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)

Recent studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. We examined the expression of p53 and vascular endothelial growth factor (VEGF), a well-characterized angiogenic inducer, together with microvessel density to investigate the role of p53 in the regulation of angiogenesis and its clinical significance in human colorectal carcinoma. Surgically resected specimens of 163 colorectal carcinomas were studied by immunohistochemical staining for p53 protein, VEGF and factor VIII-related antigen. Positive p53 protein accumulation and VEGF expression was found in 41.7% and 49.1% of tumors, respectively. p53 and VEGF staining status was identical in 65.6% of tumors. The incidence of p53- or VEGF-positive tumors was significantly higher in patients with venous invasion and liver metastases than in those without. The microvessel count (MVC) in p53- or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-positive tumors was significantly higher than that in the other subgroups. Neither synchronous nor metachronous hepatic metastases were found in patients with p53- and VEGF-negative tumors, while 52.2% of patients with both-positive tumors had liver metastases and had a poorer prognosis than those with both-negative tumors. Our findings suggest the presence of a p53-VEGF pathway regulating tumor angiogenesis in human colorectal carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the occurrence of liver metastasis in patients with this disease.
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PMID:Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. 935 71

Tumor growth and metastasis are angiogenesis dependent. Previously, we reported that angiostatin, a potent angiogenesis inhibitor, produced by a primary Lewis lung carcinoma suppressed its growth of lung metastases (O'Reilly, M.S., L. Holmgren, Y. Shing, C. Chen, R.A. Rosenthal, M. Moses, W.S. Lane, Y. Cao, E.H. Sage, and J. Folkman. 1994. Cell. 79:315-328). Now we show that a shift of balance of tumor angiogenesis by gene transfer of a cDNA coding for mouse angiostatin into murine T241 fibrosarcoma cells suppresses primary and metastatic tumor growth in vivo. Implantation of stable clones expressing mouse angiostatin in C57Bl6/J mice inhibits primary tumor growth by an average of 77%. After removal of primary tumors, the pulmonary micrometastases in approximately 70% of mice remain in a microscopic dormant and avascular state for the duration of the experiments, e.g., 2-5 mo. The tumor cells in the dormant micrometastases exhibit a high rate of apoptosis balanced by a high proliferation rate. Our study, to our knowledge, for the first time shows the diminished growth of lung metastases after removal of the primary tumor, suggesting that metastases are self-inhibitory by halting angiogenesis. Our data may also provide a novel approach for cancer therapy by antiangiogenic gene therapy with a specific angiogenesis inhibitor.
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PMID:Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases. 948 76

Nitric oxide (NO) is a free radical molecule with high reactivity, a short half life and a variety of physiological activities. The role of NO in tumor microcirculation, based on the data collected to date, can be summarized as follows: 1) NO may partially mediate tumor angiogenesis; 2) endogenous NO derived from tumor vascular endothelium and/or tumor cells increases and/or maintains tumor blood flow via dilatation of arteriolar vessels, decreases leukocyte-endothelial interaction, and increases vascular permeability; 3) exogenous NO can increase tumor blood flow via vessel dilatation, and reduce vessel tone; and 4) NO production rates and vascular response to NO are heterogeneous and tumor-dependent. Modulation of NO level in tumor vessels can alter tumor hemodynamics and thus augment oxygen, drug, gene vector and effector cell delivery to solid tumors.
Cancer Metastasis Rev 1998 Mar
PMID:Role of nitric oxide in angiogenesis and microcirculation in tumors. 954 24

Nitric oxide (NO), a potent biological mediator, plays a key role in physiological as well as pathological processes, including inflammation and cancer. The role of NO in tumor biology remains incompletely understood. While a few reports indicate that the presence of NO in tumor cells or their microenvironment is detrimental to tumor cell survival and consequently their metastatic ability, a large body of clinical and experimental data suggest a promoting role of NO in tumor progression and metastasis. We suggest that tumor cells capable of very high levels of NO production die in vivo, and those producing or exposed to lower levels of NO, or capable of resisting NO-mediated injury undergo a clonal selection because of their survival advantage; they also utilize certain NO-mediated mechanisms for promotion of growth, invasion and metastasis. The possible mechanism(s) are: (a) a stimulatory effect on tumor cell invasiveness, (b) a promotion of tumor angiogenesis and blood flow in the tumor neovasculature, and (c) a suppression of host anti-tumor defense. In this review, we discuss these mechanisms on the basis of data derived from experimental models, in particular, a mouse mammary tumor model in which the expression of eNOS by tumor cells is positively correlated with invasive and metastatic abilities. Tumor-derived NO was shown to promote tumor cell invasiveness and angiogenesis. The invasion-stimulating effects of NO were due to an upregulation of matrix metalloproteases and a downregulation of their natural inhibitors. Treatment of tumor-bearing mice with NO-blocking agents reduced the growth and vascularity of primary tumors and their spontaneous metastases. We propose that selected NO-blocking drugs may be useful in treating certain human cancers either as single agents or as a part of combination therapies.
Cancer Metastasis Rev 1998 Mar
PMID:Role of nitric oxide in tumor progression: lessons from experimental tumors. 954 25

Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.
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PMID:Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. 954 82

Tumor induced angiogenesis is responsible for the nutrition of the growing tumor and can also increase the probability of hematogenous tumor dissemination. Data obtained from morphological analysis of tumor angiogenesis can contribute to the development of new anti-angiogenic therapies. Based on in vitro and in vivo observations several models of angiogenesis were introduced, explaining the mechanism of lumen formation and the timing of basement membrane depositon. (1) Lumen is formed either by cell body curving or by fusion of intracellular vacuoles of nonpolarized endothelial cells. New basement membrane is deposited after lumen formation. (2) Slit-like lumen is immediately formed by migrating polarized endothelial cells. Basement membrane is continuously deposited during endothelial cell migration, only cellular processes of the endothelial cell migrating on the tip of the growing capillary are free of deposited basement membrane material. (3) Development of transluminal bridges in larger vessels a process called intussusceptive growth leads to the division of the vessels. These models, however, describe angiogenesis in tissues rich in connective tissue. Different processes of angiogenesis take place in organs such as liver, lungs, adrenals, which are the most frequent sites of metastasis having high vessel density without sufficient space for capillary sprouting. In the case of liver metastases of Lewis lung carcinoma the proliferation of endothelial cells was elicited only by direct contact between tumor and endothelial cells, leading to the development of large convoluted vessels inside the metastases. These vessels were continuous with the sinusoidal system, suggesting that these metastases have dual blood supply. This observation, among others, is in contrast to the generally accepted view that liver tumors have arterial blood supply. The increasing number of data demonstrating the dual or venous blood supply of liver metastases should be taken into consideration in the therapy of liver metastasis.
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PMID:Current concepts of tumor-induced angiogenesis. 955 24

Concomitant resistance (CR), the phenomenon by which tumor-bearing hosts are able to inhibit secondary implants of the same tumor at distant sites of the body, has been previously observed by us and others in different murine tumor models. Here, we verified the generation of CR in nude mice by tumors induced by SC inoculation of Calu-6, a human lung carcinoma cell line. Histological analysis of secondary tumors subject to CR did not reveal macrophage infiltration nor cytotoxic signs. Although serum from tumor-bearing mice inhibited in vitro [3H]thymidine uptake by Calu-6 cells, no significant differences in [3H]thymidine labeling index of tumors implanted in the right flank of mice with and without a primary tumor in the left flank were detected. In our model, the presence of a primary tumor hindered remote tumor angiogenesis, as well as serum from tumor-bearing mice inhibited in vitro proliferation of an endothelial cell line derived from a murine hemangioendothelioma. Conversely, an enhancement of the apoptotic index was observed in secondary tumor implants carried out in tumor-bearing mice. The results reported herein show that human tumor cells are capable of inducing CR, and that this phenomenon would be a consequence of an impaired neovascularization as well as an increased programmed cell death at sites distant from the primary tumor.
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PMID:Antiangiogenesis and apoptosis as mediators of concomitant tumor resistance induced by Calu-6, a human lung carcinoma cell line, in nude mice. 961 53

Angiogenesis is required for tumor growth and metastasis, and inhibition of angiogenesis is a promising approach for anticancer therapy. Tie2 (a.k.a Tek) is an endothelium-specific receptor tyrosine kinase known to play a role in tumor angiogenesis. To explore the therapeutic potential of blocking the Tie2 pathway, an adenoviral vector was constructed to deliver a recombinant, soluble Tie2 receptor (AdExTek) capable of blocking Tie2 activation. Two days after i.v. injection of AdExTek, the plasma concentration of ExTek exceeded 1 mg/ml and was maintained for about 8 days. Administration of AdExTek to mice with two different well established primary tumors, a murine mammary carcinoma (4T1) or a murine melanoma (B16F10.9), significantly inhibited the growth rate of both tumors (64% and 47%, respectively). To study the effect of ExTek on tumor metastasis, both tumor cell lines were coinjected i.v. with either AdExTek or a control virus. Mice coinjected with control virus developed numerous large, well vascularized lung metastases. In contrast, mice coinjected with AdExTek virus developed few, if any, grossly apparent metastases, and histologic examination revealed only small avascular clusters of tumor cells. Administration of AdExTek also inhibited tumor metastasis when delivered at the time of surgical excision of primary tumors in a clinically relevant model of tumor metastasis. This study demonstrates the potential utility of gene therapy for systemic delivery of an antiangiogenic agent targeting an endothelium-specific receptor, Tie2.
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PMID:Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. 967 64

Prostate-specific membrane antigen is a type II membrane protein with folate hydrolase activity produced by prostatic epithelium. The expression of this molecule has also been documented in extraprostatic tissues, including small bowel and brain. In the present study, an extensive immunohistochemical analysis was performed on a panel of well-characterized normal and malignant human tissues to further define the pattern of prostate-specific membrane antigen (PSMA) expression. Detectable PSMA levels were identified in prostatic epithelium, duodenal mucosa, and a subset of proximal renal tubules. A subpopulation of neuroendocrine cells in the colonic crypts also exhibited PSMA immunoreactivity. All other normal tissues, including cerebral cortex and cerebellum, had undetectable levels of PSMA. Thirty-three of 35 primary prostate adenocarcinomas and 7 of 8 lymph node metastases displayed tumor cell PSMA immunostaining. Eight of 18 prostate tumors metastatic to bone expressed PSMA. All of the other nonprostatic primary tumors studied had undetectable PSMA levels. However, intense staining was observed in endothelial cells of capillary vessels in peritumoral and endotumoral areas of certain malignancies, including 8 of 17 renal cell carcinomas, 7 of 13 transitional cell carcinomas, and 3 of 19 colon carcinomas. Extraprostatic PSMA expression appears to be highly restricted. Nevertheless, its diverse anatomical distribution implies a broader functional significance than previously suspected. The decrease in PSMA immunoreactivity noted in advanced prostate cancer suggests that expression of this molecule may be linked to the degree of tumor differentiation. The neoexpression of PSMA in endothelial cells of capillary beds in certain tumors may be related to tumor angiogenesis and suggests a potential mechanism for specific targeting of tumor neovasculature.
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PMID:Prostate-specific membrane antigen expression in normal and malignant human tissues. 981 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


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