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

Eukaryotic mRNAs are transcribed as precursors containing their intronic sequences. These are subsequently excised and the exons are spliced together to form mature mRNAs. This process can lead to transcript diversification through the phenomenon of alternative splicing. Alternative splicing can take the form of one or more skipped exons, variable position of intron splicing or intron retention. The effect of alternative splicing in expanding protein repertoire might partially underlie the apparent discrepancy between gene number and the complexity of higher eukaryotes. It is likely that more than 50% form. Many cancer-associated genes, such as CD44 and WT1 are alternatively spliced. Variation of the splicing process occurs during tumor progression and may play a major role in tumorigenesis. Furthermore, alternatively spliced transcripts may be extremely useful as cancer markers, since it appears likely that there may be striking contrasts in usage of alternatively spliced transcript variants between normal and tumor tissue than in alterations in the general levels of gene expression.
 ...
PMID:Alternative spliced transcripts as cancer markers. 1167 53

The ability of tumor cells to adhere and detach from extracellular matrix and endothelial cells, is a crucial step in the metastatic process and may alter the clinical prognosis of some human tumors such as melanomas. CD44, the major cell surface receptor for hyaluronate, has been implicated in cell adhesion and in tumor progression. We studied the expression of standard CD44 molecule (CD44s) and its variants v3 and v6 in 57 human primary melanoma biopsies, without previous treatment. We analyzed the association between CD44 expression and the principal clinicopathological features, including survival. Fifty-six of 57 tumors expressed CD44s, associated to the cytoplasmic membrane. No expression of CD44v3 or CD44v6 was detected. No association between CD44s expression and prognostic factors such as tumor thickness, growth type, stage or anatomic site of the lesion was found. However, a positive correlation between CD44s expression and Clark level (Spearman, p<0.001) was found. While only 33.3% of melanomas Clark I + II showed high expression of CD44s (more than 50% of positive cells), 82.6% of melanomas Clark IV + V did so. Kaplan-Meier analysis revelead that patients whose melanomas had high expression of CD44s showed a reduced relapse free survival (RFS) rate, though without statistical significance. No difference between the level of CD44 expression and overall survival (OS) was found. We conclude that melanomas only expressed CD44s, and that its level was associated with Clark's stage. CD44s seems not to be useful as a tumor marker, because it does not predict either RFS or OS.
 ...
PMID:Expression of CD44s and CD44 splice variants in human melanoma. 1174 54

An association between cell adhesion molecules expression in neoplastic tissues and cancer progression has been the focus of many recent studies. In certain tumours down-regulation of CD44 expression has been linked to the poor prognosis. The aim of the study was to evaluate CD44 expression and to determine the correlation between CD44 expression and the clinicopathological features of laryngeal cancer. The group consisted of 80 patients with primary laryngeal cancer. Tissue samples were taken from removed tumour mass during surgical treatment, CD44 expression was assessed by immunohistochemical method. The down-regulation of CD44 expression significantly correlated with a shorter disease-free survival (p<0.05). Our results suggest that CD44 expression may be useful as a prognostic marker in laryngeal cancer.
 ...
PMID:CD44 glycoprotein as a prognostic factor in laryngeal cancer. 1182 May 81

Cell surface adhesion molecules are crucial for the development and/or pathogenesis of various diseases including cancer. CD44 has received much interest as a major adhesion molecule that is involved in tumor progression. We have previously demonstrated that the ectodomain of CD44 undergoes proteolytic cleavage by membrane-associated metalloproteases in various tumor cell lines. The remaining membrane-bound CD44 cleavage product can be detected using antibodies against the cytoplasmic domain of CD44 (anti-CD44cyto antibody). However, the cleavage of CD44 in primary human tumors has not been investigated. Using Western blots with anti-CD44cyto antibody to assay human tumor tissues, we show that the CD44 cleavage product can be detected in 58% (42 of 72) of gliomas but not in normal brain. Enhanced CD44 cleavage was also found in 67% (28 of 42) of breast carcinomas, 45% (5 of 11) of non-small cell lung carcinomas, 90% (9 of 10) of colon carcinomas, and 25% (3 of 12) of ovarian carcinomas. Tumors expressing a CD44 splice variant showed a significantly higher incidence of enhanced CD44 cleavage. The wide prevalence of CD44 cleavage suggests that it plays an important role in the pathogenesis of human tumors.
 ...
PMID:Proteolytic cleavage of the CD44 adhesion molecule in multiple human tumors. 1183 64

Mammalian cells express two homologs of the SWI2 subunit of the SWI/SNF chromatin-remodeling complex called BRG1 and BRM. Whether the SWI/SNF complexes formed by these two subunits perform identical or different functions remains an important question. In this report, we show concomitant down-regulation of BRG1 and BRM in six human tumor cell lines. This down-regulation occurs at the level of mRNA abundance. We tested whether BRM could affect aberrant cellular functions attributed to BRG1 in tumor cell lines. By transient transfection, we found that BRM can restore RB-mediated cell cycle arrest, induce expression of CD44 protein and suppress Cyclin A expression. Therefore, BRM may be consistently down-regulated with BRG1 during neoplastic progression because they share some redundant functions. However, assorted tissues from BRM null/BRG1-positive mice lack CD44 expression, suggesting that BRM-containing SWI/SNF complexes regulate expression of this gene under physiological conditions. Our studies further define the mechanism by which chromatin-remodeling complexes participate in RB-mediated cell cycle arrest and provide additional novel evidence that the functions of SWI/SNF complexes containing BRG1 or BRM are not completely interchangeable.
 ...
PMID:Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression. 1185 Aug 39

Matrix metalloproteinases (MMPs) play an important role in degradation of extracellular matrix (ECM), which is an essential step in the cascade of metastasis. Various types of MMPs are expressed and activated in head and neck squamous cell carcinoma (HNSCC) as well as other human cancers. MMP-2 is a prominent predictor of poor prognosis. Membrane type 1-MMP (MT1-MMP) was originally identified as an activator of MMP-2. In addition to the original role, recent studies show other important functions of MT1-MMP such as degradation of type I collagen and cleavage of CD44. Tissue inhibitor of MMP-2 (TIMP-2) was identified as an inhibitor of MMP-2 and MT1-MMP. However, TIMP-2 was reported to be essential for cell-mediated activation of MMP-2, and thus the contribution of TIMP-2 to tumor invasion has remained controversial. Some studies also suggested a role of TIMP-2 as a predictor of poor prognosis. Thus, inhibition of MMP activation by TIMPs is not a suitable strategy for suppressing invasion and metastasis. Instead of TIMP-2, various MMP inhibitors (MMPI) such as BB-2516 have been investigated with regard to suppression of tumor progression and improvement of prognosis in patients with advanced cancers, which resulted in no clinical efficacy. MMPs are especially important in the early stage of cancer progression, and thus strategies for future MMPI trials should be reconsidered.
 ...
PMID:Recent advances in the regulation of matrix metalloproteinase 2 activation: from basic research to clinical implication (Review). 1195 36

In this study we have examined the interaction between CD44 (a hyaluronan (HA) receptor) and the transforming growth factor beta (TGF-beta) receptors (a family of serine/threonine kinase membrane receptors) in human metastatic breast tumor cells (MDA-MB-231 cell line). Immunological data indicate that both CD44 and TGF-beta receptors are expressed in MDA-MB-231 cells and that CD44 is physically linked to the TGF-beta receptor I (TGF-betaRI) (and to a lesser extent to the TGF-beta receptor II (TGF-betaRII)) as a complex in vivo. Scatchard plot analyses and in vitro binding experiments show that the cytoplasmic domain of CD44 binds to TGF-betaRI at a single site with high affinity (an apparent dissociation constant (K(d)) of approximately 1.78 nm). These findings indicate that TGF-betaRI contains a CD44-binding site. Furthermore, we have found that the binding of HA to CD44 in MDA-MB-231 cells stimulates TGF-betaRI serine/threonine kinase activity which, in turn, increases Smad2/Smad3 phosphorylation and parathyroid hormone-related protein (PTH-rP) production (well known downstream effector functions of TGF-beta signaling). Most importantly, TGF-betaRI kinase activated by HA phosphorylates CD44, which enhances its binding interaction with the cytoskeletal protein, ankyrin, leading to HA-mediated breast tumor cell migration. Overexpression of TGF-betaRI by transfection of MDA-MB-231 cells with TGF-betaRIcDNA stimulates formation of the CD44.TGF-betaRI complex, the association of ankyrin with membranes, and HA-dependent/CD44-specific breast tumor migration. Taken together, these findings strongly suggest that CD44 interaction with the TGF-betaRI kinase promotes activation of multiple signaling pathways required for ankyrin-membrane interaction, tumor cell migration, and important oncogenic events (e.g. Smad2/Smad3 phosphorylation and PTH-rP production) during HA and TGF-beta-mediated metastatic breast tumor progression.
 ...
PMID:Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor beta receptor I in metastatic breast tumor cells. 1214 87

Multi-cellular spheroids (MCS) generated from tumor cells serve as excellent in vitro models for understanding the mechanisms of tumor progression and micro-metastasis. We have compared the expression of molecular markers with reference to their growth as conventional adherent monolayers (2-D) and anchorage independent cultures (3-D) using two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines differed in their ability to form spheroids with respect to their aggregation potential, with B16F10 forming large clusters compared to Clone M3. A panel of molecular markers comprising cell adhesion molecules, cyclin dependent kinase inhibitors and members of the cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D cultures. There was a distinct difference in the patterns of expression of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells grown as monolayers in both cell lines. Also, there was an increase in cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10 cell line. The expression of alpha and gamma catenin was down regulated in spheroids. As these molecules are implicated in the regulation of cell proliferation, alterations in the expression of these molecules in 3-D cultures compared to their 2-D counterparts suggests the importance of spheroids as experimental model for tumorigenesis.
 ...
PMID:Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. 1219 73

CD44 is a receptor for the matrix glycosaminoglycan hyaluronan. Proteoglycan forms of CD44 also exhibit affinity for fibronectin and collagen as well as chemokines and growth factors. CD44 plays a role in autoimmunity, inflammation, and tumor progression. Soluble CD44 (sCD44) is found in plasma, and the levels of sCD44 correlate with immune function and some malignancies. The mechanisms by which sCD44 is generated and its function are unknown. We demonstrate here that normal bronchial epithelial cells spontaneously release sCD44. Exposure to phagocyte- and bacterium-derived proteinases markedly increased the release of sCD44 from epithelial cells. The spontaneously released sCD44 was incorporated into high molecular mass complexes derived from the matrix that also contained chondroitin sulfate, fibronectin, hyaluronan, and collagens I and IV. Enzymatic digestion with proteinases liberated sCD44 from the high molecular mass complex. Consistent with the homology of CD44 to proteoglycan core and link proteins, these data suggest that CD44 spontaneously released from normal bronchial epithelial cells can accumulate as an integral component of the matrix, where it may play a role in the organization of matrices and in anchoring growth factors and chemokines to the matrix. Increases in plasma CD44 during immune activation and tumor progression therefore may be a manifestation of the matrix remodeling that occurs in the face of the enhanced proteolytic activity associated with infection, inflammation, and tumor metastasis, leading to alterations in cell-matrix interactions.
 ...
PMID:Proteinase-mediated release of epithelial cell-associated CD44. Extracellular CD44 complexes with components of cellular matrices. 1222 94

The erbB2 receptor tyrosine kinase and the CD44 transmembrane glycoprotein interact with one another in numerous cell types. This interaction helps to maintain erbB2 activity that contributes to tumor progression. We investigated whether CD44 and erbB2 similarly interact in endometrial carcinomas in vitro and in situ. In contrast to other carcinomas, CD44 did not colocalize with erbB2 in any of the 51 cases of endometrial cancer analyzed. CD44 also did not coimmunoprecipitate or colocalize with erbB2 in two endometrial carcinoma cell lines. We propose that the lack of CD44-erbB2 interactions may reduce the contribution of erbB2 to endometrial carcinoma progression.
 ...
PMID:Endometrial carcinoma cells are nonpermissive for CD44-erbB2 interactions. 1237 51


<< Previous 1 2 3 4 5 6 7 8 9 10