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)

We have previously reported that p53 mutations, loss of bax expression or decreased spontaneous tumor apoptosis were associated with poorer prognoses in maxillary sinus squamous cell carcinoma (SCC)(Cancer 94: 1968-1980, 2002). In the present study, we analyzed tumor angiogenesis monitored by expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and tumor microvessel density, in correlation with p53 status, spontaneous apoptosis or disease prognosis in the same group of 70 maxillary sinus SCC patients. Tumor biopsy specimens obtained prior to initiation of treatment were examined for expression of VEGF and bFGF and tumor microvessel density using immunohistological methods. Average vessel density (AVD) (range: 3-75; median: 25) and maximum vessel density (MVD) (range: 4-125; median: 53) were assessed by the number of microvessels stained with anti-CD31 mAb in tumor lesions. VEGF was expressed in 35 (50%) of 70 patients and bFGF was in 43 (61%). Patients with VEGF expression showed significantly higher levels of MVD than those without VEGF expression (57 vs. 38; P=0.019). The VEGF expression was observed more frequently in patients with p53 overexpression and/or mutation than in those with normal p53 status (P=0.048). The MVD inversely correlated with the apoptotic index (AI) defined as the number of single stranded (ss)-DNA-positive cells per 1000 tumor cells (r= -0.23; P=0.022). Patients with neck lymph node and/or distant metastases after surgery showed significantly higher levels of MVD than patients without any metastasis (64 vs. 42; P=0.048). Low histological effectiveness of radiochemotherapy correlated with bFGF expression (P=0.0059). To clarify actual prognostic factors for maxillary sinus SCC, we selected 57 patients treated uniformly with preoperative radiochemotherapy followed by maxillectomy. Kaplan-Meier analysis showed that survival was significantly worse in patients with high MVD (> or =80) than in those with low MVD (<80) (P=0.042). These data suggest that the VEGF expression in association with the p53 overexpression and/or mutations may cause increased microvascularity, decreased spontaneous apoptosis or metastases, while the bFGF expression may be associated with resistance to radiochemotherapy, thereby resulting in poorer prognoses in maxillary sinus SCC. VEGF and bFGF expression and tumor microvessel density in tumor lesions were analyzed in 70 patients with maxillary sinus squamous cell carcinoma. The VEGF expression dependent of p53 overexpression and/or mutations was associated with angiogenesis, decreased spontaneous tumor apoptosis and metastases, while the bFGF expression was associated with resistance to radiochemotherapy, resulting in poor prognosis.
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PMID:VEGF and bFGF expression and microvessel density of maxillary sinus squamous cell carcinoma in relation to p53 status, spontaneous apoptosis and prognosis. 1514 81

Patients with breast cancer brain metastases cannot be cured and have a poor prognosis, with a median survival time of six months after diagnosis, despite developments in diagnostic and therapeutic modalities. In large part the progress in understanding the biology of breast cancer brain metastasis has been limited by the lack of suitable cell lines and experimental models. The objective of this study was to develop a reliable experimental model to study the pathogenesis of breast cancer brain metastases, using intra-internal carotid artery injection of breast cancer cells into nude mice. Brain metastasis-selected variant cells were recovered after three cycles of injection into the internal carotid artery of nude mice and harvest of brain metastases, resulting in variants termed MDA-231 BR1, -BR2 and -BR3. The metastasis-selected cells had increased potential for experimental brain metastasis and mice injected with these cells had significantly shorter mean survival than mice injected with the original cell line. Brain metastatic lesions of the selected variants contained significantly more CD31-positive blood vessels than metastases of the non-selected cell line. The variants selected from brain metastases released significantly more VEGF-A and IL-8 into culture supernatants than the original cell line, and more VEGF-A RNA when cultured in normoxic conditions. Mice injected with MDA-231 BR3 into the carotid artery were treated with the VEGF-receptor tyrosine kinase inhibitor PTK787/Z 222584. Oral administration of the inhibitor resulted in a significant decrease in brain tumor burden, reduced CD31-positive vessels in the brain lesions and incidence of PCNA positive tumor cells, and increased apoptosis in the tumor, as measured by TUNEL labeling. We conclude that elevated VEGF expression contributes to the ability of breast cancer cells to form brain metastases. Targeting endothelial cells with a VEGF-receptor specific tyrosine kinase inhibitor reduced angiogenesis and restricted the growth of the brain metastases.
Clin Exp Metastasis 2004
PMID:Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. 1516 28

Concomitant antitumoral resistance (CAR), the phenomenon by which the growth of distant secondary tumor implants or metastases in some tumor-bearing hosts is inhibited by the presence of a primary tumor, has been previously ascribed to an antiangiogenic process. Here, we investigated vascular endothelial growth factor (VEGF) and endostatin serum levels in nude or BALB/c mice bearing human lung tumors (Calu-6 and H460) or murine mammary tumors (M3MC, M-234p and M-234m), respectively. In these experimental models we previously found an association between in vivo generation of CAR and in vitro conversion of plasminogen into angiostatin. Serum endostatin level in CAR+ Calu-6-bearing mice was significantly higher than in CAR- H460 counterpart. Sera from mammary tumor-bearing mice showed similar levels of endostatin, regardless of their ability to induce CAR. Conversely, serum VEGF levels in mice bearing CAR+ tumors were lower than those found in CAR- tumor-bearing hosts. Immunostaining with an anti-CD31 antibody revealed that secondary tumors subjected to CAR were significantly less vascularized than primary tumors, while this difference was not observed in CAR- tumors. In vitro studies showed an inhibitory effect of sera from CAR-inducing tumors on endothelial cell proliferation as compared to normal sera, whereas sera from non-CAR-inducing tumors did not alter endothelial proliferation and, in some instances, even caused stimulation of endothelial proliferation. These data suggest that the antiangiogenic mechanism operating in concomitant antitumoral resistance is the result of an increase in the ratio of antiangiogenic/proangiogenic regulators. The levels of the factors involved in this phenomenon can vary in the different tumor models, but the trend favoring the inhibition of angiogenesis is always conserved.
Clin Exp Metastasis 2004
PMID:Angiogenic and antiangiogenic balance regulates concomitant antitumoral resistance. 1516 35

In animal models, explosive growth of metastases after removal of the primary tumor has been attributed to abolishment of angiogenesis inhibition. We investigated the influence of (removal of) the primary tumor on vascularization of liver metastases in human colorectal cancer patients. We analyzed vascular density in synchronous liver metastases from patients with the primary tumor in situ, in synchronous metastases from patients with the primary tumor resected and in metachronous metastases. In a limited number of cases, biopsies from metastases from the same patient before and within 3 months after resection were analyzed. In addition, vascular density in metastases was compared to the vascular density in the corresponding primary tumor. Peritumoral and intratumoral vascular density were determined by staining for endothelial antigens CD31 and CD34, respectively. Both peritumoral and intratumoral vascular density were elevated in synchronous metastases from patients with the primary tumor removed compared to synchronous metastases from patients with the primary tumor in situ. Comparable results were observed in patients with metachronous metastases. An increase in vascular density after resection of the colorectal malignancy was also observed in biopsies taken from the same patient before and after tumor resection. Remarkably, vascular density in the liver metastases was always lower than that in the corresponding primary tumor. Our data show for the first time in humans that the presence of a primary tumor is correlated with decreased vascularization of its distant metastases. Resection of the primary tumor results in an increased vascularization of metastatic lesions.
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PMID:Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. 1538 35

We report a rare finding of bone marrow metastasis from an angiosarcoma. The patient was a 36-year-old man who initially presented with a high-grade angiosarcoma of the spleen and was treated with splenectomy and chemotherapy. He developed leukoerythroblastic anemia three years after splenectomy. Bone marrow biopsy revealed extensive infiltrate by angiosarcoma with typical features of spindle tumor cells and anastomosing vascular channels. The immunohistochemistry showed tumor cells positive for the endothelial markers of CD31, CD34, and von Willebrand factor. Angiosarcomas are rare and aggressive tumors. Although metastases occur commonly, bone marrow findings have been rarely documented. We have found in the literature two other cases of bone marrow metastasis of angiosarcoma, and all these patients had a primary tumor of the spleen. It would seem that splenic angiosarcomas have a virtually unique propensity for infiltration in the bone marrow.
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PMID:Bone marrow metastasis of angiosarcoma. 1546 3

Our aim was to study the effect of hypercholesterolemia on angiogenesis induced by breast carcinoma. Of 51 patients with invasive ductal carcinoma, 28 had hypercholesterolemia and 23 had normocholesterolemia. The intratumoral microvessel density (MVD) was evaluated by using anti-CD31 antibody. The expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on endothelial and tumor cells was examined and graded semiquantitatively. Patients with normocholesterolemia had a higher MVD (76.4 +/- 8.2) than those with hypercholesterolemia (54.6 +/- 5.1) (P < .01). The risks of recurrence and distant metastasis were higher in patients with normocholesterolemia than in patients with hypercholesterolemia (P < .01). Patients with hypercholesterolemia showed lower expression of endothelial VEGF and bFGF than patients with normocholesterolemia (P < .05 and P < .01, respectively). In addition, tumoral bFGF and VEGF expression showed negative correlation with the presence of hypercholesterolemia (P < .01). We suggest that hypercholesterolemia impairs angiogenesis by suppressing endothelial and tumoral bFGF and VEGF expression and, therefore, lowers the risk of metastases in cases of invasive breast carcinoma.
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PMID:Hypercholesterolemia impairs angiogenesis in patients with breast carcinoma and, therefore, lowers the risk of metastases. 1549 62

Angiosarcoma is a relatively uncommon primary malignant tumor of the heart derived from the endothelial cells. The authors report a case of primary cardiac angiosarcoma of the right atrium with pulmonary, hepatic, cerebellar and bony metastases in a 46-year-old man who clinically presented as pulmonary hemorrhage. The patient's occupational history had occasional exposure to polyvinyl chloride. The autopsy examination of the cardiac angiosarcoma characterized macroscopically by a right atrial tumor and histologically by anastomosing vascular channels and minute atypical pleomorphic endothelial cells. Immunohistological stainings were positive CD31, CD34 and focal positive factor VII-related antigen. Clinical and pathologic features with briefly reviewed relevant literatures are discussed This is the first reported description in the literature of a primary cardiac angiosarcoma with systemic metastases to multiple organs in Thailand.
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PMID:Primary cardiac angiosarcoma with systemic metastases; a case report and review of the literature. 1551 16

Diffuse lung involvement by metastatic tumor from an unknown primary site often constitutes a diagnostic dilemma. Although cytologic features and pattern of metastatic spread can guide in narrowing the list of possible primary neoplasms, immunohistochemistry remains pivotal in determining the phenotype of metastatic disease. We report a case with extensive involvement of lung parenchyma by a metastatic epithelioid neoplasm exhibiting a variety of distinctive patterns with a predominance of intra-arterial and lymphangitic spread. Immunohistochemical studies showed no evidence of epithelial, melanocytic, or lymphoid differentiation. The neoplastic cells were strongly positive for vimentin and CD31 but negative for CD34 and factor VIIIR:Ag. Electron microscopy of formalin-fixed tissue revealed multiple Weibel-Palade bodies and pinocytosis, supporting the diagnosis of epithelioid angiosarcoma. Doppler studies performed after pathologic diagnosis was rendered demonstrated 2 discrete hypoechoic masses within the medial aspect of the left proximal calf musculature, suggestive of solid soft tissue neoplasm-a possible source of pulmonary metastatic disease.
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PMID:Epithelioid angiosarcoma involving the lungs. 1562 28

Heparanase is an endoglycosidase that degrades heparan sulfate (HS) in the extracellular matrix (ECM) and cell surfaces, and fulfills a significant role in cancer metastasis and angiogenesis. We evaluated the expression of heparanase and its possible association with the expression of angiogenic molecules in malignant mesothelioma (MM), and analyzed whether expression of these proteins is site-related (pleural vs peritoneal MM, solid lesions vs effusions). Sections from 80 MM (56 biopsies, 24 effusions) were analyzed for heparanase protein expression using immunohistochemistry (IHC). Sixty MM were of pleural origin, and 20 were peritoneal. Effusion specimens consisted of 6 peritoneal and 18 pleural effusions, while biopsies consisted of 14 peritoneal and 42 pleural lesions. Fifty-four specimens were additionally evaluated for expression of basic fibroblast growth factor (bFGF), interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) proteins using IHC. Microvessel density (MVD) was studied in 28 biopsies using an anti-CD31 antibody. mRNA expression of heparanase (HPSE-1), VEGF and the VEGF receptor KDR was analyzed in 23 effusions using RT-PCR. Heparanase protein expression was seen in 69/80 (86%) tumors. Of these, 35 showed combined membrane and cytoplasmic expression, 30 cytoplasmic expression, and four exclusively membrane expression. Both total (P = 0.001) and cytoplasmic (P = 0.002) expression was significantly higher in solid tumors compared to effusions. Protein expression of VEGF, IL-8 and bFGF was seen in 21/54 (39%), 22/54 (41%) and 44/54 (81%) specimens, respectively. Protein expression of bFGF was significantly higher in solid tumors (P < 0.001) and correlated with heparanase expression (P = 0.005). HPSE-1 and VEGF mRNA expression was detected in all 23 effusions using RT-PCR, while KDR mRNA was found in 12/23 MM. KDR mRNA expression correlated with that of both HPSE-1 (P = 0.005) and VEGF (P = 0.001). Our results document frequent expression of heparanase in MM, in agreement with the biological aggressiveness of this tumor. The co-expression of heparanase with bFGF is in agreement with the role of the former in releasing bFGF from the ECM. The concomitant reduction in protein expression of both molecules in effusions as compared to solid tumors, supports the hypothesis of a reduced need for pro-angiogenic stimuli in effusions, and may aid in defining tumor progression in this setting.
Clin Exp Metastasis 2004
PMID:Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. 1567 72

Osteopontin (OPN) is a secreted phosphoglycoprotein known to interact with a number of integrin receptors. While increased OPN expression has been reported in a number of human cancers, and its cognate receptors (alphav-beta3, alphav-beta5, and alphav-beta1 integrins and CD44) have been identified, its role in colon cancer development and progression has not been extensively studied. We previously identified, using a combination of gene expression and tissue microarrays, that increased OPN expression is concordant with tumor stage. The current study examined the functional role of OPN in colon cancer progression and metastatic potential. The principal findings of this study were that both endogenous OPN expression (via stable transfection) as well as exogenous OPN (added to culture medium) enhanced the motility and invasive capacity of human colon cancer cells in vitro. OPN appeared to regulate motility though interaction with CD44. OPN expression also reduced intercellular (homotypic) adhesion, an important characteristic of metastatic cancer cells. Stable transfection of four poorly tumorigenic human colon cancer cell lines with OPN also resulted in enhanced tumorigenicity in vivo with increased proliferation and increased CD31 positive microvessel counts, concordant with the degree of OPN expression. Collectively, these results suggest that OPN may affect multiple functional components contributing to human colon cancer progression and solidifies its role in this process.
Clin Exp Metastasis 2004
PMID:Osteopontin regulates multiple functions contributing to human colon cancer development and progression. 1567 49


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