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)

As BCL-2 oncoprotein has been implicated as a survival factor in a number of tissues, we examined colorectal tumour specimens and cell lines for BCL-2 expression. BCL-2 protein was expressed in 19/22 adenocarcinomas and 12/13 adenomas. 6/9 carcinoma cell lines and 7/8 adenoma cell lines were also BCL-2 positive. BCL-2 expression was retained in metastases to the regional lymph nodes (3/3 specimens) and in the cell line SW620, derived from a lymph node metastasis. These studies suggest a role for BCL-2 in promoting cell survival of benign and malignant colorectal tumours and that BCL-2 deregulation may be a relatively early event in colorectal carcinogenesis. The retention of BCL-2 expression in the carcinomas and lymph node metastases may explain the resistance of colorectal tumours to chemotherapeutic treatment.
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PMID:BCL-2 expression in human colorectal adenomas and carcinomas. 793 63

High frequencies of loss of heterozygosity (LOH) in chromosome 11q22-qter have been observed in various malignancies, including breast cancer. Previous studies on breast carcinomas by Winqvist et al (Cancer Res 55: 2660-2664) have indicated that a survival factor gene is located in band 11q23, and that the highly informative microsatellite polymorphism at the APOC3 locus would be a suitable tool to perform more extensive LOH studies. In this European multicentre study, we have examined the occurrence of APOC3 LOH and evaluated the effect of LOH of this chromosomal subregion on the clinical behaviour of the disease in a cohort of 766 breast cancer patients in more detail. LOH for APOC3 was found in 42% of the studied tumours, but it was not found to be significantly associated with any of the studied clinical variables, including cancer-specific survival time or survival time after recurrent/metastatic disease. According to the present findings, the putative survival factor gene on 11q23 is not located close enough to the APOC3 gene, but apparently at a more proximal location.
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PMID:European multicenter study on LOH of APOC3 at 11q23 in 766 breast cancer patients: relation to clinical variables. Breast Cancer Somatic Genetics Consortium. 1036 Jun 69

Increased vascular endothelial growth factor (VEGF) expression is associated with colon cancer metastases. We hypothesized that inhibition of VEGF receptor activity could inhibit colon cancer liver metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate metastases. Mice received daily i.p. injections of vehicle, tyrosine kinase inhibitor for Flk-1/KDR (SU5416) or tyrosine kinase inhibitor for VEGF, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). SU5416 and SU6668 respectively inhibited metastases (48.1% and 55.3%), microvessel formation (42.0% and 36.2%), and cell proliferation (24.4% and 27.3%) and increased tumor cell (by 2.6- and 4.3-fold) and endothelial cell (by 18.6- and 81.4-fold) apoptosis (P<0.001). VEGF receptor inhibitors increased endothelial cell apoptosis, suggesting that VEGF may serve as an endothelial survival factor.
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PMID:Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. 1055 7

Vascular endothelial growth factor (VEGF) is the predominant regulator of colon cancer angiogenesis and is associated with a poor prognosis and the development of metastases. We hypothesized that DC101, an antibody against the VEGF receptor-2 (flk-1), may be efficacious in the therapy of colon cancer peritoneal carcinomatosis in a murine model. BALB/c mice underwent intraperitoneal injection of CT-26 colon cancer cells to generate peritoneal metastases. Mice received control solvent or DC101 for up to 60 days. In parallel studies, mice were sacrificed at sequential time points to determine the effect of DC101 on tumor angiogenesis, tumor cell proliferation and apoptosis, and endothelial cell apoptosis. Mice treated with DC101 demonstrated a 30% increase in mean survival. In addition, DC101 also led to a significant decrease in tumor vascularity, growth and tumor cell proliferation. In sequential studies, anti-VEGF-R therapy led to a progressive increase in endothelial cell apoptosis followed by an increase in tumor cell apoptosis. These findings suggest that anti-flk-1 therapy may prolong survival in patients with colon cancer carcinomatosis. The temporal studies demonstrating that anti-flk-1 therapy lead to an increase in endothelial cell apoptosis that in turn lead to an increase in tumor cell apoptosis confirms the role of VEGF as an endothelial cell survival factor.
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PMID:Effects of an antibody to vascular endothelial growth factor receptor-2 on survival, tumor vascularity, and apoptosis in a murine model of colon carcinomatosis. 1117 85

Vascular endothelial growth factor (VEGF), a potent cytokine secreted by virtually all cells plays a key role in tumor angiogenesis. Disruption of one VEGF allele in mice has revealed a dramatic lethal effect in early embryogenesis, suggesting a very tight regulation of this gene. This commentary reviews the mechanisms whereby VEGF mRNA is controlled within the tumor environment by hypoxia and the MAP kinase signaling cascades. Using hamster fibroblasts as a cellular model, we demonstrated that the Ras-mediated activation of p42/p44 MAP kinases exerts a prominent action at the transcriptional level. In normoxic conditions, p42/p44 MAPKs activate the VEGF promoter at the proximal (-88/-66) region where Sp 1/AP-2 transcriptional factor complexes are recruited. At low O2 tension, the stabilized and nuclear hypoxia inducible factor- 1alpha (HIF-1alpha) is directly phosphorylated by p42/p44 MAPKs, an action which enhances HIF-1-dependent transcriptional activition of VEGF. In addition, MAPKs activated under various cellular stresses (p38MAPK and JNK), contribute to the increased expression of this angiogenic growth and survival factor by stabilizing the VEGF mRNA.
Cancer Metastasis Rev 2000
PMID:MAP kinases and hypoxia in the control of VEGF expression. 1119 Oct 53

The local microenvironment at the sites of cancer metastases protects tumour cells from anticancer drug-induced apoptosis via mechanisms, such as soluble growth factors and cytokines. The concept of antisurvival factor (ASF) therapy as a component of anticancer treatments aims at neutralising the protective effect conferred upon cancer cells by the survival factor(s) derived by the local microenvironment, in order to enhance the sensitivity and/or reverse the resistance of tumour cells to other anticancer therapeutic strategies. Herein, we review the translation of this concept from ex vivo studies to clinical applications in the setting of prostate cancer refractory to androgen ablation (stage D3). At this stage, which predominantly involves bone metastases, insulin-like growth factor 1 (IGF-1) production (either growth hormone (GH)-dependent or GH-independent) can protect tumour cells from apoptosis, despite the significant suppression of androgens. The application of the ASF therapeutic concept involves the combination of dexamethasone (which suppresses GH-independent IGF-1) and somatostatin analogue (which suppresses endocrine, GH-dependent IGF-1) with the pro-apoptotic effect of the testicular androgen suppression by sustained use of LHRH analogues. In stage D3, patients who had failed anti-androgen withdrawal, chemotherapy and also had several other adverse prognostic features, the ASF-based combination achieved durable objective responses and major symptomatic improvement, paving the way for future applications of this approach. The ASF-based combination therapy illustrates a novel paradigm in cancer treatment: anti-tumour treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumour microenvironment and neutralise the protection it confers on metastatic cancer cells. The favourable toxicity profile of this therapeutic approach calls for its testing in a randomised controlled setting in metastatic prostate cancer and, conceivably, in other IGF-1-responsive malignancies.
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PMID:Combination of dexamethasone and a somatostatin analogue in the treatment of advanced prostate cancer. 1182 17

The effect of CNTF and BDNF on a proteolytic complement instrumental to invasion and on differentiation was studied in two murine neuroblastoma clones, N1 and N7. At the membrane level, gelatinase MMP-2--mainly the activated form--was restrained by CNTF and BDNF to a residual 34% with both factors; membrane-type 1 MMP was down-regulated to 50% (10 h) and 34% (24 h) with both factors; and urokinase-type plasminogen activator was restrained mainly by BDNF to 70%. In the medium, the two gelatinases MMP-2 and MMP-9 were mainly in zymogen form: only MMP-2 was restrained in N1 cells, while only MMP-9 was restrained in N7 cells by both factors, single or in combination. These effects were paralleled by the induction of neurite outgrowth, which was more stimulated in the less differentiated clone. These dose-dependent and transient effects make CNTF and BDNF ideal candidates for constraining the potentially invasive behavior of nervous system tumors.
Clin Exp Metastasis 2002
PMID:Modulation of proteolytic potential and differentiation by CNTF and BDNF in two mouse neuroblastoma clones: relation to invasion. 1255 77

As the TNF and TNFR superfamilies have grown to more than two dozen combined members over the past 30 years, their involvement in interactions between immune cells, with regard to the events governing cellular differentiation, activation, and survival have been well established. The recently identified TNF superfamily cytokine, TRANCE (RANKL/OPGL/ODF/TNFSF11), which interacts with two receptors-one functional, TRANCE-R (RANK/TNFRSF11A), and one decoy, OPG (TNFRSF11B)-is a survival factor for activated dendritic cells, and may also be important for the maintenance of immune tolerance. TRANCE is also the key cytokine involved in osteoclast differentiation and activation, making TRANCE signaling crucial for proper bone homeostasis, and a potential therapeutic target in diseases such as osteoporosis, osteolytic metastatic cancer, arthritis, and periodontitis. Importantly, the positive role that TRANCE has in activating the immune system, appears to significantly contribute to pathologic bone loss. These observations have spurred intense study of the various ways in which the immune system can influence bone. Furthermore, TRANCE has also been demonstrated to play essential roles in the developmental processes leading to both lymph node formation, and the expansion and function of mammary glands during pregnancy and lactation. Thus, TRANCE is quickly emerging as a cytokine of significant importance to further understanding unique aspects of mammalian biology.
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PMID:Biology of the TRANCE axis. 1278 63

Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that are activated and translocated into the nucleus after phosphorylation at a conserved tyrosine residue. Mouse model studies have demonstrated that activated Stat5a acts as a critical survival factor for normal, preneoplastic and malignant mammary epithelial cells. Very limited information is available, however, on the expression, tyrosine phosphorylation status and nuclear localization of Stat5a in human breast cancers. In our study, the pattern of Stat5a cellular localization was analyzed by immunohistochemistry in a series of 83 randomly selected primary human breast adenocarcinomas. Immunoprecipitation/Western blotting and immunohistochemistry assays employing different phospho-specific antibodies verified Stat5a tyrosine phosphorylation status. Stat5a was nuclear localized and tyrosine phosphorylated in 59 of 78 (76%) breast cancers examined; 38 of 78 (49%) demonstrated Stat5a nuclear localization in more than 25% of the breast cancer cells within the adenocarcinomas. Nuclear localized Stat5a was associated positively with increased levels of histologic differentiation (p = 0.03). A statistically significant positive association with p27 nuclear localization also was identified (p = 0.05). No relationship was found between nuclear localized Stat5a and menopausal status, tumor size, ploidy, percentage of cells in S-phase, lymph node metastases, ER, ErbB2, nuclear localized p21 or nuclear localized Stat5b/Stat3. As its role in human breast cancer progression and response to therapy is defined, Stat5a could become a new molecular target for breast cancer therapy.
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PMID:Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers. 1469 92

VEGF is a specific mitogen and survival factor for endothelial cells and a key promoter of angiogenesis in physiological and pathological conditions. Nevertheless, VEGF tissue evaluation in cancer patients as a prognostic factor compared to the conventional histological and biological parameters is still controversial. In this case-control study, tissue VEGF was retrospectively determined by immunohistochemistry and related to T, N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 in 129 breast cancer patients. Seventy-four of these patients had developed distant metastases postoperatively. The remaining 55 patients had remained disease-free >10 years after surgery. In 17 (13%) of the 129 patients (six with distant metastases and eleven disease-free) tissue and plasma VEGF were concomitantly evaluated. In univariate analysis no significant differences in VEGF and tumor size were found between metastatic and disease-free patients, whereas there were significant differences in N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 (p ranging from 0.001 to 0.0001). In multivariate analysis VEGF showed less significance than N, ER, c-erbB-2, MIB-1 and cyclin D1 (p = 0.012, p = 0.007, p = 0.005, p = 0.005, p = 0.002 and p = 0.001, respectively). VEGF was a significant unfavorable prognostic indicator only in the N+ subset (p = 0.015), while ER (p = 0.05 and p = 0.021) and MIB-1 (p = 0.031 and p = 0.022) were significant in both the N+ and N- subgroups. In multivariate analysis in the 74 metastatic cases VEGF did not show any significance in relation to disease-free interval and overall survival from the time of mastectomy and from the time of relapse, whereas N and PgR did (p ranging from 0.018 to 0.001). In conclusion, tissue VEGF does not seem a suitable candidate to replace conventional histological and other common biological prognostic factors in breast cancer.
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PMID:Vascular endothelial growth factor (VEGF) and other common tissue prognostic indicators in breast cancer: a case-control study. 1564 33


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