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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to clarify the mechanism underlying early enhanced MR images of breast cancer by dynamic MR imaging from the aspect of tumor angiogenesis. The images depicted by dynamic MR imaging of breast cancer were divided into the following two groups: a marginal strong enhancement (MSE) pattern and a variable pattern without marginal strong enhancement (non-MSE). Twenty patients with invasive ductal carcinoma (maximum diameter < 2 cm) were examined by dynamic MR imaging, and the histological materials were submitted to two-dimensional computer image analysis with immunohistochemistry and histochemistry; morphological microvessel characteristics and microvessel density were examined; and the expression of vascular endothelial growth factor (VEGF) was investigated. In the MSE cases, vessel wall irregularity of capillaries and venules in the peripheral area adjacent to the tumor correlated (p < 0.001) with the enhancement pattern, and the total microvessel density (especially of arterioles with a maximum diameter less than 50 microns) of the peripheral area adjacent to the tumor was significantly higher than that of the tumor area. However, in the non-MSE cases, total microvessel density showed no significant difference between the peripheral area adjacent to the tumor and the tumor area, whereas the capillary density of the tumor area was four times greater than that of the peripheral area adjacent to the tumor. The expression of VEGF was strongly positive for the tumor nest adjacent to the capillaries. These results suggest that the enhanced images of the MSE pattern depend on abundant blood supply from arterioles and that the images of the non-MSE pattern might be reflective of angiogenic activity including variable VEGF expression of tumor cells. Thus the mechanism underlying early dynamic MR images of breast cancer was a complex result of tumor angiogenesis and the microcirculatory environment.
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PMID:[Dynamic MRI and tumor angiogenesis of breast cancer]. 1092 Dec 97

Invasion and metastasis of cancer cells is a complex process requiring the activity of proteins that promote extracellular matrix degradation, motility of cancer cells, and angiogenesis. Although exclusively the cancer cells make several of these proteins, few key proteins are derived from stromal cells in response to cancer cell-stromal cell interaction. In this report, we show that the breast cancer cell-derived interleukin-1alpha (IL-1alpha) plays an important role in expression of pro-metastatic genes in cancer as well as in stromal cells. Neutralizing antibody against IL-1alpha inhibited IL-6, and IL-8 expression in IL-1alpha-expressing cancer cells. In addition, this antibody also prevented induction of IL-6, IL-8, and matrix metalloproteinase 3 (MMP3) but not vascular endothelial growth factor (VEGF) in fibroblasts by conditioned medium (CM) from IL-1alpha-expressing breast cancer cells. These results suggest that inhibition of IL-1alpha activity by either neutralizing antibody against IL-1alpha or chemical inhibitor of IL-1alpha processing may prevent invasion and metastasis of breast cancer.
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PMID:Cancer cell-derived interleukin 1alpha contributes to autocrine and paracrine induction of pro-metastatic genes in breast cancer. 1094 41

Tumor cells stimulate the formation of stroma that secretes various mediators pivotal for tumor growth, including growth factors, cytokines, and proteases. However, little is known about the local regulation of these soluble mediators in the human tumor microenvironment. In this study, the local expression of cytokines, chemokines, and angiogenic factors was investigated in primary breast cancer tissue. The concentrations of interleukin (IL)-1, IL-4, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-8, macrophage chemoattractant protein (MCP)-1, epithelial-neutrophil activating peptide-78, vascular endothelial growth factor, and thymidine phosphorylase (TP) were measured in 151 primary breast cancer extracts by ELISA. Tumor-associated macrophages (TAMs) were also examined by immunohistochemistry with anti-CD68 antibodies. The correlation between soluble mediators and the relationship between TAM count and soluble mediators were evaluated. MCP-1 concentration was correlated significantly with the level of vascular endothelial growth factor, TP, TNF-alpha, and IL-8, which are potent angiogenic factors. IL-4 concentration was correlated significantly with IL-8 and IL-10. On the other hand, an inverse association was observed between TP and IL-12. The level of MCP-1 was associated significantly with TAM accumulation. In the immunohistochemical analysis, MCP-1 expression was observed in both infiltrating macrophages and tumor cells. Prognostic analysis revealed that high expression of MCP-1, as well as of VEGF, was a significant indicator of early relapse. These findings indicate that interaction between the immune network system and angiogenesis is important for progression of human breast cancer, and that MCP-1 may play an important role in the regulation of angiogenesis and the immune system.
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PMID:Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. 1095 14

Heregulin-beta1 promotes the activation of p21-activated kinase 1 (Pak1) and the motility and invasiveness of breast cancer cells. In this study, we identified vascular endothelial growth factor (VEGF) as a gene product induced by heregulin-beta1. The stimulation by heregulin-beta1 of breast cancer epithelial cells induced the expression of the VEGF mRNA and protein and its promoter activity. Heregulin-beta1 also stimulated angiogenesis in a VEGF-dependent manner. Herceptin, an anti-HER2 antibody inhibited heregulin-beta1-mediated stimulation of both VEGF expression in epithelial cells and angiogenesis in endothelial cells. Because the activation of Pak1 and VEGF expression are positively regulated by heregulin-beta1, we hypothesized that Pak1 regulates VEGF expression, and hence explored the role of Pak1 in angiogenesis. We provide new evidence to implicate Pak1 signaling in VEGF expression. Overexpression of a kinase-dead K299R Pak1 leads to suppression of VEGF promoter activity, as well as VEGF mRNA expression and secretion of VEGF protein. Conversely, kinase-active T423E Pak1 promotes the expression and secretion of VEGF. Furthermore, expression of the heregulin-beta1 transgene, HRG, in harderian tumors in mice enhances the activation of Pak1 as well as expression of VEGF and angiogenic marker CD34 antigen. These results suggest that heregulin-beta1 regulates angiogenesis via up-regulation of VEGF expression and that Pak1 plays an important role in controlling VEGF expression and, consequently, VEGF secretion and function.
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PMID:Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. 1096 14

In our previous study, the growth of KPL-1 human breast cancer cells was found to be stimulated by an antiestrogen, ICI 182, 780, and inhibited by 17 beta-estradiol (E2) in vivo but not in vitro. To investigate the action mechanisms of these paradoxical responses, the effects of E2, ovariectomy (Ovex) and medroxyprogesterone acetate (MPA) on the growth, angiogenesis, apoptosis and expression of vascular endothelial growth factor (VEGF) were investigated. E2 stimulated the growth of KPL-1 cells but MPA inhibited it in vitro. In contrast, E2 propionate inhibited the growth of KPL-1 cells in female nude mice but Ovex and MPA stimulated it. E2 propionate suppressed angiogenesis and increased apoptosis in KPL-1 tumors, but Ovex and MPA promoted angiogenesis and decreased apoptosis. Both mRNA expression and secretion of VEGF were stimulated by MPA in KPL-1 cells, but in E2-dependent ML-20 cells they were both inhibited by MPA. E2 did not significantly influence VEGF expression in either cell line. These findings suggest that the abnormal modulation of VEGF expression by MPA and of the other angiogenic factor by E2 are responsible for the paradoxical growth responses of KPL-1 cells in vivo. To support this hypothesis, an antiangiogenic agent, TNP-470, was administered to mice bearing KPL-1 tumors. TNP-470 significantly inhibited the growth of KPL-1 tumors stimulated by MPA. Antiangiogenic agents may be effective for the treatment of hormone-refractory breast cancer.
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PMID:Paradoxical hormone responses of KPL-1 breast cancer cells in vivo: a significant role of angiogenesis in tumor growth. 1097 Nov 76

In recent studies, we have shown that silymarin, a naturally occurring flavonoid antioxidant, exhibits anti-cancer effects against several epithelial cancers. Here, we assessed its potential as an anti-angiogenic agent employing human umbilical vein endothelial cells (HUVEC) and human prostate and breast cancer epithelial cells. When sub-confluent HUVEC were treated for 48 h, adherent cell number decreased by 50 and 90% at 50 and 100 microg/ml doses, respectively. Apoptotic cell death principally accounted for cell loss at >50 microg/ml doses. In biochemical analysis, silymarin treatment of HUVEC for 6 h resulted in a concentration-dependent decrease in the secretion and cellular content of matrix metalloproteinase (MMP)-2/gelatinase A. Silymarin also inhibited HUVEC tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel. In other studies, 5 to 6 h exposure of DU145 prostate, and MCF-7 and MDA-MB-468 breast cancer cells to silymarin resulted in a dose-dependent decrease in the secreted vascular endothelial growth factor (VEGF) level in conditioned media without any visible change in cell morphology. The inhibitory effect of silymarin on VEGF secretion occurred as early as 1 h. These observations indicate a rapid inhibitory action of silymarin on the secretion of this primary angiogenic cytokine by cancer epithelial cells. Taken together, the results of this study support the hypothesis that silymarin possesses an anti-angiogenic potential that may critically contribute to its cancer chemopreventive efficacy.
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PMID:Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. 1100 31

Estrogens increase the expression of vascular endothelial growth factor (VEGF) mRNA in the rodent uterus. This regulatory effect is rapid, beginning within 1 hr after hormone treatment, dose dependent, and blocked by the pure antiestrogen ICI 182,780. The induction of the transcript is blocked by inhibitors of RNA but not of protein synthesis, and we have recently identified estrogen response elements in the VEGF gene. Collectively, these findings indicate that estrogens regulate uterine VEGF expression at the transcriptional level via the classical nuclear estrogen receptor pathway. Estrogen induction of VEGF occurs in the stromal layer of the rodent uterus, and estradiol induces expression of VEGF transcript levels in cultured human uterine stromal cells. Progestins also induce VEGF expression in the rodent uterus, although the effect is less marked and slower in onset than estrogenic effects. The effect of progestins is blocked by the antiprogestin mifepristone (RU-486), suggesting that it is also mediated by a classical nuclear receptor pathway. In addition, progestins regulate expression of VEGF mRNA and protein in cultured human T47-D breast cancer cells. The development of uterine leiomyomas is associated with exposure to ovarian sex steroids, abnormal uterine bleeding is commonly seen in patients with leiomyomas, and fibroids require an increased vascular supply for their growth. These observations suggest that VEGF and other angiogenic factors may represent potential targets for the treatment and prevention of uterine fibroids.
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PMID:Regulation of vascular endothelial growth factor expression by estrogens and progestins. 1103 83

Platelet-activating factor (PAF), a phospholipid mediator of inflammation, is present in breast cancer tissue and correlates with microvessel density. In the present study, we investigated the biological significance of PAF synthesized within breast cancer. In vitro, we observed the production of PAF by two estrogen-dependent (MCF7 and T-47D) and an estrogen-independent (MDA-MB231) breast cancer cell lines after stimulation with vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, tumor necrosis factor, thrombin but not with estrogen, progesterone, and oxytocin. The sensitivity to agonist stimulation and the amount of PAF synthesized as cell-associated or released varied in different cell lines, being higher in MDA-MB231 cells, which are known to be highly invasive. We further demonstrate, by reverse transcriptase-polymerase chain reaction and cytofluorimetry, that all of the breast cancer cells express the PAF receptor and respond to PAF stimulation in terms of proliferation. Moreover, in MDA-MB231 cells PAF elicited cell motility. In vivo, two structurally different PAF receptor antagonists WEB 2170 and CV 3988 significantly reduced the formation of new vessels in a tumor induced by subcutaneous implantation of MDA-MB231 cells into SCID mice. In conclusion, these results suggest that PAF, produced and released by breast cancer cells, can contribute to tumor development by enhancing cell motility and proliferation and by stimulating the angiogenic response.
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PMID:PAF produced by human breast cancer cells promotes migration and proliferation of tumor cells and neo-angiogenesis. 1107 30

Immunohistochemical staining for CD9, CD31 and vascular endothelial growth factor(VEGF)was performed in breast carcinoma specimens. CD9 was expressed in the membrane of carcinoma cells in 61 of 93 cases(67%), CD31 in the membrane of carcinoma cells in 23 of 86 cases(27%), and VEGF in the cytoplasm of carcinoma cellsin 26 of 86 cases(30%). The expression of CD9, CD31 and VEGF did not singly correlate with any clinicopathological factors. However, a loss of CD9 with concurrent expression of CD31 or VEGF in the invasive component showed a slight correlation with lymph node metastasis. These findings suggest that the potential for metastatic spread to lymph nodes in breast carcinoma may be synergically affectedby various factors.
Breast Cancer 1998 Apr 25
PMID:Loss of CD9 with Expression of CD31 and VEGF in Breast Carcinoma, as Predictive Factors of Lymph Node Metastasis. 1109 38

Predictive markers and variables for response to anticancer therapy provide cancer patients with refinement of therapeutic options and a decreased likelihood of receiving an ineffective therapy. The best-established predictive marker for response to endocrine therapy for breast cancer is the status of estrogen receptors (ER) in the primary breast tumor. However, although patients with ER-positive tumors have a greater than 50% objective response rate to endocrine therapy, other patients can not obtain an objective response. Therefore additional markers, such as better molecular biologic markers, are needed. Our previous study using multivariate analysis revealed that the ER status of primary tumors and the dominant site of metastasis are independent predictors for response to first-line endocrine therapy and that a response to first-line endocrine therapy is only an independent predictor for response to second-line endocrine therapy. However, all these factors are already well-established predictive markers for response to endocrine therapy. Recently, a number of new hormonal agents, such as more selective aromatase inhibitors and specific antiestrogens, have been developed and introduced. However, several questions, such as the best sequences when using hormonal agents, remain to be elucidated. On the other hand, several molecular biologic markers predicting response to endocrine therapy, such as the expression of the HER family of tyrosine kinase receptors, pS2, Bcl-2, and vascular endothelial growth factor, have been reported. To elucidate the most effective use of endocrine therapy for recurrent breast cancer, classical and new predictive factors for response to endocrine therapy are reviewed, and the clinical implications of these factors are discussed.
Breast Cancer 2000
PMID:Predictive factors for response to endocrine therapy in patients with recurrent breast cancer. 1111 53


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