UMLS:C0178874 - FACTA Search

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

Several studies suggest that cellular adhesion molecules (CAM) play a role in cancer progression and metastasis. To evaluate the role of these molecules as possible tumor markers in patients with urological malignancies, we examined the serum levels of intercellular cell adhesion molecule-1 (ICAM-1), vascular cellcular adhesion molecule-1 (VCAM-1) and E-selectin in patients with renal cell-, bladder-, prostate- and testicular cancer. Serum levels of 237 patients with urological cancers, renal cell carcinoma (n = 47), bladder cancer (n = 81), prostate cancer (n = 87) and testicular cancer (n = 22) and a group of 41 patients with benign prostate hyperplasia (BPH) as well as a 42 healthy control persons were examined for CAMs by specific ELISA tests. Serum CAM concentrations of all tumor patients were compared with controls and within the group according to T stage, N stage, tumor grade and extent of distant metastasis. Our results demonstrate that ICAM-1 and VCAM-1 serum levels are not stage dependently elevated; in contrary, they demonstrate a wide range and are highly variable throughout the different cancer types. In renal cell cancer and in bladder cancer, there is a significant difference for ICAM-1 between controls and T3 and T4 and metastatic cancers. A similar difference was found for VCAM-1, however not for E-selectin in any tumor group. Testicular cancer and prostate cancer did not demonstrate any difference in CAM serum levels between patients with tumors and controls. In metastatic renal cell-, bladder- and prostate cancer, the serum levels of ICAM-1 and VCAM-1 showed a tendency to correlate with the extent of metastatis although no statistical difference between patients with a single metastatic lesion and patients with multiple lesions could be demonstrated. The results of this study implicate a rather limited role of cellular adhesion molecules. Despite of significant ICAM-1 or VCAM-1 serum levels in some locally advanced tumors or metastatic disease, this observation does not provide enough relevant clinical information for use as tumor markers.
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PMID:Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in urological malignancies. 1475 78

Phenotypic and genotypic analyses of cutaneous melanoma have identified the endothelin B receptor (ET(B)R) as tumor progression marker, thus representing a potential therapeutic target. Here, we demonstrate that activation of ET(B)R by endothelin-1 (ET-1) and ET-3 leads to loss of expression of the cell adhesion molecule E-cadherin and associated catenin proteins and gain of N-cadherin expression. Exposure of melanoma cells to ET-1 leads to a 60% inhibition in intercellular communication by inducing phosphorylation of gap junctional protein connexin 43. Additionally, activation of the ET(B)R pathway increases alpha(v)beta(3) and alpha(2)beta(1) integrin expression and matrix metalloproteinase (MMP)-2 and MMP-9, membrane type-1-MMP activation, and tissue inhibitor MMP-2 secretion. The ET(B)R pathway results into the downstream activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2 signaling pathways, which lead to enhanced cell proliferation, adhesion, migration, and MMP-dependent invasion. The small molecule A-192621, an orally bioavailable nonpeptide ET(B)R antagonist, significantly inhibits melanoma growth in nude mice. These findings demonstrate that ET-1 and ET-3 through ET(B)R activation trigger signaling pathways involved in events associated with disruption of normal host-tumor interactions and progression of cutaneous melanoma. Pharmacological interruption of ET(B)R signaling may represent a novel therapeutic strategy in the treatment of this malignancy.
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PMID:Endothelin B receptor blockade inhibits dynamics of cell interactions and communications in melanoma cell progression. 1497 17

Hyaluronan plays important roles in the complex processes of tumor invasion and metastasis. It is now known that three hyaluronan synthase (HAS) isoforms catalyze hyaluronan synthesis, which raises the question of how they are involved in malignant tumor progression. In this study, we examined the correlation between tumor progression and transcriptional levels of three HAS isoforms in specimens of human colon cancers. Tumor tissues from 31 patients with different diagnostic grades were assessed to determine the level of each HAS isoform by real time RT-PCR. The mean expression coefficients for HAS1, HAS2 and HAS3 in the cancerous parts were 0.82-, 0.91- and 1.22-fold, respectively; of those in the noncancerous parts at Dukes' stage A; 1.00-, 0.95- and 1.06-fold, respectively, at stage B; and 1.95-, 1.16- and 1.19-fold, respectively, at stage C. In survival analysis, a significant correlation was observed between poor survival and the HAS1 transcript level. When the ratio of tumor to normal tissue in the HAS1 level was compared with that of the HA receptor transcript level, there was a positive correlation with that of the CD44 variant 6 level at Dukes' stage C. Our current results therefore suggest that HAS1 plays a role in the malignant progression of human colon cancer cells.
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PMID:Elevated transcript level of hyaluronan synthase1 gene correlates with poor prognosis of human colon cancer. 1506 3

E-cadherin is a cell-cell adhesion molecule that plays a pivotal role in the development and maintenance of cell polarity. Disruption of E-cadherin-mediated adhesion represents a key step toward the invasive phenotype in a variety of solid tumors, including hepatocellular carcinoma (HCC). Here, we investigate whether deregulation of E-cadherin occurs along the multistep process of hepatocarcinogenesis in transgenic mouse models, including c-Myc, E2F1, c-Myc/TGF-alpha and c-Myc/E2F1 mice. Liver tumors from the transgenic mouse lines could be divided into two categories based on E-cadherin levels. Of 28, 20 (71.4%) c-Myc HCCs showed marked reduction of E-cadherin expression when compared with wild-type livers. In contrast, all of c-Myc/TGF-alpha and the majority of E2F1 and c-myc/E2F1 preneoplastic and neoplastic lesions exhibited overexpression of E-cadherin. Downregulation of E-cadherin was associated with promoter hypermethylation in seven of 20 c-Myc HCCs (35%), while no loss of heterozygosity at the E-cadherin locus was detected. Nuclear accumulation of beta-catenin did not correlate with E-cadherin downregulation. Furthermore, c-Myc HCCs with reduced E-cadherin displayed upregulation of hypoxia-inducible factor-1alpha and vascular endothelial growth factor proteins. Importantly, loss of E-cadherin was associated with increased cell proliferation and higher microvessel density in c-Myc tumors. Taken together, these data suggest that loss of E-cadherin might favor tumor progression in relatively more benign HCC from c-Myc transgenic mice by stimulating neoplastic proliferation and angiogenesis under hypoxic conditions.
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PMID:Disregulation of E-cadherin in transgenic mouse models of liver cancer. 1522 Sep 35

Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. The cell adhesion molecule E-cadherin is frequently down-regulated or mutated in tumors. In addition to down-regulation of cell adhesion, degradation of the extracellular matrix by matrix metalloproteinases is necessary for tumor cell spread. To investigate a possible link between E-cadherin and matrix metalloproteinase 3 (MMP-3), we examined expression of MMP-3 in human MDA-MB-435S cells transfected with wild-type (wt) or three different tumor-associated mutant E-cadherin variants with alterations in exons 8 or 9, originally identified in gastric carcinoma patients. In the presence of wt E-cadherin, the MMP-3 protein level was decreased in cellular lysates and in the supernatant where a secreted form of the protein is detectable. Down-regulation of MMP-3 was not found in MDA-MB-435S transfectants expressing mutant E-cadherin variants which indicates that E-cadherin mutations interfere with the MMP-3 suppressing function of E-cadherin. The mechanism of regulation of MMP-3 by E-cadherin is presently not clear. We have previously found that cell motility is enhanced by expression of the mutant E-cadherin variants used in this study. Here, we found that application of the synthetic inhibitor of MMP-3 NNGH and small interfering RNA (siRNA) directed against MMP-3 reduce mutant E-cadherin-enhanced cell motility. Taken together, our results point to a functional link between MMP-3 and E-cadherin. MMP-3 is differentially regulated by expression of wt or mutant E-cadherin. On the other hand, MMP-3 plays a role in the enhancement of cell motility by mutant E-cadherin. Both observations may be highly relevant for tumor progression since they concern degradation of the extracellular matrix and tumor cell spread.
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PMID:Effect of tumor-associated mutant E-cadherin variants with defects in exons 8 or 9 on matrix metalloproteinase 3. 1538 40

The expression of the alphavbeta3 integrin (CD51/CD61) on human melanoma cells has been shown to be associated most closely with tumor progression and metastases formation in melanoma. Here, we demonstrated a specific interaction of the alphavbeta3 integrin on melanoma cells with the human Thy-1, an inducible cell adhesion molecule expressed on the cell surface of activated endothelial cells (EC). The interaction was shown by the binding of purified Thy-1 protein to alpha(V)beta(3) transfected cells, to alphavbeta3-expressing melanoma cells and to purified alpha(V)beta(3) integrin. Moreover, melanoma cells adhere specifically to Thy-1 transfectants via alphavbeta3 on melanoma cells showing the functional relevance of this interaction for cell adhesion. Finally, the importance of the alphavbeta3/Thy-1 interaction for the adhesion of melanoma cells to the activated endothelium was confirmed under static and flow conditions by the inhibition of melanoma cell adhesion to and transmigration across activated EC by blocking the alphavbeta3/Thy-1 interaction. In conclusion, we have identified a new pair of adhesion molecules Thy-1 and alphavbeta3 mediating the interaction of melanoma cells and activated EC. These data explain at least in part the high tumorigenicity of alphavbeta3-expressing melanoma cells and the association of alphavbeta3-positive melanoma cells with a high risk of metastasis and poor prognosis.
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PMID:Interaction of human Thy-1 (CD 90) with the integrin alphavbeta3 (CD51/CD61): an important mechanism mediating melanoma cell adhesion to activated endothelium. 1589 8

Melanoma cells exhibit a high level of intrinsic or acquired resistance to the cytotoxic agents often associated with the over-expression of drug transporters such as P-glycoprotein (P-gp). In this in vitro study, we investigated the possible relationship between P-gp and CD44, the cell adhesion molecule involved in metastasis and tumor progression of melanoma cells. CD44 expression appeared to be similar in the parental sensitive M14 WT cells and in their resistant counterparts M14 ADR cells. Double-labeling of cryosectioned cells showed that P-gp and CD44 were transported from the synthesis loci to the cell periphery by different vesicles and began to coalesce in proximity of the plasma membrane; thus, P-gp and CD44 seemed to reach together the cell surface. Moreover, P-gp and CD44 appeared to be associated with ERM proteins. The invasive activities of both M14 WT and M14 ADR cells were analyzed by the "transwell chamber invasion" assay. M14 WT cells revealed low capacity to traverse the filters, both in the absence (motility) and in the presence (invasion) of a Matrigel coating. In comparison, M14 ADR cells displayed significantly higher motility and invasion. SEM observations showed that sensitive cells employed lamellar cytoplasmic extrusions to pass through the filter pores whereas resistant cells elongated along the hole through globular processes. In conclusion, the results herein reported suggest that drug resistance in melanoma cells appears associated with a more aggressive behaviour. P-gp and CD44 might cooperate to confer this more invasive phenotype.
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PMID:Invasive properties of multidrug resistant human melanoma cells. 1610 Oct 31

The two-stage initiation-progression model of cancer is widely accepted. Although mutations explain initiation of neoplasia, the assumption that mutations are responsible for progression of neoplasia to cancer appears to have little experimental support. The "cell clone ecology hypothesis" explains why neoplasia evolve and the "cell fusion model of cancer progression and metastasis" describes how they evolve into clinically significant tumors. A brief history of important concepts and experiments is provided. Clinically significant cancers are effectively new parasite species that live, expand and evolve within the host. It is hypothesized that survival and fate of the parasite clones called "cancer" are governed by the principles of ecology. It is argued that while mutations or aneuploidy (asexual reproduction) can result in transient/self-limiting neoplasia, neither of these asexual modes of forming new karyotypes can maintain the ecologically fit parasites that develop into clinically significant cancer. Mutations and/or unstable genomes (aneuploidy) progressively degrade cell lines and if only these mechanisms were at work, neoplasia would spontaneously become extinct or benign (enfeebled) before reaching clinical significance (an example of "Muller's ratchet"). In the cell fusion model of (clinically significant) cancer progression and metastasis, cell-cell fusion is the essential element allowing normal cells or (transient) neoplasia to evolve into clinically significant cancers. Cell-cell fusion is required for producing and sustaining clinically significant cancer because it provides a sex-like mode of reproduction essential for an ecologically fit parasite organism. Cell-cell fusion provides the opportunity needed for tumors to rejuvenate cell lines containing abnormal genomes and rapidly evolve to acquire dramatically aggressive traits such as metastasis. Indeed, metastasis appears to require cell-cell fusion. Cell-cell fusion also partially overcomes erosion of teleomeres during clone expansion and allows the essential elements of a tumorigenic genome to hide from chemotherapy as recessive traits in cells with normal phenotypes and re-emerge (by cell-cell fusion) as a new cancer after the phenotypically cancerous cells have been eradicated by classical chemotherapy. Eradication of the cancer parasite cannot be routinely achieved by classical toxic chemotherapy alone or even by chemotherapy augmented with techniques needed to overcome anti-apoptotic traits of cancer cells. Direct chemical intervention against cell-cell fusion concurrent with classical toxic chemotherapy holds a promise of preventing re-lapse of the disease. Intervention against cell-cell fusion may also directly suppress metastasis based on the model presented here. The paper also summarizes work on the cell surface glycoprotein CD44 that implicates it as a key element in cell-cell fusion and hence cancer.
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PMID:The cell clone ecology hypothesis and the cell fusion model of cancer progression and metastasis: history and experimental support. 1765 30

Epithelial-mesenchymal transition (EMT) is an important process during development by which epithelial cells acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility. Accumulating evidence points to a critical role of EMT-like events during tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. Several oncogenic pathways (peptide growth factors, Src, Ras, Ets, integrin, Wnt/beta-catenin and Notch) induce EMT and a critical molecular event is the downregulation of the cell adhesion molecule E-cadherin. Recently, activation of the phosphatidylinositol 3' kinase (PI3K)/AKT axis is emerging as a central feature of EMT. In this review, we discuss the role of PI3K/AKT pathways in EMT during development and cancer with a focus on E-cadherin regulation. Interactions between PI3K/AKT and other EMT-inducing pathways are presented, along with a discussion of the therapeutic implications of modulating EMT in order to achieve cancer control.
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PMID:Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. 1628 91

The development and progression of tumor cells is controlled by their interactions with neighboring host cells and a variety of microenvironmental factors including extracellular matrix (ECM) molecules, growth factors and proteinases. Cell-adhesive ECM proteins are a prerequisite for growth and migration of many types of cells. Their interactions with integrins and other cell surface receptors induce intracellular signaling that regulates the actin cytoskeleton and gene expression. The basement membrane protein laminin-5 is a notable cell adhesion molecule, which promotes cellular adhesion and migration much more efficiently than other ECM proteins. There is accumulating evidence that laminin-5 is involved in tumor growth and progression. With special reference to laminin-5, this article reviews the regulatory mechanisms of cellular adhesion and migration by ECM molecules and their significance in tumor progression.
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PMID:Laminin-5 (laminin-332): Unique biological activity and role in tumor growth and invasion. 1644 18

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