Angiogenesis extent and expression of matrix metalloproteinase‐2 and ‐9 correlate with upgrading and myometrial invasion in endometrial carcinoma

Iurlaro,; Loverro,; Vacca, None; Cormio, Gennaro; Ribatti,; Minischetti,; Ria,; Cevallos, Bruno; Selvaggi,

doi:10.1046/j.1365-2362.1999.00532.x

Cited by 67 publications

(55 citation statements)

References 35 publications

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“…MMPs are an important group of zinc enzymes that are responsible for degradation of extracellular matrix components, such as collagen and proteoglycans, in normal embryogenesis and in many disease processes, such as arthritis and invasion by carcinoma (8,9). In our study, we showed that MMP-2 and MMP-9 mRNA and protein expressions were significantly down-regulated in LKB1-transfected MDA-MB-435 cells both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Expression of LKB1 in Breast Cancer Cells Attenuates Angiogenesis, Invasion, and Metastatic Potential

Zhuang

Shen

et al. 2006

Molecular Cancer Research

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LKB1 (also known as STK11) is a recently identified tumor suppressor gene whose mutation can lead to Peutz-Jeghers syndrome, which is characterized by gastrointestinal polyps and cancers of different organ systems. Approximately 30% of sporadic breast cancer samples express low levels of LKB1. This suggests that the LKB1 gene may be related to the tumorigenesis of breast cancer. We reintroduced LKB1 into MDA-MB-435 breast cancer cells that lack the LKB1 gene to investigate how overexpression of LKB1 affects tumor invasiveness and metastasis. Overexpression of the LKB1 protein in breast cancer cells resulted in significant inhibition of in vitro invasion. In vivo, LKB1 expression reduced tumor growth in the mammary fat pad, microvessel density, and lung metastasis. LKB1 overexpression was associated with down-regulation of matrix metalloproteinase-2, matrix metalloproteinase-9, vascular endothelial growth factor, and basic fibroblast growth factor mRNA and protein levels. Overexpression of the LKB1 protein in human breast cancer is significantly associated with a decrease in microvessel density. Our results indicate that LKB1 plays a negative regulatory role in human breast cancer, a finding that may lead to a new therapeutic strategy. (Mol Cancer Res 2006;4(11):843 -9)

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Section: Discussionmentioning

confidence: 99%

Enhanced Expression of LKB1 in Breast Cancer Cells Attenuates Angiogenesis, Invasion, and Metastatic Potential

Zhuang

Shen

et al. 2006

Molecular Cancer Research

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“…All these were related to upregulation of MMP-9 and Ets-1 levels. MMPs are important group of zinc enzymes that are responsible for degradation of extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and in many disease processes such as arthritis and invasion by carcinoma (Iurlaro et al, 1999;Sillem et al, 1999). In the endometrium, it has been reported that some MMPs play important roles in endometrial physiologic characteristics and these roles are regulated by ovarian steroid hormones (Irwin et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

ERβ exerts multiple stimulative effects on human breast carcinoma cells

Hou

Yuan

et al. 2004

Oncogene

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Recent studies of ERs in breast cancer have demonstrated the existence of ERb in addition to ERa. Some clinical data indicated that ERb had prognostic value for patient's survival, which suggested that ERb plays a key role in breast cancer development and metastasis. To test this hypothesis, we generated an ERb high-expression cell line by reintroduced human ERb cDNA into MDA-MB-435 cells. We demonstrated that ERb exerted multiple tumor-stimulative effects on human breast carcinoma cells both in vivo and in vitro. In in vitro studies, ERb was able to increase the proliferation and invasion of MDA-MB-435 cells significantly, while these effects were totally estradiol independent. Also, this stimulation was characterized by downregulation of p21 and upregulation of MMP-9, as well as transcriptional factor Est-1. In in vivo studies, we also demonstrated that ERb-transfected MDA-MB-435 cells grew much faster and had more pulmonary metastasis than mock or wild-type cells in nude mice. In ERb-transfected MDA-MB-435 xenografts, ERb caused significant reduction in p21 protein levels. Similar effects of ERb on MMP-9 and Ets-1 expression noted in vitro studies were also observed in the in vivo studies. These in vitro and in vivo studies indicated that ERb exerted multiple stimulative effects on breast cancer development and metastasis.

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“…Pro-MMP9 (7.5 ng) was incubated at 37°C with MMP3 (7.5 ng) in the absence or presence of TSP1 (0, 10, 30, 90, or 270 ng) in a total volume of 15 l for 2 h. The enzyme activity of the preincubated samples (10-l aliquots diluted to 50 l in gelatinase assay buffer) was determined by incubating at 37°C for 1 h and using [ ber of studies have documented that activation of MMP2 is associated with robust new vessel growth, while inhibition of its activity leads to depressed angiogenesis (46,47). Given the high degree of sequence homology between the TSR of TSP1 and TSP2, we have investigated whether TSP1 TSR also interacts with MMP2.…”

Section: Figmentioning

confidence: 99%

Thrombospondin Type 1 Repeats Interact with Matrix Metalloproteinase 2

Bein

Simons

2000

Journal of Biological Chemistry

231

167

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Thrombospondins are thought to function as inhibitors of angiogenesis. However, the mechanism(s) of this activity is not well understood. In this study, we have used the yeast two-hybrid system to identify proteins that interact with the thrombospondins 1 (TSP1) and 2 (TSP2) properdin-like type 1 repeats (TSR). One of the proteins identified that interacted with both TSR was matrix metalloproteinase 2 (MMP2). The isolated MMP2 cDNA clone encoded amino acid residues 237-633, which include the fibronectin-like gelatin binding region flanking the catalytic center and the carboxyl hemopexin-like region. Further testing of this clone demonstrated that the TSR interacted with the NH 2 -terminal region of the MMP2 that contains the catalytic domain. The protein interaction observed in yeast was further demonstrated by immunoprecipitation and Western blotting using purified intact TSP1, TSP2, MMP2, and MMP9. Although MMP2 interacted with TSP1 and TSP2 via its gelatin-binding domain or a closely mapping site, neither TSP1 nor TSP2 was degraded by MMP2 in vitro. Tissue culture and in vitro assays demonstrated that the presence of purified TSR and intact TSP1 resulted in inhibition of MMP activity. The ability of TSP1 to inhibit MMP3-dependent activation of pro-MMP9 and thrombin-induced activation of pro-MMP2 suggests that the TSPs may inhibit MMP activity by preventing activation of the MMP2 and MMP9 zymogens.The thrombospondin (TSP) 1 family of proteins includes at least five related extracellular matrix glycoproteins encoded by separate genes (1). Each thrombospondin contains NH 2 -and COOH-terminal globular domains flanking different structural modules ( Ref. 2; Fig. 1A). The modules common to all TSP proteins include epidermal growth factor-like type 2 and Ca 2ϩ -binding type 3 repeats. In addition to these common features, TSP1 and TSP2 share two additional modules: a procollagen homology region and three properdin-like type 1 repeats (TSR).The NH 2 and COOH termini contain regions that are low in cysteine content, do not possess internal repeating motifs, and do not show homology with other proteins (3). The aminoterminal domain is largely responsible for the heparin binding properties of thrombospondins (4, 5). The procollagen region contains a region homologous to a cysteine-rich domain in the NH 2 -terminal propeptide of the ␣ 1 -chain of type 1 procollagen (6). The type 1 repeats are homologous to sequences in a variety of proteins found in protozoans (7-9), invertebrates (10), and mammals (11-16).Thrombospondin 1 has been the most extensively studied TSP protein to date. TSP1 contains a growing number of sites that have been implicated in interactions with more than 30 cell surface and matrix proteins, including structural proteins (e.g. collagen and fibronectin), cell surface receptors (e.g. integrins, syndecans, and CD36), enzymes (e.g. elastase and plasmin), and cytokines (e.g. transforming growth factor-␤1) (17). Because of its ability to interact with such a wide variety of proteins, TSP1 has been implicat...

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Angiogenesis extent and expression of matrix metalloproteinase‐2 and ‐9 correlate with upgrading and myometrial invasion in endometrial carcinoma

Abstract: These in situ data suggest that angiogenesis and degradation of extracellular matrix occur simultaneously with EC upgrading and advancing depth of invasion, and that EC cells and some host stromal cell populations cooperate in tumour progression.

Cited by 67 publications

References 35 publications

Enhanced Expression of LKB1 in Breast Cancer Cells Attenuates Angiogenesis, Invasion, and Metastatic Potential

Enhanced Expression of LKB1 in Breast Cancer Cells Attenuates Angiogenesis, Invasion, and Metastatic Potential

ERβ exerts multiple stimulative effects on human breast carcinoma cells

Thrombospondin Type 1 Repeats Interact with Matrix Metalloproteinase 2

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