Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We hypothesize that early events in the development of at least some human breast cancers involve faulty epithelial-mesenchymal interactions and that the stromal cells themselves play an active role in this abnormal process. In contrast, later events accelerating breast tumor progression may occur in association with genetic changes involving only the malignant epithelial cells. These conclusions arise from a review of the literature, our comparative studies of HA metabolism in fibroblasts cultured from either normal or malignant breast tissues, and from molecular-genetic studies performed on sequential specimens from a single patient and on a wide variety of human breast tumor samples. HA is a proteoglycan component of the ECM which is known to stimulate epithelial cell detachment and motility and is most abundant in fetal and rapidly growing tissues. We find that many breast cancer-derived fibroblasts are stimulated to produce HA in response to TGF-beta under conditions where HA accumulation by normal tissue fibroblasts is almost uniformly inhibited. In a single patient, we had the opportunity to examine three malignant effusions that occurred sequentially to identify genetic changes associated with the later stages of breast cancer progression. Although, common cytogenetic abnormalities were found in all the effusion samples, only the last effusion exhibited a loss of heterozygosity at the c-Ha-ras locus. In this case, the allelic loss correlated with improved growth in vitro of the primary cells and with ability to become a permanently established cell line.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early and late events in the development of human breast cancer. 181 93

Tumour progression involves a series of sequential steps leading to metastasis. For several of these steps, tumour cells must be equipped with the appropriate adhesive phenotype. Contact with adjacent cells in the primary tumour must be reduced, and invasion and metastasis require adhesive interactions with ECM components. A group of adhesion molecules called integrins is involved in many of these interactions. Integrins are heterodimeric transmembrane molecules that link the cell to the cytoskeleton. They mediate adhesion to ECM components and to other cells. They may be present in an active or inactive conformation, and in addition to adhesive events, they transfer signals into the cell inducing changes in gene expression. Both functions implicate integrins in tumour progression, and their role in cancer has been the subject of many studies over the past 5 years. Several studies of human cutaneous melanoma have demonstrated that the expression of integrins correlates with tumour progression in vivo. Furthermore, integrin expression and function in melanoma cell lines have been found to correlate with invasive or metastatic potential. Finally, evidence from experimental studies in vitro and in vivo shows that integrins have a role in melanoma tumorigenesis, invasion, angiogenesis and metastasis. Integrins might be used as prognostic markers for clinical outcome and they may be useful therapeutic targets in melanoma.
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PMID:Role of integrins as signal transducing cell adhesion molecules in human cutaneous melanoma. 755 62

8701-BC cells, derived from a primary carcinoma of the breast, constitutively express mRNA for urokinase-type plasminogen activator (uPA). In this paper, we demonstrated the presence of uPA in the conditioned medium, and of uPA-receptor (uPAR) on the cell surface of 8701-BC cells, which therefore have the potential for an autocrine mechanism of uPA-mediated stimulation. We examined whether exogenous addition of either intact uPA, or its amino-terminal fragment (uPA-ATF), which lacks catalytic activity but retains the uPAR binding site and a growth factor-like domain, or immunoneutralisation of endogenous uPA-uPAR interactions could exert any effect on the proliferative and invasive behaviour of 8701-BC cells. The data demonstrate that, while uPA promotes growth and invasion of 8701-BC cells, its effect reversed by blocking uPA-uPAR interactions, uPA-ATF not only fails to impart growth factor-like signals, but also restrains cell invasion in vitro. In the light of these and other data, an active participation of ATF in the complex cell-ECM network of interactions underlying cancer progression can be postulated. In addition, it appears worth considering the possibility of testing the effect of this uPA fragment in vivo for the therapy of breast (and possibly other) human invasive carcinomas.
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PMID:In vitro anti-proliferative and anti-invasive role of aminoterminal fragment of urokinase-type plasminogen activator on 8701-BC breast cancer cells. 869 76

Gliomas exhibit diffuse infiltration into the normal brain parenchyma, and the tumor cells often show morphological features similar to reactive glia cells, making it difficult to discriminate tumor cells from other neural cell populations both in vitro and in vivo. Several methods have therefore been developed in order to observe migrating tumor cells in experimental tumor models. These include labeling of tumor cells with vital dyes as well as by using genetic markers. Despite the fact that these malignancies are highly invasive in the brain, they rarely metastazise out of the central nervous system (CNS). The dissemination of tumor cells is probably mediated both by passive cell displacement and by active cell migration. Tumor cells may be displaced within the brain by the passive flow of cerebrospinal fluid (CSF) within the perivascular space and along ventricular linings. Tumor growth and invasion occur in a micromillieu that is regulated both by cancer cells and normal cells. The biological attributes of invasion and cell migration include cell adhesion to extracellular matrix components, cell locomotion, and the ability to create space into which to move. This process is characterized by the degradation and turnover of ECM components, which implies the production of specific proteases and inhibitors. Tumor progression is also influenced by numerous growth factors which may stimulate the malignant cells both by paracrine and autocrine mechanisms. Tumor growth requires the persistent formation of new blood vessels and the induction of angiogenesis is most likely occurring during early stages of tumor development. This process is regulated both by several inducers and inhibitors of endothelial cell proliferation and migration.
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PMID:Brain tumor cell invasion, anatomical and biological considerations. 942 45

We previously showed that the extracellular matrix component tenascin-C (TN-C) is upregulated in oral squamous cell carcinoma (SCC) compared with the normal oral mucosa. In this study we examined oral biopsy specimens of mild to moderate dysplasia or carcinoma in situ to study TN-C expression. We found that carcinoma in situ is the stage at which TN-C becomes widely expressed, suggesting it may be involved in the initial stages of tumor progression. To study TN-C matrix production in vitro, we used an invasive oral SCC cell line (HSC-3) and peri-tumor fibroblasts (PTF). Neither cell type organized a TN-C matrix when cultured alone; however, when co-cultured with HSC-3 cells, PTF were able to assemble a TN-C matrix. PTF retained the ability to organize a TN-C matrix when separated from the HSC-3 cells by a semi-permeable membrane, indicating that cell-cell contact is not necessary for TN-C matrix organization and suggesting that soluble factors may be involved. Moreover, PTF were induced to assemble TN-C matrices when grown in medium conditioned by both the PTF and HSC-3 cells. Antibodies to fibronectin (FN) and to the first FN type III repeat blocked both FN and TN-C matrix assembly, indicating that TN-C matrix organization is dependent on an FN template. Antibodies to alpha5, alphav and beta1 integrins also blocked TN-C matrix formation. When seeded onto FN matrices, the co-cultures were unaffected by the anti-integrin and anti-FN antibodies and were able to organize a TN-C matrix. Our results suggest that progression of malignant oral SCC is accompanied by an alteration of the normal ECM to one rich in TN-C, and that the organization of a TN-C matrix is dependent on soluble cues provided by both the SCC cells and the PTF.
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PMID:Tenascin-C matrix assembly in oral squamous cell carcinoma. 949 34

Basic fibroblast growth factor (bFGF) is a pluripotent polypeptide which plays an important role in tumor progression and angiogensis. We determined the expression and localization patterns of bFGF and one of its receptor (FGFR-1) in normal renal as well as in renal cancers. The results were compared with clinicopathologic features. Using bFGF and FGFR-1 antibody, the repairing method of antigen with microwave oven heating and LSAB immunohistochemistry we used in 36 cases of paraffin-embedded renal cell carcinoma (RCC) and their paired normal renal tissues. The expression of bFGF and FGFR-1 was nearly consistent. The normal renal tissues and ECM of 29 cases of renal cancer tissues showed heterogenous immunoreactivities. Renal cancer cell cytoplasm of 12 primary tumors and 2 metastatic tumors, as in the cytoplasmic bFGF of cultured GRC-1 cells, were positively homogenous stained. The bFGF and FGFR-1 can be consistently expressed in normal renal and renal cancer tissues, reflecting that the expression and function of these substances were closely associated. The cytoplasmic bFGF expression of renal cancer was related to tumor stages, suggesting that b bFGF plays an important role in the progression of renal cell carcinoma.
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PMID:[Expression of basic fibroblast growth factor and its receptor in renal cell carcinoma]. 959 Jul 49

CD44, a major hyaluronan receptor, exists as several isoforms and is widely distributed in different cells and tissues. The isoforms of CD44, such as CD44s (the standard form), CD44E (the epithelial form) and CD44v (variant isoforms) (arise from differential splicing of one to ten (or eleven) variable exons that encode portions of the membrane proximal extracellular domain. The molecular diversity of CD44 isoforms is further compounded by differential biosynthetic processes and post-translational modifications [e.g. N-/O-glycosylation or glycosaminoglycan (GAG) addition]. This structural arrangement, which occurs within either the invariant region or the extracellular domain of the variant region, is important for CD44-mediated communication between extracellular matrix materials [ECM-hyaluronic acid (HA), collagen and fibronectin] and intracellular protein components (e.g cytoskeletal proteins and various regulatory enzymes). The 15 amino acid sequence [e.g. NSGNGAVEDRKPSGL (in human) or NGGNGTVEDRKPSEL (in mouse)] residing in the cytoplasmic domain of CD44 isoforms is the ankyrin-binding domain of this family of transmembrane glycoproteins. Biochemical analyses plus in vitro mutagenesis indicate that the ankyrin-binding domain is required for CD44-mediated "outside-in" and "inside-out" cell activation events. Furthermore, CD44s-cytoskeleton interaction is tightly coupled with signal transducing molecules (e.g. p185HER2 or Src kinases) during oncogenic signaling. Moreover, the transmembrane linkage between CD44v isoforms (CD44v10 and CD44v3) and the cytoskeleton up-regulates invasive and metastatic-specific tumor phenotypes [e.g. matrix degradation (MMPs) activities, tumor cell invasion and migration]. These findings strongly suggest that the interaction between CD44 isoforms and the cytoskeleton plays a pivotal role in the onset of oncogenesis and tumor progression.
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PMID:CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression. 963 39

Tumor progression and metastasis may result in part from the selection of cell clones competent for survival, invasion and growth at secondary sites and characterized by loss of growth inhibitory responses, acquisition of increased adhesiveness and enhanced motility and protease expression. Transforming growth factor-beta1 (TGF-beta1) is produced by osteoblasts (OB) in a latent form and is activated by proteases in a cell-dependent manner. We show here that OB conditioned medium (OB CM) modulates Matrigel invasion of a bone metastatic prostate cancer cell line (PC3) and that this effect is blocked by antibody against TGF-beta1 and by uPA/plasmin inhibitors, suggesting that TGF-beta1 can modulate OB-mediated cell recruitment and that PC3 cells can activate TGF-beta1. TGF-beta1 induces uPA and PAI-1 secretion and promotes binding of uPA at the external plasma membrane with increased membrane-associated plasmin activity. Matrix metalloprotease-9 (MMP-9) is induced both in the medium and in the membrane associated form. Moreover, the balance between proteolytic activity and inhibition is crucial in the metastatic event. Indeed, the increment of PAI-1 could have an important regulatory role on the extracellular proteolysis and might explain the decrease of net PA and gelatinolytic activities measured in the medium. In addition, PAI-1 plays a regulative role localizing matrix degradation in some specific sites, such as areas of cell-to-cell or cell-to-ECM contacts. In conclusion, TGF-beta1 enhances PC3 Matrigel invasion by a uPA/plasmin-dependent mechanism, also involving the MMP-9, and thus may play a central role in malignant prostate tumor progression as a result of stimulating bone matrix invasion.
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PMID:Osteoblast-derived TGF-beta1 modulates matrix degrading protease expression and activity in prostate cancer cells. 1065 34

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


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