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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a solid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM produced in vitro and in basement membranes of the cornea and blood vessels in vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.
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PMID:Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. 170 86

Many enzymes capable of proteolytic degradation of extracellular matrix and basement membranes have been implicated in tumor progression, including the matrix metalloproteinases, cathepsins, plasminogen activators, and heparanase. Matrix metalloproteinases, a family of zinc-dependent proteases, participate in several steps in tumor progression, including invasion, metastasis, and angiogenesis. In this review, we will give a brief overview of this protease family, and we will review in vitro and in vivo evidence implicating a particular metalloproteinase, the 92-kD type IV collagenase/gelatinase (MMP-9 or gelatinase B), as well as other metalloproteinases, in cancer progression. Finally, using recent studies from our laboratory, we will demonstrate the importance of both tumor cell and host stromal cell production of MMP-9 in tumor progression.
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PMID:Metalloproteinases in tumor progression: the contribution of MMP-9. 765 17

The human heparanase gene, an endo-beta-glucuronidase that cleaves heparan sulfate at specific intrachain sites, has recently been cloned and shown to function in tumor progression and metastatic spread. Antisense digoxigenin-labeled heparanase RNA probe and monoclonal anti-human heparanase antibodies were used to examine the expression of the heparanase gene and protein in normal, dysplastic, and neoplastic human colonic mucosa. To our knowledge, this is the first systematic study of heparanase expression in human colon cancer. Both the heparanase gene and protein were expressed at early stages of neoplasia, already at the stage of adenoma, but were practically not detected in the adjacent normal-looking colon epithelium. Gradually increasing expression of heparanase was evident as the cells progressed from severe dysplasia through well-differentiated to poorly differentiated colon carcinoma. Deeply invading colon carcinoma cells showed the highest levels of the heparanase mRNA and protein associated with expression of both the gene and enzyme by adjacent desmoplastic stromal fibroblasts. A high expression was also found in colon carcinoma metastases to lung, liver, and lymph nodes, as well as in the accompanying stromal fibroblasts. Moreover, extracts derived from tumor tissue expressed much higher levels of the heparanase protein and activity as compared to the normal colon tissue. In all specimens, the heparanase gene and protein exhibited the same pattern of expression. These results suggest a role of heparanase in colon cancer progression and may have both prognostic and therapeutic applications.
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PMID:Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma. Evidence for its role in colonic tumorigenesis. 1102 21

Recently, mammalian heparanase was cloned, and its probable function in tumor progression was reported. However, its expression in human clinical cancers has not been fully studied. Thus we determined the heparanase mRNA expression in 30 esophageal cancer cell lines and 144 clinical samples including 38 esophageal squamous cell carcinomas, 71 gastric adenocarcinomas, and 35 colorectal adenocarcinomas. The fresh surgical specimens of cancer tissue (T) and its paired normal tissue (N) were used. The heparanase mRNA was evaluated by reverse transcriptase-polymerase chain reaction, and the T/N expression ratio was determined in clinical cases. All 30 esophageal cancer cell lines expressed heparanase mRNA. The T/N ratio was determined as high (> or =1.3), equal (0.8 approximately 1.2) or low (< or = 0.7) in each clinical case. In cases of esophageal cancer, 7 showed high, 10 equal and 21 low expression. In cases of colorectal cancer, 3 showed high, 16 equal and 16 low expression. On the other hand, 42 showed high, 22 equal and 7 low expression in cases of gastric cancer. The frequency of high expression cases was greater in gastric cancer than in esophageal or colorectal cancers (p < 0.05). There were no differences in clinicopathologic factors including prognosis between high and low expression cases of each cancer. Our mRNA study of heparanase indicated that its expression status was different among gastrointestinal cancers. The clinical and pathological impact was low compared to other proteinases, although further studies are recommended for final conclusion.
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PMID:Heparanase expression in clinical digestive malignancies. 1129 76

Ovarian cancer is the most lethal of gynecological malignancies. Yet early diagnosis and prognosis are far from being satisfactory. Degradation of heparan sulfate proteoglycans by heparanase appears to play an important role in the invasiveness of tumor cells through the basement membrane and into the extracellular matrix. Recent cloning of the heparanase gene and generation of monoclonal antibodies against the enzyme permit to examine tumor cell expression of the enzyme. The aim of the present study was to assess heparanase activity and localization in various subtypes of epithelial ovarian cancer in correlation with oncogene expression. Histologically confirmed malignant ovarian tissue from ten women and tissue from 2 benign ovarian tumors and 4 normal ovaries were assessed for heparanase presence, activity and localization, incidence of apoptosis and expression of the oncogenes erbB2 and Mdm2. Heparanase immunohistostaining and activity were present in mucinous carcinomas and were more intense than in endometrioid and in serous carcinomas. The lowest activity was observed in benign ovarian tumors and normal ovaries. In ovarian carcinomas the enzyme was intensely concentrated in the cytoplasm of the cancerous cells. In contrast, in normal ovaries and benign tumors the enzyme was predominantly localized in endothelial cells lining blood capillaries. The rate of apoptosis was considerably higher in mucinous and endometrioid carcinomas, and was lower in serous and primary peritoneal carcinomas. Extremely high concentration of heparanase was often demonstrated in apoptotic cells. Endometrioid and serous carcinomas showed high expression of Mdm2 and erbB2 while mucinous carcinomas showed low expression. In benign ovarian tumors and normal ovaries the expression of both oncoproteins was extremely low. In conclusion ovarian carcinomas demonstrate higher levels of heparanase than benign tumors and normal ovaries suggesting that the enzyme may play an important role in metastatic spread of the cancerous cells. Apoptosis may be a significant part of the mechanism of the enzyme release into the extracellular space. Although heparanase activity seems to play an essential role in tumor progression, expression of oncogenes, such as erbB2 and Mdm2 seems to play the dominant role in the development of ovarian cancer.
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PMID:Expression of heparanase, Mdm2, and erbB2 in ovarian cancer. 1135 Dec 42

We had demonstrated previously a functional bridge between altered homebox (HOX) gene expression and tumor progression through HOXB7 transactivation of basic fibroblast growth factor. Here, we have studied whether HOXB7, in addition to basic fibroblast growth factor, may induce other genes directly or indirectly related to neoangiogenesis and tumor invasion. Parental, beta-galactosidase-transduced, and HOXB7-transduced SkBr3 cell lines were examined for the expression of several growth factors and growth factor receptors involved in the proliferative and angiogenic processes. Vascular endothelial growth factor, melanoma growth-stimulatory activity/growth-related oncogenene alpha, interleukin-8, and angiopoietin-2 were up-regulated by HOXB7 transduction. The exception was angiopoietin-1 expression that was abrogated. Additional analyses included the expression levels of enzymes such as matrix metalloprotease (MMP)-2 and MMP-9 and heparanase, capable of proteolytic degradation of extracellular matrix and basement membranes. Results showed an induction of only MMP-9. The functional implication of such a finding was tested using an in vitro coculture assay in a three-dimensional matrix. A delay of differentiation with persistent nests of proliferating cells was found in endothelial cells cocultured with HOXB7-transduced SkBr3 cells. Tumorigenicity of these cells has been evaluated in vivo. Xenograft into athymic nude mice showed that SkBr3/HOXB7 cells developed tumors in mice, either irradiated or not, whereas parental SkBr3 cells did not show any tumor take unless mice were sublethally irradiated. Comparison of tumor nodules for vascularization by CD-31 and CD-34 immunostaining revealed an increased number of blood vessels in tumors expressing HOXB7. Together, the results indicate HOXB7 as a key factor up-regulating a variety of proangiogenic stimuli. Thus, HOXB7 gene or protein is a target to aim at to inhibit tumor-associated neoangiogenesis, considering the number and the redundancy of proangiogenic molecules that should be targeted one by one to theoretically achieve the same effect.
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PMID:HOXB7: a key factor for tumor-associated angiogenic switch. 1152 51

Heparan sulfate proteoglycans (HSPGs) play a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Hence, cleavage of heparan sulfate (HS) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Here, we describe the molecular properties, expression and function of a human heparanase, degrading HS at specific intrachain sites. The enzyme is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and human tumor tissues. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The heparanase enzyme also releases ECM-resident angiogenic factors in vitro and its overexpression induces an angiogenic response in vivo. Heparanase may thus facilitate both tumor cell invasion and neovascularization, both critical steps in cancer progression. The enzyme is also involved in cell migration associated with inflammation and autoimmunity. The unexpected identification of a single predominant functional heparanase suggests that the enzyme is a promising target for drug development. In fact, treatment with heparanase inhibitors markedly reduces tumor growth, metastasis and autoimmune disorders in animal models. Studies are underway to elucidate the involvement of heparanase in normal processes such as implantation, embryonic development, morphogenesis, tissue repair, inflammation and HSPG turnover. Heparanase is the first functional mammalian HS-degrading enzyme that has been cloned, expressed and characterized. This may lead to identification and cloning of other glycosaminoglycan degrading enzymes, toward a better understanding of their involvement and significance in normal and pathological processes.
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PMID:Molecular properties and involvement of heparanase in cancer progression and normal development. 1153 Feb 16

Tumor spread involves degradation of various components of the extracellular matrix and blood vessel wall. Among these is heparan sulfate proteoglycan, which plays a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Expression of an endoglycosidase (heparanase) which degrades heparan sulfate correlates with the metastatic potential of tumor cells, and treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. Heparin-binding angiogenic proteins are stored as a complex with heparan sulfate in the microenvironment of tumors. These proteins are released and can induce new capillary growth when heparan sulfate is degraded by heparanase. Here, we describe the molecular properties, expression and involvement in tumor progression of a human heparanase. The enzyme is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic human cell lines and in tumor biopsy specimens, including breast carcinoma. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The heparanase enzyme also released ECM-resident bFGF in vitro, and its overexpression elicited an angiogenic response in vivo. Heparanase may thus facilitate both tumor cell invasion and neovascularization, two critical steps in tumor progression. Mammary glands of transgenic mice overexpressing the heparanase enzyme exhibit precocious branching of ducts and alveolar development, suggesting that the enzyme promotes normal morphogenesis and possibly pre-malignant changes in the mammary gland.
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PMID:Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis. 1154

Cleavage of heparan sulfate proteoglycans affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Heparanase, degrading heparan sulfate (HS) at specific intrachain sites, is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase enzyme is preferentially expressed in human tumors and its overexpression in low-metastatic tumor cells confers a highly invasive phenotype in experimental animals. Heparanase also releases angiogenic factors and accessory fragments of HS from the tumor microenvironment and induces an angiogenic response in vivo. These effects were best demonstrated when the enzyme was secreted and/or expressed on the cell surface. Heparanase may thus facilitate tumor cell invasion, vascularization and survival, all critical events in cancer progression. These observations, the anti-cancerous effect of heparanase-inhibiting molecules, and the unexpected identification of a single predominant functional heparanase suggest that the enzyme is a promising target for drug development.
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PMID:Properties and function of heparanase in cancer metastasis and angiogenesis. 1199 Apr 83

Cleavage of heparan sulphate proteoglycans (HSPGs) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Heparanase, degrading heparan sulphate (HS) at specific intrachain sites, is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase enzyme is preferentially expressed in human tumours and its overexpression in low-metastatic tumour cells confers a highly invasive phenotype in experimental animals. Heparanase also releases angiogenic factors and accessory fragments of HS from the tumour microenvironment and induces an angiogenic response in vivo. Heparanase may thus facilitate tumour cell invasion, vascularization and survival in a given microenvironment, all critical events in cancer progression. These observations, the anticancerous effect of heparanase-inhibiting molecules, and the unexpected identification of a single predominant functional heparanase suggest that the enzyme is a promising target for drug development.
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PMID:Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development. 1202 84


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