensive metastases and all mice succumbed to tumor by day 46. Treatment of the human breast cancer bearing SCID mice with GAP31 or MAP30 at 10 micrograms/injection EOD for 10 injections resulted in significant increases in survival, with 20-25% of the mice remaining tumor free for 96 days. Thus, anti-tumor agents GAP31 and MAP30 are effective against human breast cancer MDA-MB-231 in vitro and in vivo. These agents may therefore be a potential therapeutic use against breast carcinomas.
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PMID:Inhibition of MDA-MB-231 human breast tumor xenografts and HER2 expression by anti-tumor agents GAP31 and MAP30. 1081 Mar 36

The objective of the present study was to investigate the effect of dietary phytosterols on the growth and metastasis of the human breast cancer MDA-MB-231 cell line xenografted in SCID mice. Two groups of animals were fed AIN-93G diet supplemented with 0.2% cholic acid and 2% sterol (cholesterol or phytosterol mixture) for 15 days before inoculation of the tumor into the right inguinal mammary fat pad. Tumor growth and food consumption were recorded weekly throughout the 8 weeks of the experiment. At the end of the experiment, the animals fed phytosterol had a 40% lower serum cholesterol and 20 and 30 fold higher serum beta-sitosterol and campesterol, respectively as compared to those fed cholesterol. There was no difference between the two groups in body weight and food consumption. However, the tumor size in animals fed phytosterols was 33% smaller (P < 0.03) and had 20% fewer metastases to lymph nodes and lungs than the cholesterol group. At termination, the tumor weight of the animals fed the phytosterol diet was also less (P < 0.07) than that of the cholesterol group. It is concluded that dietary phytosterols retard the growth and spread of breast cancer cells.
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PMID:Dietary phytosterol inhibits the growth and metastasis of MDA-MB-231 human breast cancer cells grown in SCID mice. 1081 Mar 60

HER-2/neu is overexpressed on a variety of human adenocarcinomas and overexpression has been associated with a poor prognosis. For this reason, HER-2 has become an attractive target for immunotherapy. To facilitate testing of anti-HER-2-monoclonal antibodies (MAbs) and immunotoxins (ITs), we have evaluated the in vivo growth and metastatic spread of three HER-2-overexpressing human breast cancer cell lines (BT474, MDA-MB-453 and HCC1954) and one ovarian cancer cell line (SKOV3.ip1) in pre-irradiated male SCID mice using subcutaneous (s.c.), intravenous (i.v.) and intraperitoneal (i.p.) routes of injection. All the cell lines tested grew as s.c. tumors and the growth of BT474 and MDA-MB-453 cells after s.c. injection was improved by co-inoculation with Matrigel. Metastases to the lungs were detectable by PCR or histopathology after s.c. injection of BT474 and to a much lesser extent after s.c. injection of HCC1954, MD-MB-453 and SKOV3.ip1 cells. I.p. injection of HCC1954 and SKOV3.ip1 cells produced fatal ascites while i.v. injection of SKOV3.ip1, but not BT474 or MDA-MB-453 cells, resulted in infiltration of lungs and death within 9-11 weeks.
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PMID:The growth and metastasis of human, HER-2/neu-overexpressing tumor cell lines in male SCID mice. 1096 98

We examined parathyroid hormone-related peptide (PTHrP) production and regulation in both normal human melanocytes and in a human amelanotic melanoma cell line (A375). Northern blot and immunocytochemical analysis demonstrated that both cultured A375 cells and normal human melanocytes express PTHrP, but A375 cells expressed much higher levels of the peptide. PTHrP secretory rate increased at least 10-fold after treatment with 10% fetal bovine serum (100.2 +/- 2.8 pmol/10(6) cells vs. basal <15 pmol/10(6) cells) in proliferating A375 cells but only twofold in confluent cells. Treatment of A375 cells with increasing concentrations of 1, 25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] or its low-calcemic analog EB-1089 revealed that EB-1089 was 10-fold more potent than 1, 25-(OH)(2)D(3) on inhibition of both cell proliferation and PTHrP expression. Furthermore, inoculation of A375 cells into the mammary fat pad of female severe combined immunodeficiency mice resulted in the development of hypercalcemia and elevated concentrations of plasma immunoreactive PTHrP in the absence of detectable skeletal metastases. Our study, therefore, demonstrates a stepwise increase in PTHrP expression when cells progress from normal to malignant phenotype and suggests that EB-1089 should be further evaluated as a therapeutic agent in human melanoma.
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PMID:Expression and regulation of parathyroid hormone-related peptide in normal and malignant melanocytes. 1100 3

In vitro, tumor-selective Hsp70 plasma membrane localization correlates with increased sensitivity to lysis mediated by a subpopulation of human natural killer (NK) cells that adhere to plastic following cytokine stimulation. In the present study, we analyzed the capacity of adoptively transferred human NK cells in SCID/beige mice for local tumor control and prevention of metastatic dissemination of Hsp70-expressing CX(+) and non-expressing CX(-) tumors following orthotopic (o.t.) injection. Both tumor sublines were derived by cell sorting of the original cell line, CX2, and thus exhibit an identical MHC and adhesion molecule expression pattern but differ with respect to Hsp70 plasma membrane expression. Viability of adherent, human NK cells in SCID/beige mice up to 18 days and the capacity to migrate have been demonstrated. Growth of Hsp70-expressing and non-expressing CX(+) and CX(-) tumor cells was completely suppressed when 10 x 10(6) NK cells were injected into the i.p. cavity on day 4 after inoculation of 2.5 x 10(6) tumor cells. Although a single injection of 5 or 2.5 x 10(6) NK cells was not sufficient to suppress tumor growth completely in all mice, the reduction in size of CX(+) tumors was significantly greater than that of CX(-) tumors. To mimic the clinical situation, ex vivo stimulated NK cells were injected i.v. on day 4 after o.t. injection of tumor cells. Under these conditions, growth of Hsp70-expressing primary tumors and metastases was suppressed. If CX(-) tumor cells were injected, 3 of 9 mice developed Hsp70-negative primary tumors. However, none of these mice developed distant metastases. In summary, our data indicate that Hsp70 acts as a recognition structure for adherent NK cells in a SCID/beige mouse model.
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PMID:Adoptive transfer of human natural killer cells in mice with severe combined immunodeficiency inhibits growth of Hsp70-expressing tumors. 1107 50

In orthotopic animal models of human lung cancer, bone and lymph node metastases have been observed with high frequency after periods of a few weeks, but metastases to other organs are rare. This study evaluated development of distant metastases over a six-month period in a model of orthotopic lung carcinoma in immunocompromised mice. Human A549 lung adenocarcinoma cells were stably transfected to express high levels of green fluorescent protein. Suspensions of 1 x 10(6) cells were instilled into the lungs of athymic and SCID mice to produce orthotopic human lung carcinomas. All animals had primary tumors at termination of the experiment six months later. Splenic metastases and lymph node metastases were present in 70% of the animals and two of the three SCID mice had thymic metastases. Three animals had bony metastases. Thus, a high percentage of immunocompromised mice with orthotopic lung carcinomas ultimately develop metastases.
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PMID:Splenic, thymic, bony and lymph node metastases from orthotopic human lung carcinomas in immunocompromised mice. 1113 72

The recently described CC chemokine, 6C-kine, is unique in that it contains -six rather than the usual four conserved cysteines typical of this family. Furthermore, murine 6C-kine binds to one of the CXC chemokine receptors CXCR3, in addition to its other known receptor CCR7. We have shown that two other ligands of CXCR3, IP-10 and MIG, are potent inhibitors of tumor growth in severe combined immunodeficiency (SCID) mice. We postulated that murine 6C-kine may also inhibit tumor growth via inhibition of angiogenesis in this model. SCID mice (n = 6 per group) inoculated with A549 human lung cancer cells were treated with either 6C-kine (100 ng intra-tumor injection every other day) or control protein for 8 weeks. Tumors from murine 6C-kine-treated mice (288 +/- 26 mm3) were significantly smaller than tumors from control treated mice (788 +/- 156 mm3, P = 0.005). Additionally, murine 6C-kine reduced metastases compared with controls (0.5 +/- 0.3 vs 3.0 +/- 1.2 metastases per animal, P = 0.05). Tumor vascularity (as assessed by vessel density counting) was reduced in murine 6C-kine-treated mice compared with controls. Murine 6C-kine had no direct effect on proliferation of A549 cells, and there were no differences in the infiltration of leukocyte sub-populations, assessed by flow cytometry, in the treatment groups. Interestingly, human 6C-kine, unlike murine 6C-kine, does not bind CXCR3 and had no anti-tumor effect in the same model. These data suggest that murine 6Ckine has anti-tumor effects independent of its leukocyte-recruiting activity. Furthermore, while not confirmatory, these data lend further support to the fact that CXCR3 may be the receptor for angiostatic CXC chemokines.
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PMID:The murine CC chemokine, 6C-kine, inhibits tumor growth and angiogenesis in a human lung cancer SCID mouse model. 1122 89


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