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)

Multi-autocrine loops of the epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), platelet-derived growth factor (PDGF) and TGF beta system are expressed in human gastrointestinal carcinomas. In esophageal and gastric carcinomas, they evidently play an important role in tumor progression. Gastrin, one of the major gut hormones, may also act as an autocrine growth factor for gastric and colonic carcinomas. The HST1 and INT-2 genes, belonging to the fibroblast growth factor gene family, are coamplified in approximately 50% of primary tumors and in all the metastatic tumors of esophageal carcinoma. TGF alpha and EGF are the ligands of the tumor cells that overexpress EGF receptor in esophageal carcinomas. The synchronous expression of EGF and its receptor, as well as TGF alpha and ras p21, is evidently correlated with the depth of tumor invasion, metastasis and prognosis of gastric carcinomas. Amplification of c-erbB-2 and EGF receptor genes has been observed in many metastatic sites of gastric carcinomas regardless of histological type. In addition to TGF alpha and EGF, TGF beta and PDGF A chain produced by tumor cells may stimulate collagen synthesis not only by fibroblasts but also by tumor cells themselves, resulting in extensive progression and diffuse fibrosis of scirrhous gastric carcinomas. Moreover, TGF alpha or EGF and estrogen may also play a cooperative role in the development of scirrhous gastric carcinoma. In colorectal carcinoma, it has been shown that the accumulation of several alterations in ras genes and p53 genes is most important for the conversion of adenoma to carcinoma. Critical genetic changes, including activation of oncogenes, mutation and deletion of tumor suppressor genes and disturbances in transcriptional regulatory sequences, may bring about aberrant expression of growth factors and their receptors in gastrointestinal carcinomas. The understanding of the significance of EGF-related growth factors in tumor progression provides a framework for a biological approach to the therapy of human gastrointestinal carcinomas. 8-Cl-cAMP, which inhibits expression of oncogenes and TGF alpha, may be useful not only for cancer therapy but also for the study of cell differentiation.
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PMID:Growth factors and oncogenes in human gastrointestinal carcinomas. 215 13

The generation of invasiveness in transformed cells represents an essential step of tumor progression. We show here, first, that nontransformed Madin-Darby canine kidney (MDCK) epithelial cells acquire invasive properties when intercellular adhesion is specifically inhibited by the addition of antibodies against the cell adhesion molecule uvomorulin; the separated cells then invade collagen gels and embryonal heart tissue. Second, MDCK cells transformed with Harvey and Moloney sarcoma viruses are constitutively invasive, and they were found not to express uvomorulin at their cell surface. These data suggest that the loss of adhesive function of uvomorulin (which is identical to E-cadherin and homologous to L-CAM) is a critical step in the promotion of epithelial cells to a more malignant, i.e., invasive, phenotype. Similar modulation of intercellular adhesion might also occur during invasion of carcinoma cells in vivo.
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PMID:Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. 266 63

Recent studies of murine tumor models and certain human tumor cell lines have provided evidence for intratumor heterogeneity in expression of extracellular matrix receptors and in the elaboration of matrix-degrading enzymes. However, little is known about possible intratumoral heterogeneity in the production of matrix macromolecules. We have, therefore, examined the biosynthesis and secretion of matrix proteins by cells derived from a polyclonal human cell line (JH-17) established from a large cell undifferentiated carcinoma of the lung. For the present studies, we focused on the production of collagens and structural glycoproteins by two phenotypically different aneuploid clones, designated C13 and C22. These clones were distinctive in their inability to grow in soft agar or to form tumors in nude mice and had identical DNA contents. Tumor cells were labeled with [3H]proline and the newly synthesized proteins accumulating in the culture medium were identified using biochemical and immunologic techniques. Clone C13 secreted at least three genetically distinct collagens, including type V procollagen (PC), type IV procollagen, and a type VIII-like collagen. By contrast, the clone C22 synthesized fibronectin, and a single bacterial collagenase-sensitive and pepsin-resistant component consistent with type I trimer. These studies emphasize the potential diversity of matrix proteins synthesized by neoplastic cells and suggest that there is intratumoral heterogeneity in matrix protein biosynthesis in vivo. These studies further suggest that tumor-derived matrix may be altered during tumor progression or cell selection in vivo.
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PMID:Heterogeneity in the production of collagens and fibronectin by morphologically distinct clones of a human tumor cell line: evidence for intratumoral diversity in matrix protein biosynthesis. 282 40

Rabbit bladder epithelium, grown on collagen gels and exposed to the chemical carcinogen benzo[a]pyrene, produced nontumorigenic altered foci as well as tumorigenic epithelial cell lines during 120-180 d in culture. Immunofluorescence studies revealed extensive keratin filaments in both primary epithelial cells and benzo[a]pyrene-induced altered epithelial foci but showed no detectable vimentin filaments. The absence of vimentin expression in these cells was confirmed by two-dimensional gel electrophoresis. In contrast, immunofluorescence staining of the cloned benzo[a]pyrene-transformed rabbit bladder epithelial cell line, RBC-1, revealed a reduction in filamentous keratin concomitant with the expression of vimentin filaments. The epithelial nature of this cell line was established by the observation that cells injected into nude mice formed well-differentiated adenocarcinomas. Frozen sections of such tumors showed strong staining with antikeratins antibodies, but no detectable staining with antivimentin antibodies. These results demonstrated a differential expression of intermediate filament type in cells at different stages of neoplastic progression and in cells maintained in different growth environments. It is apparent that the expression of intermediate filaments throughout neoplastic progression is best studied by use of an in vivo model system in parallel with culture studies.
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PMID:Expression of keratin and vimentin intermediate filaments in rabbit bladder epithelial cells at different stages of benzo[a]pyrene-induced neoplastic progression. 616 27

The histologic features of 63 renal tumors induced in 39 rabbits of two partially inbred strains, IIIVO/J and WH/J, by transplacental exposure to N-ethylnitrosourea (ENU) were analyzed. All tumors in the series conformed to nephroblastoma, permitting the establishment of histologic standards for this neoplasm in the rabbit as well as observations on tumor progression. Essentially, nephroblastoma proved to be predominantly an epithelial tumor identifying with metanephrogenic blastema, which was presumed to be the tissue of origin during fetal development. The outstanding features comprised clusters or sheets of undifferentiated blastemalike tissue and differentiation along the epithelial pathway into tubular profiles and structures suggestive of primitive, nonvascularized glomeruli. The latter were frequently of a complex nature, with a papillary configuration. On the other hand, no definitive evidence of bipotential differentiation into malignant secondary mesenchyme was found, there being no recognizable areas of fibrosarcomatous elements or specialized connective tissue such as smooth or striated muscle, adipose tissue, cartilage, or osteoid. Mesenchymelike fascicular disposition of neoplastic cells between blastemal clusters was an acquired feature seen in advanced tumors but not in small early lesions. By light microscopy alone it was not possible to determine whether this represented a conformational change of tumor cells or true bipotential differentiation into neoplastic secondary mesenchyme. However, the reticulin pattern was not characteristic of sarcoma. A conspicuous feature accompanying the growth and development of tumors was the magnitude of host fibrous reaction discernible only as a simple ramifying stroma in the earliest lesions but attaining impressive proportions both within and around the tumor with advancing age. Increasing collagen formation appeared to be associated with ischemic necrosis of tumor tissue. Other features of advanced tumors were the presence of discrete foci of differentiated tubular structures suggestive of mature medullary elements and small islands of squamoid differentiation. Metastases occurred only in rabbits of strain IIIVO/J, which had been subjected to a single dose of the carcinogen, representing an incidence in this subgroup of 25%. Nephroblastomas resulting from transplacental induction in IIIVO/J rabbits, particularly by single, high doses of ENU, appear to provide a suitable model for the predominant histologic form of the Wilms' tumor complex in man.
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PMID:Histologic characterization of renal tumors (nephroblastomas) induced transplacentally in IIIVO/J and WH/J rabbits by N-ethylnitrosourea. 631 4

Basement membranes are extracellular structures with a heterogeneous molecular composition. Several components have been identified and could be localized in specific morphological structures. Type IV collagen is found in the lamina densa, whereas laminin is the major component of the lamina lucida. Small amounts of heparan sulfate proteoglycan are also present in the lamina lucida. In some basement membranes, fibronectin and another glycoprotein, nidogen, could be identified. Epidermal basement membranes contain, in addition, the bullous pemphigoid antigen. Basement membranes are involved in several diseases and play an important part in tumor progression. Antibodies against distinct components of basement membranes have been shown to be useful as diagnostic tools in bullous disorders (e.g., epidermolysis bullosa) and for identifying the extracellular matrix of skin tumors (e.g., neurofibroma, cylindroma, granular cell myoblastoma).
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PMID:[Basement membranes--structure, function, pathology]. 638 6

After intraperitoneal implantation into Swiss Silver rabbits, V2 rabbit carcinoma cells invade the mesentery where they form nodules of different size and texture: compact (less than 120 microns in diameter), loose (120-250 microns) and mixed (above 200 microns). Together with tumor development, certain changes take place in the loose connective tissue of the mesentery. Application of TEM, together with use of safranin O, has shown that, in areas free of tumor growth, collagen bundles become thick and heavy and proteoglycan density is increased. Concurrently, the number of fibrocytes, now transformed to fibroblasts, increases. Small, compact nodules are surrounded by a concentrically arranged extracellular matrix. Its overall density is similar to that of nodule-free areas. In the immediate vicinity of large, loose nodules, all constituents of the extracellular matrix disappear. Adjacent connective tissue is partly destroyed but still contains collagen fibers and proteoglycans. These findings suggest the following: The presence of V2 carcinoma cells induces marked alterations in the structured and non-structured components of the extracellular matrix. These changes are, at the same time, progressive and regressive and the occurrence of one or the other depends on local tumor progression. Progressive alterations may result from an increased activity of fibroblasts. Since degradative effects, on the other hand, are only seen in the immediate vicinity of larger tumor aggregates, it is assumed that a minimal number of tumor cells is essential for destruction of extracellular matrix.
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PMID:Morphology of peritumoral proteoglycan alterations in the rabbit mesentery invaded by V2 carcinoma cells. 649 Feb 6

The exponential growth of solid tumors depends upon induction of new vessel growth, a process mediated by diffusable angiogenic factors produced by tumor cells. By inhibiting angiogenesis, it is now possible to modulate tumor growth and metastasis in laboratory animals. The first described inhibitor of angiogenesis was a protein derived from cartilage. Other important classes of antiangiogenic agents include angiostatic steroids combined with heparin or heparin derivatives, and the synthetic derivatives of fumigallin. As the mechanisms of action of these and other angiostatic agents are being elucidated, it is becoming apparent that many modulators of collagen metabolism inhibit angiogenesis and may offer clinically useful anticancer treatments. Minocycline and other tetracycline derivatives with anticollagenase properties have been shown to be potent inhibitors of angiogenesis. These agents, when administered with other standard cancer therapies, help prolong survival in laboratory animals with solid tumors. Further studies of these biologic response modifiers of tumor progression are under way in the hope that they will offer effective new treatments for cancer in humans.
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PMID:Inhibition of tumor angiogenesis. 752 58

Matrix metalloproteinases (matrixins) constitute a group of extracellular proteinases belonging to the metzincin superfamily. They are involved in both physiological and pathological tissue remodeling processes, including those associated with cancer progression. Stromelysin-3, which is expressed in most invasive human carcinomas, is a matrix metalloproteinase with unusual functional properties. In particular, its mature form does not cleave any of the major extracellular matrix components. To define critical structural determinants involved in controlling stromelysin-3 proteolytic activity, we have used site-directed mutagenesis. We show that the deletion of at least 175 C-terminal amino-acids is sufficient to endow mouse stromelysin-3 with activities against casein, laminin, and type IV collagen. In the case of the human enzyme, however, a further and single Ala-235-->Pro substitution is necessary to observe similar activities. Ala-235, which characterizes human stromelysin-3 among matrixins, is located immediately after the C terminus of the "Met-turn," which forms a hydrophobic basis for the catalytic zinc atom in the metzincin family. We conclude that human stromelysin-3 has gained specific functional properties during evolution by amino acid substitution in the catalytic zinc environment, and that it represents an attractive target for specific inhibitors that may be used to prevent cancer progression.
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PMID:Identification of structural determinants controlling human and mouse stromelysin-3 proteolytic activities. 755 21

Prostate carcinomas often present an autocrine stimulatory loop in which the transformed cells both express the EGF receptor (EGFR) and produce activating ligands (TGF alpha and EGF forms). Up-regulated EGFR signalling has been correlated with tumor progression in other human neoplasia; however, the cell behaviour which is promoted remains undefined. To determine whether an EGFR-induced response contributes to cell invasiveness, we transduced DU-145 human prostate carcinoma cells with either a full-length (WT) or a mitogenically-active but motility-deficient truncated (c'973) EGFR. The DU-145 Parental and two transgene sublines all produced EGFR and TGF alpha, but the transduced WT and c'973 EGFR underwent autocrine downregulation to a lesser degree, with more receptor remaining intact. DU-145 cells transduced with WT EGFR transmigrated a human amniotic basement membrane matrix (Amgel) to a greater extent than did Parental DU-145 cells (175 +/- 22%). Cells expressing the c'973 EGFR invaded through the Amgel only to about two thirds the extent of the Parental cells (62 +/- 23%). A monoclonal antibody which prevents ligand-induced activation of EGFR decreased the invasiveness of WT-expressing cells by half and Parental cells by a fifth, but had little effect on the invasiveness of c'973-expressing cells; with the result that in the presence of antibody, all three cell lines transmigrated the Amgel to the same extent. The different levels of invasiveness between the three sublines were independent of cell proliferation. These findings demonstrated that EGFR-mediated signals increase tumor cell invasiveness and suggested that domains in the carboxy-terminus are required to signal invasiveness. As an initial investigation into the mechanisms underlying the EGFR-mediated enhanced invasiveness, we determined whether these cells presented different collagenolytic activity, as the major constituents of Amgel are collagen types I and IV. All three sublines secreted easily detectable levels of gelatin-directed proteases and TIMP-1, with WT cells secreting equivalent or lower levels of proteases. The proteolytic balance in these cells did not correlate with invasiveness. These data suggest that the TGF alpha-EGFR autocrine loop promotes invasiveness and that this is accomplished by signalling cell properties other than differential secretion of collagenolytic activity.
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PMID:In vitro invasiveness of DU-145 human prostate carcinoma cells is modulated by EGF receptor-mediated signals. 758 99


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