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)

The administration of recombinant human macrophage colony-stimulating factor (M-CSF) i.p. in doses of 25 or 100 micrograms twice daily for 5 consecutive days to non-tumor-bearing C57BL/6 mice resulted in a dose-dependent infiltration of mononuclear cells in the livers but not the lungs of these treated animals. Immunohistochemical examination of fixed liver tissue with the murine macrophage-specific monoclonal antibody, F4/80, revealed a greater than 5-fold increase in the number of hepatic macrophages. Quantification of F4/80-positive cells in a mononuclear single cell suspension derived from liver revealed a greater than 25-fold expansion in the number of hepatic macrophages compared to control mice. These cells were then tested in 18-h 51Cr release assays for tumoricidal activity, after an 18-h incubation with or without gamma-interferon, against cultured P815 targets. Significant tumor cell lysis by these liver-associated mononuclear cells occurred, which was enhanced by gamma-interferon preincubation. The systemic administration of M-CSF alone at high dose had no antitumor impact in vivo against 3-day pulmonary metastases from the MCA-203 sarcoma and B16 melanoma or hepatic metastases from the B16 melanoma or MCA-105, -203, or -207 sarcomas. Although the systemic administration of M-CSF in combination with tumor-specific monoclonal antibody had no effect on 3-day pulmonary metastases from the B16 melanoma, significant reductions in liver metastases were seen. These murine studies demonstrate the biological activity of recombinant human M-CSF in vivo and suggest that the administration of this cytokine in combination with specific monoclonal antibody may be useful in the treatment of patients with metastatic disease at sites of monocyte/macrophage accumulation.
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PMID:Biological and antitumor effects of recombinant human macrophage colony-stimulating factor in mice. 202 43

Malignant prostatic carcinoma, a major cause of cancer mortality in males, most often metastasizes to secondary sites in bone. Frequently, the growth rate of the secondary tumor in bone marrow is considerably greater than that of the slowly growing primary prostatic tumor. We now report that two lines of human prostatic carcinoma cells proliferate in response to conditioned media from unstimulated human, rat, or bovine bone marrow. Nonprostatic tumor cell lines showed little or no growth response to the same medium. The proliferative activity found in bone marrow was not duplicated by any of a variety of purified growth factors including epidermal growth factor (EGF), acidic or basic fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) alpha or beta, interleukins 1, 2, 3, 4 or 6, granulocyte (G), macrophage (M) or granulocyte-macrophage (GM) colony stimulating factor (CSF). Whereas a mixture of G-CSF, M-CSF, and IL 3 produced a mitogenic response in the prostatic carcinoma cells, these three factors were not present in our bone marrow samples in sufficient quantities to promote the observed proliferative response. To further identify the cellular source of the proliferative activity present in bone marrow-conditioned medium, we tested conditioned media made from human bone marrow stromal cells. The stromal cell conditioned medium stimulated increased growth of the prostatic carcinoma cells to levels equivalent to those observed with the bone marrow conditioned medium. These results suggest that novel mitogenic factors that are produced by bone marrow stromal cells and remain in the bone marrow cavity may account, in part, for the preferential growth of prostatic metastases in bone.
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PMID:Stimulation of human prostatic carcinoma cell growth by factors present in human bone marrow. 278 90

The macrophage colony-stimulating factor (CSF-1) is best known as a hematopoietic cytokine important to macrophage activation. Recently, the importance of CSF-1 and its receptor (encoded by the c-fms proto-oncogene) in epithelial ovarian cancer has also been recognized, with overexpression of CSF-1 denoting poor prognosis in ovarian cancer patients. During macrophage activation, CSF-1 promotes urokinase-type plasminogen activator (uPA) activity; in macrophages and in malignant cells of lung, breast, colon, and prostatic origin, uPA activity is strongly correlated with the ability to invade and, in the malignant cells, to metastasize. While there is clear evidence of CSF-1 and uPA expression in primary and metastatic ovarian cancer, the significance of their expression to invasion of these cells has not been explored. We find that all of our ovarian cancer cell lines which we have studied co-express CSF-1 and uPA transcripts and protein. Urokinase expression in these ovarian cancer cell lines correlates with the degree of tumorigenicity in nude mice, with the most virulent tumor resulting from Hey cells, a strong expressor of uPA. We studied the invasion of these primary and established ovarian cancer cells through a Matrigel (reconstituted basement membrane matrix) barrier. The ability of ovarian cancer cells to invade is strongly correlated with endogenous CSF-1 expression (Pearson's correlation, r = 0.91; P = 0.01). A total of 0.90 +/- 0.16% of Bix3 cells (very weak expressor of CSF-1) invaded through the barrier, in contrast to 6.95 +/- 0.75% of Hey cells (strong CSF-1 expressor) and 10.44 +/- 2.33% of Bixler cells (the strongest CSF-1 expressor). We studied the ability of two of the cell lines to invade human laminin and type IV collagen (Bix3, a weak invader of Matrigel, and Hey, a strong invader), to determine (a) whether our results on a Matrigel matrix may represent a relevant model for invasion in humans and (b) whether there is a potential confounding effect from the cytokines and proteases in Matrigel. On this human simple matrix, we confirm that Bix3 is a weakly invasive cell line (0.33 +/- 0.04% invasion) which contrasted to the strongly invasive Hey cell line (8.51 +/- 0.47%). Treatment of Bix3 cells with exogenous CSF-1 stimulates percentage of invasion by 2-fold and results in a similar increase in the level of uPA transcripts and cellular associated uPA antigen. Furthermore, cell surface-bound uPA increased from 74% in the absence of CSF-1 to 100% (fully saturated) in the presence of CSF-1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Macrophage colony-stimulating factor mediates invasion of ovarian cancer cells through urokinase. 788 68

Prostate cancer selectively metastasises to skeletal sites, where it normally produces osteoblastic lesions. This study investigated whether haematopoietic growth factors known to be present in the bone environment could be involved in the survival and proliferation of prostate skeletal metastases. To evaluate this hypothesis we investigated the effects of recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF), recombinant granulocyte colony-stimulating factor (rG-CSF), recombinant erythropoietin (rEPO) and recombinant interleukin-3 (rIL-3) on the growth of 3 human prostate cancer cell lines. Two hormone-insensitive cell lines, PC-3 and DU145, were significantly stimulated by rGM-CSF and rEPO in serum-free medium but their growth was unaffected by incubation with rIL-3 or rG-CSF. A hormone-sensitive cell line, LNCaP, was stimulated only by rGM-CSF. To investigate further the involvement of GM-CSF in prostate cancer, the presence of GM-CSF protein in the 3 prostate cancer cell lines was examined by immunohistochemistry, and analysis of cell line conditioned media was carried out by ELISA and Western blotting. These techniques demonstrated that GM-CSF-like material was produced by both DU145 and PC-3 cells but not by LNCaP. The results from ELISA found that media conditioned by DU145 and PC-3 cells contained 1.7 and 2.5 pg GM-CSF/micrograms protein, respectively, whereas no GM-CSF was detectable in the LNCaP conditioned media. Our results were also confirmed by Western blot analysis demonstrating one single band for DU145 and PC-3 conditioned media which co-migrated along with the standard rGM-CSF band. No bands were associated with the LNCaP conditioned media. The presence of GM-CSF gene transcripts in DU145 and PC-3 cells was established by reverse transcription and polymerase chain reaction of total RNA.
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PMID:Production and response of human prostate cancer cell lines to granulocyte macrophage-colony stimulating factor. 792 24

Previously we described the use of solid-phase anti-CD3 monoclonal antibody (mAb) to stimulate murine tumour-infiltrating lymphocytes (TIL) and their subsequent expansion in recombinant interleukin 2 (rIL-2). In a pulmonary metastases model using the methylcholanthrene-induced sarcoma MCA-105 anti-CD3 activated TIL were capable of eradicating disease similar to TIL cultured in rIL-2 only. Here we extend these observations by characterizing the biological effects of sequential solid-phase anti-CD3 activation. TIL from MCA-105 tumour activated with solid-phase anti-CD3 on day 1 were reactivated on day 14, or day 26, or both and compared to TIL grown in rIL-2 only or TIL activated with anti-CD3 once on day 1. Reactivation enhanced in vitro proliferation 1.8- to 4-fold compared to TIL activated once with anti-CD3 (P < 0.05). In addition, the total lytic capacity of the cultures was enhanced after reactivation without changing the phenotype of the TIL cultures. Reactivation resulted in a greater in vivo efficacy when the TIL were administered within 72 h of reactivation. In contrast, TIL activated with anti-CD3 on day 1 and day 14 were least effective of all TIL cultures (P < 0.05). This correlated with in vitro cytokine production. The most effective TIL cultures in vivo produced 4- to 100-fold higher amounts of cytokines, especially interferon gamma (IFN gamma) and granulocyte macrophage colony stimulating factor (GM-CSF), than the other cultures. On the other hand, the least effective in vivo TIL culture, TIL activated with anti-CD3 on day 1 and 14, produced little or no cytokines. These data suggest that in vitro production of cytokines is indicative of in vivo efficacy of anti-CD3 activated TIL.
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PMID:Reactivation of murine tumour-infiltrating lymphocytes with solid-phase anti-CD3 antibody: in vitro cytokine production is associated with in vivo efficacy. 795 95

Conventional chemotherapy for adult type soft tissue sarcomas is not very effective. Rarely are patients with advanced soft tissue sarcomas curable by systemic chemotherapy. Thus, the benefits from chemotherapy have been equivocal even when treatment is given postoperatively to patients whose primary sarcomas have been excised. Current research is directed toward the achievement of a high percentage of complete tumor regressions in patients with advanced metastatic disease in hope that this can be translated into truly effective adjuvant therapy. Several recent new approaches to systemic treatment for soft tissue sarcomas are assessed including prospects for possible enhancement of chemotherapy by agents which stimulate cellular immunity. Some unexpectedly favorable responses to chemotherapy+granulocyte-macrophage colony-stimulating factor (GM-CSF) in an ongoing study are discussed.
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PMID:Chemotherapeutic approaches to soft tissue sarcomas. 799 29

Recent studies have shown that macrophage colony-stimulating factor and its receptor c-fms protein are significantly overexpressed in endometrial and ovarian cancers. In the present study, we analyzed the steady-state levels of c-fms mRNA in benign and malignant endometrial tissues by Northern and slot blot analyses. The relative levels of c-fms mRNA were quantified by using a hybridization signal for each sample on Northern blot analysis. Slot blot analysis was used to further quantitate the relative increase in c-fms mRNA in malignant specimens compared to benign specimens. Correlation of c-fms expression in the endometrial cancers was made with traditional prognostic indicators. Secretory endometrium had low levels of c-fms mRNA, whereas the endometrial cancers had the highest levels. Proliferative and hyperplastic endometrium values were intermediate. Comparative assessment of c-fms expression in endometrial cancer relative to other prognostic factors demonstrated greater expression of c-fms in specimens from patients with abnormal DNA ploidy, high-grade lesions, and possibly extrauterine metastases. Our study confirms the overexpression of c-fms in endometrial cancer and demonstrates a positive correlation between the steady-state mRNA levels of c-fms and other select adverse prognostic indicators.
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PMID:The proto-oncogene c-fms is overexpressed in endometrial cancer. 850 87

In this study, cytokine release by tumor-draining lymph node cells sensitized in vitro (IVS-TDLN) was examined and correlated with therapeutic efficacy in adoptive immunotherapy. Mice bearing immunologically distinct MCA 207 and MCA 205 sarcoma tumors were utilized in criss-cross experiments. IVS-TDLN obtained from mice bearing 10-day subcutaneous (s.c.) tumors mediated immunologically specific regression of established 3-day pulmonary metastases, but demonstrated non-specific cytolytic reactivity against both tumors in a 4-h 51Cr-release assay. By contrast, these IVS-TDLN cells were found specifically to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) when restimulated in vitro with irradiated tumor cells. To determine the predictive value of tumor-specific cytokine release with in vivo therapeutic efficacy, a kinetic analysis of antitumor activities of TDLN obtained from animals bearing MCA 207 tumors for increasing lengths of time was performed. IVS-TDLN cells from mice bearing day-7, -10 and -14 s.c. tumors manifested tumor-specific release of GM-CSF and IFN gamma, and mediated significant antitumor reactivity in vivo. In contrast IVS-LN cells from day-0 and day-21 tumor-bearing animals did not release significant amounts of GM-CSF and IFN gamma, and were not therapeutically efficacious in vivo. Day-4 IVS-TDLN released high levels of GM-CSF and IFN gamma non-specifically, and were not therapeutic in adoptive immunotherapy at doses effective for day-7 and day-14 IVS-TDLN cells. In other experiments, IVS cells generated from different lymph node groups in animals bearing 10-day established s.c. tumors were examined and found to have unique profiles of cytokine release. In these studies, the ability of IVS cells to release specifically both cytokines as opposed to one was associated with greater therapeutic efficacy on a per cell basis. Our findings suggest that the tumor-specific releases of GM-CSF and IFN gamma are useful parameters to assess the in vivo therapeutic efficacy of immune lymphocytes.
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PMID:Tumor-specific granulocyte/macrophage colony-stimulating factor and interferon gamma secretion is associated with in vivo therapeutic efficacy of activated tumor-draining lymph node cells. 853 78

The effectiveness of combination therapy using a suicide gene and cytokine genes for the treatment of metastatic colon carcinoma in the mouse liver was investigated. Pre-established hepatic tumors treated with a recombinant adenoviral vector containing the herpes simplex virus thymidine kinase gene(tk) exhibited substantial regression, although all treated animals suffered from subsequent relapses. Although cotreatment with a mouse interleukin 2 (mIL-2)-containing adenoviral vector induced an effective antitumor immune response, the immunity waned with time, and the treated animals eventually succumbed to hepatic tumor relapse or distant metastases. In this study, mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) gene was tested for its ability to further enhance and prolong the antitumoral cellular immunity. A fraction of the animals treated with tk + mIL-2 + mGM-CSF developed long-term antitumor immunity and survived for more than 4 months without recurrence. This long-term antitumor immunity could be enhanced further by subsequent "vaccination" with mIL-2-expressing parental tumor cells. The results indicate that local expression of GM-CSF in the hepatic tumors and prolonged mIL-2 expression are necessary to generate persistent antitumor immunity that is essential for the prevention of tumor recurrence and long-term animal survival.
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PMID:Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival. 870 21

Earlier results [1], suggesting an autocrine tumor cell stimulation by CSF-1, are in agreement with data by Fildermann et al. [2], showing an enhanced motility and invasiveness in the CSF-1 receptor expressing BT20 breast cancer cell line upon stimulation with recombinant CSF-1. Tumor-cell secreted CSF-1 has also been shown to cause monocyte recruitment, but not cytotoxicity [3]. Down-regulation of monocyte class II antigen expression after exposure to high concentrations of CSF-1 [4] may decrease macrophage-mediated tumor cytotoxicity and favor tolerance. Raised CSF-1 serum levels may thus increase tumor metastatic behavior as well as cause immune suppression in advanced stage disease. We set out to evaluate serum CSF-1 levels in primary and metastatic breast cancer. Serum samples from one hundred and eighteen primary breast cancer patients and seventy-five patients with metastatic disease were assayed by radio-immuno-assay (RIA) for circulating colony-stimulating factor 1. Mean serum levels were significantly higher in the metastatic population (9.7 ng/ml +/- 0.8) as compared to the patients with primary tumors (4.2 +/- 0.2) (p = 0.0001). Patients with early stage tumors (T0/T1/T2) had significantly lower levels than patients with tumors of larger size (T3/T4) (p = 0.0001). Relapse and survival statistics were analyzed using Kaplan-Meier estimates. Samples from 118 primary breast cancer patients were available to study. The median follow up was 85 months (range: 1-108). An elevated CSF-1 concentration (> 6.6 ng/ml or > 550 Units/ml) was associated with a shorter disease free interval (p = 0.03). In a multivariate analysis, including T (clinical tumor size), N (clinical node status), histological grade, and hormone receptor status, CSF-1 remained significantly associated with a poorer outcome (relative risk of relapse: RR: 3.3 [1.3-8.5]), together with tumor size (RR: 2.8[1-8.2]) and clinically involved nodes (RR: 4.1[2.1-8]). These results were not modified following adjustment for type of treatment. We conclude that raised circulating CSF-1 levels may be an indicator of early metastatic relapse.
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PMID:Circulating levels of the macrophage colony stimulating factor CSF-1 in primary and metastatic breast cancer patients. A pilot study. 887 7


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