Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we showed that preinvasive breast pathologies, such as usual hyperplasia, atypical hyperplasia, and carcinoma in situ, have an increased vascularity when compared with normal breast tissue (S. C. Heffelfinger et al., Clinical Cancer Res., 2: 1873-1878, 1996). To understand the mechanism of this increased vascularity, we examined by immunohistochemistry each of these pathological lesions for the expression of angiogenic growth factors. These studies showed that normal breast tissue contains numerous angiogenic agents, particularly vascular endothelial cell growth factor and basic fibroblast growth factor. At the transition from normal epithelium to proliferative breast disease, insulin-like growth factor (IGF) II expression was increased, primarily in the stroma and infiltrating leukocytes. However, among proliferative tissues, IGF I decreased with increasing vascularity. Finally, both epithelial vascular endothelial growth factor and epithelial and leukocytic platelet-derived endothelial cell growth factor increased at the transition to carcinoma in situ, whereas stromal and leukocytic basic fibroblast growth factor were elevated only in invasive carcinoma. Therefore, during histological progression there is also a complex progression of angiogenic growth factors. For CIS, two forms of vascularity are found: stromal microvascular density (MVD), and vascularity associated with the epithelial basement membrane (vascular score). There was 35% discordance between these two measurement systems. Among carcinoma in situ cases, decreases in stromal IGF II were associated with increasing vascular scores but not MVD, and increases in platelet-derived endothelial cell growth factor were associated with increasing MVD but not the vascular score. The presence of discordance and differential association with specific angiogenic agents suggests that these two forms of vascularity may be differentially regulated.
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PMID:Angiogenic growth factors in preinvasive breast disease. 1053 55

Interleukin-12 (IL-12) is known to be a key cytokine for regulating immune response, but it is also known to provide some other biological function including inhibition of angiogenesis. We have determined using an enzymatic immunoassay the endogenous levels of IL-12 in 390 cytosols of primary breast cancers previously tested also for the angiogenic peptides, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). The concentration of IL-12 ranged from 0 to 7.6 ng/mg protein, and 124 (31.8%) out of 390 cancers showed a detectable dose (>0.1 ng/ml). There was no statistical association of IL-12 levels with tumor size and menopausal status. IL-12 levels tended to be higher in the tumors of node-positive patients as compared to those of node-negative ones (t-test, p=0.082). In addition, IL-12 levels were inversely associated with hormone receptor status, particularly progesterone receptor expression (p=0.0013). There was a significant inverse association between IL-12 and TP concentration (p=0.0007). The proportion of tumors with detectable levels of IL-12 and low levels of either VEGF or TP was higher among the patients with node-negative as compared to those with node-positive disease. On the contrary, the proportion of tumors with no detectable IL-12 and high levels of either VEGF or TP was higher in node-positive versus node-negative cancers. In conclusion, our study evaluated the balance between pro-angiogenic factors (TP and VEGF) and IL-12, as a detectable naturally occurring inhibitor of angiogenesis, in the same series of node-negative and node-positive breast cancers. Further studies are warranted to investigate the biological and clinical significance of the co-determination of pro and contra angiogenic factors in human breast carcinoma.
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PMID:Endogenous interleukin-12: relationship with angiogenic factors, hormone receptors and nodal status in human breast carcinoma. 1056 24

Surgical removal of a primary tumour is often followed by rapid growth of previously dormant metastases. Endotoxin or lipopolysaccharide, a cell wall constituent of Gram-negative bacteria, is ubiquitously present in air and may be introduced during surgery. BALB/c mice received a tail vein injection of 10(5) 4T1 mouse mammary carcinoma cells. Two weeks later, animals were subjected to surgical trauma or an intraperitoneal injection of endotoxin (10 microg per animal). Five days later, animals which underwent open surgery, laparoscopy with air sufflation or received an endotoxin injection displayed increased lung metastasis compared to anaesthetic controls. These increases in metastatic tumour growth were reflected in increased tumour cell proliferation and decreased apoptosis within lung metastases. Circulating levels of the angiogenic cytokine, vascular endothelial growth factor (VEGF), were also elevated in these groups and correlated with increased plasma levels of endotoxin. Endotoxin treatment for 18 h (>10 ng ml(-1)) directly up-regulated VEGF production by the 4T1 tumour cells in vitro. Metastatic tumour growth in mice undergoing carbon dioxide laparoscopy, where air is excluded, was similar to anaesthetic controls. These data indicate that endotoxin introduced during surgery is associated with the enhanced growth of metastases following surgical trauma, by altering the critical balances governing cellular growth and angiogenesis.
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PMID:The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. 1060 27

To elucidate the role of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, in tumour angiogenesis and malignant progression, an expression vector harboring human VEGF cDNA was stably transfected into three human cancer cell lines with poor VEGF productivity. Though their in vitro growth rate and intrinsic productivity of another angiogenic factor, basic fibroblast growth factor (bFGF), were not changed by transfection, those clones with higher VEGF production were endowed with tumorigenic and angiogenic potentials as follows: firstly, nontumorigenic, lung carcinoma QG90 cells having lower bFGF productivity acquired tumorigenicity as well as significant in vivo angiogenesis-inducing ability, secondly, tumorigenic colorectal carcinoma RPMI4788 cells having higher potency for bFGF production could form more vascularized solid tumour with faster growth rate and thirdly, oestrogen-dependent breast carcinoma MCF-7 cells, which did not produce detectable bFGF, acquired tumorigenicity even in the absence of oestrogen and the solid tumour growth rate was remarkably enhanced, accompanied with increased vascularization, in the presence of oestrogen. These results suggest that tumour progression closely depends on angiogenesis, and VEGF significantly contributes to malignant progression of a variety of tumour cells through its potent angiogenic activity, independent on the bFGF productivity of tumour cells.
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PMID:Vascular endothelial growth factor overproduced by tumour cells acts predominantly as a potent angiogenic factor contributing to malignant progression. 1060 18

To study the relationship between tumor angiogenesis and lymph node metastasis in primary breast carcinoma. Agiogenesis was assessed by the microvessel density (MVD) and expression of vascular endothelial growth factor (VEGF) using immunohistochemical staining. Paraffin-embedded specimens from 70 patients with primary breast cancer who had undergone radical mastectomy from 1984 to 1985 were studied. Thirty-one patients had histologically proven positive axillary lymph node (N+). The axillary node negative (N-) group was composed of thirty-nine patients. Microvessels per 200x (as MVD) and VEGF positively stained cancer cells per 400x were counted with light microscope. MVD and VEGF expression were higher in tumors with N+ showed than those with N-, MVD and VEGF expression were higher in N+ than in N-. MVD and the expression of VEGF are highly correlated with metastasis in primary breast cancer, which may serve as a parameter for determining tumor biological, metastatic potential and prognosis.
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PMID:[The correlation between tumor angiogenesis and lymph node metastasis in primary breast carcinoma]. 1067 42

Neuropilin-1 (NRP1) is a 130-kDa transmembrane receptor for semaphorins, mediators of neuronal guidance, and for vascular endothelial growth factor 165 (VEGF(165)), an angiogenesis factor. A 2.2-kb truncated NRP1 cDNA was cloned that encodes a 644-aa soluble NRP1 (sNRP1) isoform containing just the a/CUB and b/coagulation factor homology extracellular domains of NRP1. sNRP1 is secreted by cells as a 90-kDa protein that binds VEGF(165), but not VEGF(121). It inhibits (125)I-VEGF(165) binding to endothelial and tumor cells and VEGF(165)-induced tyrosine phosphorylation of KDR in endothelial cells. The 3' end of sNRP1 cDNA contains a unique, 28-bp intron-derived sequence that is absent in full-length NRP1 cDNA. Using a probe corresponding to this unique sequence, sNRP1 mRNA could be detected by in situ hybridization differentially from full-length NRP1 mRNA, for example, in cells of liver, kidney, skin, and breast. Analysis of blood vessels in situ showed that NRP1, but not sNRP1, was expressed. sNRP1 was functional in vivo. Unlike control tumors, tumors of rat prostate carcinoma cells expressing recombinant sNRP1 were characterized by extensive hemorrhage, damaged vessels, and apoptotic tumor cells. These results demonstrate the existence of a naturally occurring, soluble NRP1 that is expressed differently from intact NRP1 and that appears to be a VEGF(165) antagonist.
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PMID:Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. 1068 80

The angiogenic factor vascular endothelial growth factor (VEGF) predicts outcome in primary breast carcinoma. Alteration of the p53 gene causes down-regulation of the expression of thrombospondin-1, a natural inhibitor of angiogenesis. This study was conducted to investigate the association between mutant p53 protein and VEGF expression, and the prognostic value of these factors. VEGF165 and p53 protein were measured in tumour cytosols by enzyme immunoassays. Recurrence-free survival (RFS) and overall survival (OS) were estimated in 833 consecutive patients, 485 node-negative (NNBC) and 348 node-positive (NPBC) with primary invasive breast cancer. A significant association was found between mutant p53 protein and VEGF expression. Univariate analysis showed both p53 and VEGF to be significant predictors of survival. Similar correlation was seen when p53 was combined with VEGF. Univariate analysis of NNBC showed significant prognostic value of p53 for OS, also when combined with VEGF expression; for NPBC, significant reductions in RFS and OS were seen for p53-positive patients, and these findings were enhanced when combined with VEGF, also in the sub-group receiving adjuvant endocrine treatment. Multivariate analysis showed both p53 and VEGF as independent predictors of OS in all groups. When the 2 factors were combined, an increased relative risk of 2.7 was seen for OS in the group with both p53 positivity and high VEGF content, as compared with 1.7 in the group with one risk factor. The results suggest an association between loss of wt-p53 and increased VEGF expression, indicating that angiogenic activity may depend, at least partly, on altered p53-protein function. Combination of these 2 biological markers appears to give additional predictive information of survival. A high-risk group of patients was associated with p53 positivity and higher VEGF content.
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PMID:p53 and vascular-endothelial-growth-factor (VEGF) expression predicts outcome in 833 patients with primary breast carcinoma. 1071 31

Here we show that vascular endothelial growth factor (VEGF) mRNA expression is up-regulated in oncogene transformed rat liver epithelial (RLE) cell lines and that the extracellular signal-regulated kinase (ERK) and p38 kinase differentially regulate the oncogene-mediated stimulation of VEGF. The highest level of VEGF mRNA expression was observed in the v-H-ras transformed RLE cell line, followed by the v-raf and v-myc transformed lines. The PD98059 MEK inhibitor was used to block the ERK pathway and SB203580 inhibitor to block the p38 pathway. The parent and the v-H-ras transformed RLE cell lines showed up-regulation of VEGF RNA expression through the ERK pathway and down-regulation of VEGF through the p38 pathway. VEGF was regulated in a comparable manner in a human breast carcinoma cell line. In the v-raf and v-myc transformed RLE lines, positive regulation of VEGF was transduced through the p38 pathway. These findings suggest that (1) oncogenic ras differs from raf and myc in the recruitment of the MAPK signaling pathways for VEGF regulation; (2) that VEGF is regulated in ras transformed and human cancer cell lines in a positive and negative manner by the ERK and p38 signaling pathways.
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PMID:Different regulation of vascular endothelial growth factor expression by the ERK and p38 kinase pathways in v-ras, v-raf, and v-myc transformed cells. 1073 12

Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro, as determined in endothelial cell proliferation assays, and in vivo, by suppression of angiogenesis induced by vascular endothelial growth factor 165. Persistent high serum levels of endostatin (605-1740 ng/ml; mean, 936 ng/ml) were achieved after systemic administration of the vector to nude mice, which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma (P < 0.001 and P < 0.05, respectively). In addition, the endostatin vector treatment completely prevented the formation of pulmonary micrometastases in Lewis lung carcinoma (P = 0.0001). Immunohistochemical staining of the tumors demonstrated a decreased number of blood vessels in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy as a component in cancer therapy.
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PMID:Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases. 1075 66

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


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