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)

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

Six childhood vascular tumors were designated as "malignant endovascular papillary angioendothelioma" by Dabska in 1969. Since then, a few reports of similar cases were published, often called "Dabska tumors." Twelve similar cases were identified in review of vascular tumors from the authors' institutions. There were five men and seven women, including seven adults. Patient ages ranged from 8 to 59 years (mean, 30 years). The tumors occurred in the dermis or subcutis of the buttocks or thigh (n = 6), thumb or hand (n = 3), abdomen (n = 2), and heel (n = 1). The tumor sizes ranged from 1 to more than 40 cm (mean, 7.0 cm). The unifying feature of all cases was distinctive intravascular growth of well-differentiated endothelial cells presenting as a matchstick columnar configuration, sometimes with a large production of matrix that was positive for collagen type IV. In half the cases, these intravascular proliferations had an associated actin-positive pericytic proliferation. There was minimal cytologic atypia and rare to absent mitotic activity. Two cases had an adjacent lymphangioma, and two additional cases had clusters of lymphatic vessels adjacent to the tumor. All but two of the cases showed varying degrees of stromal or intraluminal lymphocytes. Occasional epithelioid endothelial cells were seen, but no cases had features typical of epithelioid, spindle cell, or retiform hemangioendothelioma. Tumor cells were positive for vimentin, von Willebrand factor, CD31, and focally for CD34 and were negative for keratins, epithelial membrane antigen, S-100 protein, and desmin. Vascular endothelial cell growth factor receptor type 3, a recently introduced marker for lymphatic endothelia, was positive in all eight cases that were studied, supporting a lymphatic phenotype. Follow-up in 8 of the 12 cases showed no evidence of recurrences, metastases, or residual disease during follow-ups ranging from 1 to 17 years (mean, 9 years). Based on the proliferative borderline features and the lymphatic phenotype, we propose to designate these tumors as papillary intralymphatic angioendothelioma. Additional cases with extensive follow-up should be studied to rule out variants with malignant potential.
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PMID:Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels. 1047 59

The aim of the present study was to investigate the intensity of angiogenesis and p53 protein expression in metastases of lung cancer to the brain. There were eight cases of squamous cell type and nine adenocarcinomas among 17 examined cases of metastatic carcinomas. The antibodies against von Willebrand factor (vWF)--to highlight the microvessels and against p53 protein--for detection of immunopositive cells were used. The intensity of angiogenesis was represented by the mean number of the blood vessels in three tumor fields with the highest microvascular density ("hot spots"). The measurements were taken in three microscopic fields under 200x magnification (the examined area was 0.785 mm2). The mean number of p53-positive cells in three tumor areas under 200x magnification with the highest number of p53-positive cells was the measure of protein p53 expression. The values of vascular density and p53 expression differed a lot among the examined tumors. The values of vascular density were between 4.2-106 vessels/mm2 (mean value 49.3 vessel/mm2). The number of p53-immunopositive cells was between 0-284 cells/mm2 (mean value 110.6 cells/mm2). There was no significant correlation between examined parameters (correlation coefficient 0.18).
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PMID:The metastases of lung cancer to the brain--the examination of angiogenesis and p53 expression. 1058 58

A retrospective study of surgically resectable esophageal cancers was undertaken to determine the relationship between angiogenesis score and growth factor expression with tumor size, histology, degree of differentiation, depth of invasion, nodal disease, and the presence of Barrett's esophagus. The office and hospital charts of 27 patients who had esophageal resection for carcinoma between 1990 and 1995 at Rush-Presbyterian-St. Luke's Medical Center were reviewed. Data collection included patient demographics, survival, tumor size, histology, differentiation, depth of invasion, nodal metastases, and the presence of Barrett's esophagus. The pathology specimens were immunostained for von Willebrand factor (factor VIII-related antigen). Immunostaining was also performed for vascular endothelial growth factor and transforming growth factor alpha. Twenty normal esophageal specimens served as controls. Angiogenesis score was determined by counting vessels under conventional light microscopy at x200 magnification, and growth factor expression was graded on a scale of 1 to 4. Cancers had higher angiogenesis and growth factor expression than controls (P = 0.01). Patient age, tumor size, histology, differentiation, depth of invasion, and Barrett's esophagus did not correlate with angiogenesis score or tumor growth factor expression. Lymph node status did correlate with both angiogenesis score and growth factor expression (P < or = 0.02). We conclude that high angiogenesis score and growth factor expression correlate with the presence of lymph node metastases. This may help select patients for preoperative radiation and chemotherapy or determine the extent of surgery performed for esophageal carcinoma.
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PMID:Do angiogenesis and growth factor expression predict prognosis of esophageal cancer? 1077 79

A major obstacle that limits the potential of human gene therapy is the inefficiency of gene delivery to appropriate sites in vivo. Previous studies demonstrated that the physiological surveillance function performed by von Willebrand factor (vWF) could be incorporated into retroviral vectors by molecular engineering of the MuLV ecotropic envelope (Env) protein. To advance the application of vWF targeting technology beyond laboratory animals, we prepared an extensive series of Env proteins bearing modified vWF-derived matrix-binding sequences and assembled these chimeric proteins into targeted vectors that are capable of transducing human cells. Initially, a dual envelope configuration was utilized, which required coexpression of a wild-type amphotropic Env. Subsequently, streamlined "escort" Env proteins were constructed wherein the inoperative receptor-binding domain of the targeting partner was replaced by the vWF-derived collagen-binding motif. Ultimately, an optimal construct was developed that exhibited properties of both extracellular matrix (ECM)-targeting and near wild-type amphotropic infectivity, and could be arrayed as a single envelope on a retroviral particle. On intraarterial instillation, enhanced focal transduction of neointimal cells (approximately 20%) was demonstrated in a rat model of balloon angioplasty. Moreover, transduction of tumor foci (approximately 1-3%) was detected after portal vein infusion of a matrix-targeted vector in a nude mouse model of liver metastasis. We conclude that the unique properties of these targeted injectable retroviral vectors would be suitable for improving therapeutic gene delivery in numerous clinical applications, including vascular restenosis, laser and other surgical procedures, orthopedic injuries, wound healing, ischemia, arthritis, inflammatory disease, and metastatic cancer.
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PMID:Molecular engineering of matrix-targeted retroviral vectors incorporating a surveillance function inherent in von Willebrand factor. 1081 Dec 27

The liver is the most common site of metastasis in pancreatic cancer, and there are no promising strategies to treat it. Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The effect of angiostatin on liver metastasis in pancreatic cancer was investigated by using our established hamster model of liver metastasis. Pancreatic cancer cells (PGHAM-1, 1 x 10(6)) derived from N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic tumor in Syrian golden hamsters were transplanted into the spleen of female hamsters, and the animals were subcutaneously injected with angiostatin and saline. Subsequently, the macroscopic appearance of liver surface metastases was evaluated. In addition, histological sections of the liver metastases were analyzed for neovascularization, proliferation, and apoptosis on the basis of von Willebrand factor, argyrophilic nucleolar organizer region (Ag-NOR), and TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, respectively. The results showed significant tumor growth retardation and inhibition of angiogenesis in metastatic liver tumors in response to treatment with angiostatin. Moreover, the metastases remained in a nearly dormant state due to a balance between apoptosis and proliferation of the tumor, with no detectable side effects. This is the first experimental trial of angiostatin on pancreatic cancer and liver metastasis. The results suggest that angiostatin therapy could be effective against liver metastases of pancreatic cancer.
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PMID:Effect of angiostatin on liver metastasis of pancreatic cancer in hamsters. 1092 Feb 80

Inhibition of pulmonary metastases poses a difficult clinical challenge for current therapeutic regimens. We have developed an aerosol system utilizing a cationic polymer, polyethyleneimine (PEI), for topical gene delivery to the lungs as a novel approach for treatment of lung cancer. Using a B16-F10 murine melanoma model in C57BL/6 mice, we previously demonstrated that aerosol delivery of PEI-p53 DNA resulted in highly significant reductions in the tumor burden (P < .001) in treated animals, and also lead to about 50% increase in the mean length of survival of the mice-bearing B16-F10 lung tumors. The mechanisms of this antitumor effect of p53 are investigated in this report. Here, we demonstrate that the p53 transfection leads to an up-regulation of the antiangiogenic factor thrombospondin-1 (TSP-1) in the lung tissue and the serum of the mice. Furthermore, there is a down-regulation of vascular endothelial growth factor (VEGF) in the lung tissue and serum of the B16-F10 tumor-bearing mice treated with PEI-p53 DNA complexes, compared with untreated tumor-bearing animals. In addition, staining for von Willebrand factor (vWF), a marker for the angiogenic blood vessels, revealed that p53 treatment leads to a decrease in the angiogenic phenotype of the B16-F10 tumors. Immunohistochemistry for transgene expression reveals that the PEI-p53 aerosol complexes transfect mainly the epithelial cells lining the airways, with diffuse transfection in the alveolar lining cells, as well as, the tumor foci in the lung tissue. There was also some evidence of apoptosis in the lung tumor foci of animals treated with p53. The data suggest that aerosol delivery of PEI-p53 complexes leads to inhibition of B16-F10 lung metastases, in part by suppression of angiogenesis.
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PMID:Aerosol delivery of PEI-p53 complexes inhibits B16-F10 lung metastases through regulation of angiogenesis. 1191 42

Malignant change in a benign vascular tumor is exceedingly rare, and there have been only five previously reported convincing cases. Four new cases of angiosarcoma (AS) arising in a hemangioma/vascular malformation (HVM) are described. All patients were in the 6th or 7th decade of life (two female, two male). Development of an enlarging deep-seated mass was the main presenting symptom. MRI disclosed the presence of two separate soft tissue masses in both thighs in one patient. No patient had a history of prior radiotherapy at the same site. Preoperative duration, known in three cases, ranged from 1 to 24 months (median 12 months). Three tumors were located in the lower extremities (thigh and buttock), one in the retroperitoneum, and one in the parotid region. Three patients were treated by marginal excision; in one case only a biopsy was performed. Radiotherapy/chemotherapy was given in all cases. Two patients were disease free 2 and 14 months after surgery and two developed metastases. Grossly, the tumors were described as frankly hemorrhagic masses or as firm, whitish areas with hemorrhagic nodules and were centered in skeletal muscle in three cases. Size ranged between 2.2 cm and 8 cm (median 4.3 cm). Histologically, all the tumors had two distinct components. In three cases the benign and the malignant components were variably intermixed, whereas in one case the HVM was mainly located at the edge of the malignant tumor. The benign component showed features of an arteriovenous hemangioma (three cases) or intramuscular capillary hemangioma. AS showed epithelioid morphology in three cases and a well-differentiated dissecting pattern in one case. An imperceptible transition between the two components was noted in two cases. The two anatomically separate masses excised from one patient appeared almost identical. All cases were positive for at least two endothelial markers (CD31, CD34, VWF) and negative for the epithelial markers (EMA, AE1/AE3, Pan-keratin). Possible mechanisms for this exceptional phenomenon are discussed.
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PMID:Angiosarcoma arising in hemangioma/vascular malformation: report of four cases and review of the literature. 1236 47

Since solid tumours and metastases depend on adequate blood supply, much research is focused on inhibition of angiogenesis. Unfortunately, most known angiogenesis inhibitors have serious side effects when used as therapeutic agents in man. It is therefore important to develop methods to identify well-tolerated and efficient angiogenesis inhibitors. As a method for identification of new angiogenesis inhibitors we have further developed the procedure described by Bishop et al. (Angiogenesis 1999;3:335-44) to a quantitative ELISA-based fibroblast and endothelial cell co-culture angiogenesis assay. In each well of a 96-microwell plate, human umbilical vein endothelial cells (HUVEC) are seeded onto normal human dermal fibroblasts (NHDF) and propagated in co-culture for 72 h with or without a potential angiogenesis inhibitor. The effect on total cell proliferation is evaluated by quantitative immunochemical measurement of DNA, and on endothelial tube formation by quantification of CD 31, von Willebrand factor, and collagen IV. After ELISA reading, the morphology of the tubular structures formed by HUVEC is visualised with BCIP/NBT, permitting a quantitative result and a qualitative evaluation of cell morphology from the same well. We have used the assay to demonstrate the effect of well-known angiogenesis inhibitors on HUVEC tube formation.
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PMID:A quantitative ELISA-based co-culture angiogenesis and cell proliferation assay. 1296 22

Some studies have shown the influence of proteases and vascular density in colorectal primary tumors on spreading and on the course of colorectal cancer. In the present study we have analyzed the relationships between overexpression of cathepsin B protein and angiogenesis intensity in resected colon tumors and their impact on prognosis. It has been investigated in a series of 90 colon cancer patients. Immunohistochemistry was used to evaluate cathepsin B overexpression in cancer cells and to visualize microvessels with antibodies against von Willebrand factor. Overexpression of cathepsin B was observed if more than 50% of cancer cells in searched field showed immunoreactivity with antibody against cathepsin B. Intensity of angiogenesis was evaluated as a mean number of microvessels from three fields with highest vessel number. In 36 cases (40%) overexpression of cathepsin B was detected. Increased angiogenesis (above median 31 vessels per 0.785 mm2) correlated positively with cathepsin B overexpression (p=0.0006). Higher vascular density associated with the presence of metastases in regional lymph nodes (p=0.01). Overexpression of cathepsin B was observed more often in group of older people (age above median 65 years; p=0.005). According to univariate analysis metastases in regional lymph nodes (p=0.0007), increased angiogenesis (p=0.0085), and distant metastases (p=0.02) were the features potentially influencing prognosis. Multivariate analysis revealed independent prognostic value only in case of metastases in regional lymph nodes (p=0.013) and when distant metastases were present (p=0.021), but not when increased angiogenesis in primary colon adenocarcinoma was observed (p=0.078). In conclusion we can say that there is a close relationship between intensity of angiogenesis and overexpression of cathepsin B protein in cancer cells in resected colon adenocarcinoma.
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PMID:Overexpression of cathepsin B correlates with angiogenesis in colon adenocarcinoma. 1500 58


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