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 shown that ovarian carcinoma cell adhesion to mesothelial cell monolayers and migration toward fibronectin, type IV collagen, and laminin is partially mediated by CD44, a proteoglycan known to affect the functional abilities of tumor cells. The purpose of this study was to determine the role of cell membrane glycosylation in the metastatic abilities of ovarian carcinoma cells. NIH:OVCAR5 cells were treated with glycosidases to remove carbohydrate moieties from molecules on the cells' surface. The ability of the treated cells to adhere to extracellular matrix components or mesothelial cell monolayers, migrate toward extracellular matrix proteins, and invade through Matrigel was assessed. We observed that the loss of different carbohydrate moieties resulted in altered ovarian carcinoma cell adhesion, migration, and/or invasion toward extracellular matrix components or mesothelial cell monolayers. Gene array analysis of NIH:OVCAR5 cells revealed the expression of several proteoglycans, including syndecan 4, decorin, and perlecan. In tissue samples obtained from patients, altered proteoglycan gene expression was observed in primary ovarian carcinoma tumors and secondary metastases, compared to normal ovaries. Taken together, these results suggest that ovarian carcinoma cell proteoglycans affect the cells' ability to adhere, migrate, and invade toward extracellular matrix components and mesothelial cell monolayers. Thus, the carbohydrate modifications of several proteoglycans may mediate the formation and spread of secondary tumor growth in ovarian carcinoma.
Clin Exp Metastasis 2003
PMID:Cell membrane glycosylation mediates the adhesion, migration, and invasion of ovarian carcinoma cells. 1270 35

Versican, a proteoglycan previously reported to increase in other malignant tumours, was studied immunohistochemically in 299 primary epithelial ovarian cancers, their 43 metastases and 6 normal ovaries to evaluate its prognostic value and relation to hyaluronan, another extracellular matrix molecule increased in cancer and a binding partner of versican. The stainings were scored according to the area percentage of strong versican signal of total peri- and intratumoural stroma as low (<15%) or high (>or=15%). Epithelial staining of the tumours was scored as positive or negative. Low and high area percentage of strong stromal versican staining were observed in 133 and 166 carcinomas, respectively. A low area percentage of strong stromal versican staining correlated with mucinous histology (p = 0.019) and early International Federation of Gynecologists and Obstetritians (FIGO) stage (p < 0.0005), whereas a high percentage was associated with reduced 5-year survival rate of the patients (44% vs. 32%; p = 0.032). Versican was associated with the cancer cells in 151 tumours and correlated with clear cell histology (p < 0.0005), early FIGO stage (p = 0.049) and increased recurrence-free survival (63% vs. 47%; p = 0.032). However, in Cox's multivariate analyses with the conventional prognostic factors included, neither stromal nor cancer cell-associated versican reached a significant prognostic value. Versican is thus enriched in the malignant stroma surrounding and promoting the growth of ovarian cancer, probably acting with hyaluronan, and associates with unfavourable prognosis but does not constitute an independent indicator of patient survival.
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PMID:Versican in epithelial ovarian cancer: relation to hyaluronan, clinicopathologic factors and prognosis. 1450 34

Angiogenesis, the process of new capillary formation from pre-existing vessels, has been established as an important mechanism involved in pathologic processes, such as cancer, as well as in normal physiology (Ribatti, D.; Vacca, A.; Roncali, L.; Dammacco, F. Angiogenesis under normal and pathological conditions. Haematologica 1991, 76 (4), 311-320). Basic fibroblast growth factor (FGF-2) is a critical mediator of angiogenesis that is important for normal reproduction and wound healing. FGF-2 mediates its pro-angiogenic effects by binding to heparin sulfate proteoglycan in addition to a tyrosine kinase receptor (Baird, A.; Schubert, D.; Ling, N.; Guillemin, R. Receptor and heparin-binding domain of basic fibroblast growth factor. Proc. Natl. Acad. Sci. U. S. A. 1998, 5 (7), 2324-2328; Richard, C.; Roghani, M.; Moscatelli, D. Fibroblast growth factor (FGF)-2 mediates cell attachment through interactions with two FGF receptor-1 isoforms and extracellular matrix or cell-associated heparin sulfate proteoglycans. Biochem. Biophys. Res. Commun. 2000, 276 (2), 399-405; Casu, B.; Guerrini, M.; Naggi, A.; Perez, M.; Torri, G.; Ribatti, D.; Carminati, P.; Giannini, G.; Penco, S.; Pisano, C.; Belleri, M.; Rusnati, M.; Presta, M. Short heparin sequences spaced by glycol-split urinate residues are antagonists of fibroblast growth factor 2 and angiogenesis inhibitors. Biochemistry 2002, 41 (33), 10519-10528; Murphy, P.V.; Pitt, N.; O'Brien, A.; Enright, P.M.; Dunne, A.; Wilson, S.J.; Duane, R.M.; O'Boyle, K.M. Identification of novel inhibitors of fibroblast growth factor (FGF-2) binding to heparin and endothelial cell survival from a structurally diverse carbohybrid library. Bioorg. Med. Chem. Lett. 2002, 12 (22), 3287-3290). We developed a liposomal-based peptide vaccine, L(HBD) that targets the heparin binding domain of the FGF-2 molecule. This vaccine, when inoculated into mice, inhibits angiogenesis in response to FGF-2 in a hepatic sponge model as well as tumor progression in two models of pulmonary metastatic disease. In the present studies, we further characterize the immunological and physiological responses to this vaccine. Vaccinated animals generated a specific anti-FGF-2 antibody (titer of 1:5000) that was able to inhibit FGF-2 binding to heparin sulfate in a dose dependent fashion. Cell mediated immunity was evidenced by a delayed type hypersensitivity response following challenge with the heparin binding domain peptide. Despite an immune response toward FGF-2, vaccination with L(HBD) did not result in alterations in mean time to wound healing when compared to unvaccinated animals or those treated with a liposome control. In reproductive studies, vaccinated females were not impaired in their ability to: 1) become pregnant, 2) support the growth and development of their embryos, and 3) deliver viable offspring. Furthermore, when assessed histologically, these offspring did not demonstrate any alterations in organogenesis when compared to pups born to untreated or liposome control treated females. Thus, while vaccination against FGF-2 induces a specific FGF-2 antibody response, and inhibits angiogenesis and tumor development in a pathological setting, it does not adversely alter normal physiological events dependent on FGF-2.
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PMID:Generation of a specific immunological response to FGF-2 does not affect wound healing or reproduction. 1510 30

The histological detection of laminin-rich vasculogenic mimicry patterns in human primary uveal melanomas is associated with death from metastases. We therefore hypothesized that highly invasive uveal melanoma cells forming vasculogenic mimicry patterns after exposure to a laminin-rich three-dimensional microenvironment would differentially express genes associated with invasive and metastatic behavior. However, we discovered that genes associated with differentiation (GDF15 and ATF3) and suppression of proliferation (CDKNa1/p21) were up-regulated in highly invasive uveal melanoma cells forming vasculogenic mimicry patterns, and genes associated with promotion of invasive and metastatic behavior such as CD44, CCNE2 (cyclin E2), THBS1 (thrombospondin 1), and CSPG2 (chondroitin sulfate proteoglycan; versican) were down-regulated. After forming vasculogenic mimicry patterns, uveal melanoma cells invaded only short distances, failed to replicate, and changed morphologically from the invasive epithelioid to the indolent spindle A phenotype. In human tissue samples, uveal melanoma cells within vasculogenic mimicry patterns assumed the spindle A morphology, and the expression of Ki67 was significantly reduced in adjacent melanoma cells. Thus, the generation of vasculogenic mimicry patterns is accompanied by dampening of the invasive and metastatic uveal melanoma genotype and phenotype and underscores the plasticity of these cells in response to cues from the microenvironment.
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PMID:Tumor cell plasticity in uveal melanoma: microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns. 1700 93

Emerging data in myeloma and other cancers indicates that heparan sulfate proteoglycans promote tumor progression by enhancing their growth and metastasis. By acting as key regulators of cell signaling via their interactions with multiple growth and angiogenic factors, heparan sulfates mediate a shift in the microenvironment that supports the tumor as an 'organ' and promotes an aggressive tumor phenotype. In addition, enzymatic remodeling of heparan sulfate proteoglycans provides a mechanism for rapid, localized and dynamic modulation of proteoglycan function thereby tightly regulating activities within the tumor microenvironment. New data from animal models demonstrates that heparan sulfate or the enzymes that regulate heparan sulfate are viable targets for cancer therapy. This strategy of targeting heparan sulfate may be particularly effective for attacking cancers like myeloma where extensive genetic chaos renders them unlikely to respond well to agents that target a single signaling pathway.
Clin Exp Metastasis 2008
PMID:Syndecan-1: a dynamic regulator of the myeloma microenvironment. 1802 90

Lung metastasis is the most crucial event affecting the therapeutic outcome of osteosarcoma. The prevention of lung metastasis is therefore important in improving the prognosis of patients with osteosarcoma. Decorin is a major extracellular matrix protein which has become the focus of various cancer studies. The biological role of decorin in osteosarcoma has yet to be clarified. The aim of this study was to examine the potential of decorin as a novel biological target for the treatment of osteosarcoma. In this study, the LM8 murine osteosarcoma cell line (LM8) with high metastatic potential to the lung was used. The two cell lines established were LM8-DCN which stably expressed human decorin (hDCN) and LM8-mock, established as a control. The LM8-DCN cell line was subcutaneously injected into the backs of mice. Significantly fewer pulmonary metastases were observed in mice with LM8-DCN compared to mice inoculated with LM8 and LM8-mock (P<0.001). In addition, the mice in the LM8-DCN inoculated group survived significantly longer than those in the LM8 and LM8-mock inoculated group, based on the Kaplan-Meier survival analysis and log-rank tests (P<0.005). The effect of decorin on the growth rates, motility and invasion ability of LM8 was investigated in vitro. There was no difference in the morphology and growth rates, but the motility and invasion of LM8 were inhibited by decorin. These results suggest that decorin has the therapeutic potential to prevent lung metastasis in osteosarcoma.
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PMID:Decorin suppresses lung metastases of murine osteosarcoma. 1849 61

Enhanced expression levels of NG2 proteoglycan in presurgical original lesions of soft-tissue sarcoma (STS) patients defines with 55% probability the immediate (i.e., within 12 months postsurgery) risk in these individuals to develop postsurgical secondary lesions, independently of any other clinical trait. It, therefore, provides a molecular factor that alone prospects a particularly unfavorable clinical outcome in such patients. Evaluation of the timing of metastasis formation in patients with high and low levels of NG2 in their primitive lesions further stratified the patients in subsets with diverse lag phases in the occurrence of metastatic disease. In our cohort of high-grade STS cases, transcription of NG2 also showed a 81-fold amplification in metastatic lesions, when compared to primitive ones, and this gene overexpression was accompanied by an abundant but nonuniform in situ expression of its product. In a similar manner as seen in primitive lesions, patients with higher levels of metastatic NG2 encountered a significantly more dismal clinical course. Multivariate analysis asserted that in these individuals upregulation of NG2 represented an absolute independent prognostic parameter. Therefore, minimally invasive assessment of the transcription levels of the NG2 gene represents a parameter capable of predicting the arising of metastatic disease within a definite postsurgery time interval, and affords in adjunct in the definition of life expectance in STS patients.
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PMID:NG2 expression predicts the metastasis formation in soft-tissue sarcoma patients. 1863 19

Macrophage colony stimulating factor (M-CSF, also called colony stimulating factor-1) has traditionally been viewed as a growth/differentiation factor for monocytes, macrophages, and some female-specific tumors. As a result of alternative mRNA splicing and post-translational processing, several forms of M-CSF protein are produced: a secreted glycoprotein, a longer secreted form containing proteoglycan, and a short membrane-bound isoform. These different forms of M-CSF all initiate cell signaling in cells bearing the M-CSF receptor, called c-fms. Here we review the biology of M-CSF, which has important roles in bone physiology, the intestinal tract, cancer metastases to the bone, macrophage-mediated tumor cell killing and tumor immunity. Although this review concentrates mostly on the membrane form of human M-CSF (mM-CSF), the biology of the soluble forms and the M-CSF receptor will also be discussed for comparative purposes. The mechanisms of the biological effects of the membrane-bound M-CSF reveal that this cytokine is unexpectedly involved in many complex molecular events. Recent experiments suggest that a tumor vaccine based on membrane-bound M-CSF-transduced tumor cells, combined with anti-angiogenic therapy, should be evaluated further for use in clinical trials.
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PMID:Macrophage colony stimulating factor: not just for macrophages anymore! A gateway into complex biologies. 1868 98

Increased expression of the proteoglycan, versican is strongly associated with poor outcome for many different cancers. Depending on the cancer type, versican is expressed by either the cancer cells themselves or by stromal cells surrounding the tumor. Versican plays diverse roles in cell adhesion, proliferation, migration and angiogenesis, all features of invasion and metastasis. These wide ranging functions have been attributed to the central glycosaminoglycan-binding region of versican, and to the N-(G1) and C-(G3) terminal globular domains which collectively interact with a large number of extracellular matrix and cell surface structural components. Here we review the recently identified mechanisms responsible for the regulation of versican expression and the biological roles that versican plays in cancer invasion and metastasis. The regulation of versican expression may represent one mechanism whereby cancer cells alter their surrounding microenvironment to facilitate the malignant growth and invasion of several tumor types. A greater understanding of the regulation of versican expression may contribute to the development of therapeutic methods to inhibit versican function and tumor invasion.
Cancer Metastasis Rev 2009 Jun
PMID:The biological role and regulation of versican levels in cancer. 1916 15

Decorin, the prototype of an expanding family of small leucine-rich proteoglycans, is involved in a number of cellular processes including matrix assembly, fibrillogenesis and the control of cell proliferation. In this study, we investigated the role of decorin in suppressing tumor aggressiveness and bone metastases. We used a metastatic breast cancer cell line, MDA-MB-231, to show that decorin causes marked growth suppression bothin vitro and in vivo. A cytomegaloviral vector containing the decorin transgene caused greatly reduced cell growth, motility and observed metastases. Bone metastases were decreased by >90% upon decorin transfection. These results demonstrate a novel role for decorin in the reduction or prevention of tumor metastases in this breast cancer model and could eventually lead to improved therapies for metastatic breast cancer.
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PMID:Decorin suppresses bone metastasis in a breast cancer cell line. 1959 Feb 49


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