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)

CD44 is an adhesion molecule involved in many biological functions and has been described to play a role in tumor progression as well as in promotion of metastasis. It has also been suggested that expression of certain CD44 isoforms could be useful for breast and ovarian cancer screening, detection or staging. However, many other reports document no correlation between CD44 isoform expression and tumor malignancy. In light of such contradictory findings, we evaluated by exon-specific RT-PCR whether the expression of CD44 isoforms in breast and ovarian tumors correlated with any of the diagnostic criteria used to assess these diseases. We found a deregulation in the CD44 expression pattern in malignant tumors of both type of cancer compared with the one in benign tumors or normal tissue. However, we could not find a clear correlation between this deregulation or a given CD44 isoform and any diagnostic criteria evaluated, such as age, clinical data, tumor size, hormone receptor status, histological grade or aggressiveness.
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PMID:Splice variant expression of CD44 in patients with breast and ovarian cancer. 1111 87

Interactions of the extracellular matrix component hyaluronic acid and its cellular receptors CD44 and RHAMM/IHABP have been linked to tumor progression and metastasis formation. We investigated the expression and hyaluronic-acid-dependent functions of CD44 and RHAMM/IHABP in human melanoma. Immunohistochemistry of tumor specimens at different stages of melanoma progression revealed an increased expression of CD44 and RHAMM/IHABP. High mRNA expression of CD44 was found in three highly tumorigenic melanoma cell lines compared with less tumorigenic melanoma cells or nontransformed melanocytes. RHAMM/IHABP expression was upregulated in all cell lines analyzed but not in melanocytes. In contrast to the cell surface localization of CD44, RHAMM/IHABP was detected exclusively within the cytoplasm of melanoma cells. Binding and adhesion of melanoma cells to hyaluronic acid is mainly CD44 dependent as it was inhibited to 60%--80% by an anti-CD44 monoclonal antibody whereas anti-RHAMM/IHABP sera had no effect. Culture of melanoma cells in the presence of hyaluronic acid resulted in a dose-dependent, CD44-mediated increase of melanoma cell proliferation and enhanced release of basic fibroblast growth factor and transforming growth factor beta 1. We conclude that (i) the expression of CD44 and RHAMM/IHABP is increased during melanoma progression, (ii) CD44 is the principal hyaluronic acid surface receptor on melanoma cells, and (iii) the hyaluronic-acid-induced increase of the proliferative capacity of melanoma cells is mainly dependent on CD44--hyaluronic acid interactions.
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PMID:CD44 is the principal mediator of hyaluronic-acid-induced melanoma cell proliferation. 1116 3

Deregulation of several signaling pathways have been found to be critical for the development of different types of tumors, both in transgenic and spontaneous models. The role of proteases and adhesion molecules during the early stages of tumor progression induced by oncogenes in epithelial and mesenchymal tumors has remained relatively unexplored. This review summarizes recent work showing that different but overlapping signaling effector modules (PKC, v-Ras-RalA-PLD1 or v-Src-RalA-PLD1) induce changes in the production of proteases (uPA and MMPs) and adhesion molecules (fibronectin, CD44, beta 1-integrin) in normal epithelial or mesenchymal cell lines, associated with tumor development in vivo. Overexpression of PKC gamma in normal mammary epithelial cells or of v-Src and v-Ras in NIH3T3 fibroblasts induced in all cases overproduction of uPA and MMPs and a tumorigenic phenotype. Proteases production and tumorigenicity in transformed NIH3T3 cells were dependent on the GTPase RalA. In contrast to the common outcome in protease production by the different tumor promoting stimuli, fibronectin production was high in PKC-overexpressing mammary epithelial cells and it was organized into a rich fibrillar matrix, while oncogene transformed fibroblasts displayed reduced fibronectin production and a total loss of FN fibrillogenesis, an effect also dependent on RalA. These results show that protease overexpression is a common denominator in the acquisition of a malignant phenotype both in mesenchymal and epithelial cells. In contrast there is a dramatic difference in the expression and function of adhesion molecules like fibronectin between these two cell types, suggesting different regulatory roles for this glycoprotein during tumor progression, in cells of different tissular origin.
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PMID:[Signaling pathways regulating the expression of proteases during tumor progression]. 1118 28

CD44 is a cell adhesion molecule with numerous isoforms created by mRNA alternative splicing. Expression of CD44 variants has been suggested to play a potential role in tumor progression and metastasis. We designed primers CD44V, CD44V6/7, CD44R1 and CD44V6-10 to analyze and compare the roles of each CD44 variants. Expressions of CD44 variants were investigated in normal colonic mucosa, the lymph nodes which was histopathologically free of cancer cell, and cancer tissues of 44 human colorectal cancer patients by RT-PCR method. The expression of CD44V was observed in 28 out of 39 (71.8%) tumors and 7 out of 11 (63.6%) N1 normal regional lymph nodes, and CD44V6/7 was observed in 28 out of 39 (71.8%) tumors and 9 out of 11 (81.8%) N1 normal regional lymph nodes. The expressions of CD44V and CD44V6/7 were most frequently observed compared with any other CD44 variants. In normal colonic mucosa, the expression of CD44 variants are low but in cancer tissue and its regional lymph node, the expression of CD44V and CD44V6/7 were significantly higher and more frequent than any other CD44 variants (p<0.05). These results suggest that CD44V and CD44V6/7 can be a molecular marker for colorectal cancer and its micrometastasis to the regional normal lymph node.
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PMID:The significance of CD44 variants expression in colorectal cancer and its regional lymph nodes. 1119 97

CD44 is a group of cell surface molecules involved in cell-cell and cell-matrix interactions. CD44 spliced variants (CD44V) have been found to enhance the metastatic potential of rat tumors. Tumors from the breast, colon, and thyroid express many alternatively spliced products; nonneoplastic tissues do not. Some authors suggest that CD44V5 and V6 may play a role in gastric carcinoma. The aim of the current study was to investigate the role of CD44V6 as a prognostic marker and predictor of metastatic potential in gastric carcinomas. One hundred fifty-five cases of gastric adenocarcinomas were studied: 36 cases of early (EGC), 19 cases of intermediate (MGC), and 100 cases of advanced gastric adenocarcinomas (AGC). A monoclonal antibody against CD44V6 (R&D) was used. CD44V6 expression was positively correlated with advanced stage (P = 0.05). Strong positivity was only detected in those cases of AGC with metastases. Patients with CD44V6 positive tumors revealed a lower 3- and 5-year survival rate (P = 0.0002). Immunohistochemical detection of CD44V6 could now be used as an indicator of tumor progression in biopsies of patients with gastric carcinoma.
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PMID:CD44V6 in gastric carcinoma: a marker of tumor progression. 1139 31

In epithelial cells, hepatocyte growth factor (HGF) activates a genetic program involving cell-cell dissociation ("scattering"), growth and invasiveness. The full program is not elicited by other growth factors like epidermal growth factor, and is aberrantly activated during cancer progression to the invasive-metastatic phenotype. To identify genes involved in the onset of invasive growth, we explored by cDNA microarrays the in vitro transcriptional response to HGF of mouse embryo liver cells. We identified osteopontin (OPN), a secreted matrix protein, as a major HGF transcriptional target. The wave of OPN induction is maximal at 6 h, in concomitance with the initiation of scattering, and is specific, because no other matrix protein among those explored by the microarray is affected. Interestingly, HGF, but not epidermal growth factor, promotes cell adhesion to OPN via the CD44 receptor. Scattering is significantly impaired by antibodies against OPN and CD44; conversely, constitutive OPN overexpression dramatically increases the motile and invasive responses to HGF, leading to disruption of the ordered morphogenetic program triggered by this ligand.
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PMID:Osteopontin is an autocrine mediator of hepatocyte growth factor-induced invasive growth. 1147 27

CD44, a hyaluronan (HA) receptor, belongs to a family of transmembrane glycoproteins which exists as several isoforms. Cell surface expression of certain CD44 isoforms is closely correlated with the progression and prognosis of breast cancers. A number of angiogenic factors (e.g., VEGF and FGF-2) and matrix degrading enzymes (MMPs) are tightly complexed with CD44 isoforms, suggesting that they are involved in the onset of oncogenic signals required for breast tumor cell invasion and migration. Most importantly, interaction of extracellular matrix components (e.g., HA) with cells triggers the cytoplasmic domain of CD44 isoforms to bind its unique downstream effectors (e.g., the cytoskeletal protein ankyrin or various oncogenic signaling molecules-Tiam1, RhoA-activated ROK, c-Src kinase and p185HER2) and to coordinate intracellular signaling pathways (e.g., Rho/Ras signaling and receptor-linked/non-receptor-linked tyrosine kinase pathways), leading to a concomitant onset of multiple cellular functions (e.g., tumor cell growth, migration and invasion) and breast tumor progression.
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PMID:CD44-mediated oncogenic signaling and cytoskeleton activation during mammary tumor progression. 1154 98

Interleukin-10 (IL-10) is a multifunctional cytokine that can exert suppressive and stimulatory effects on T cells. It was investigated whether IL-10 could serve as an immunostimulant for specific CD8(+) cytotoxic T cell (CTL) in vivo after vaccination and, if so, under what conditions. In tumor prevention models, administration of IL-10 before, or soon after, peptide-pulsed primary dendritic cell immunization resulted in immune suppression and enhanced tumor progression. Injection of IL-10, however, just after a booster vaccine significantly enhanced antitumor immunity and vaccine efficacy. Analysis of spleen cells derived from these latter animals 3 weeks after IL-10 treatment revealed that the number of CD8(+) CD44(hi) CD122(+) T cells had increased and that antigen-specific proliferation in vitro was enhanced. Although cytotoxicity assays did not support differences between the various treatment groups, 2 more sensitive assays measuring antigen-specific interferon-gamma production at the single-cell level demonstrated increases in the number of antigen-specific responder T cells in animals in the vaccine/IL-10 treatment group. Thus, IL-10 may maintain the number of antitumor CD8(+) T cells. In adoptive transfer studies, the ability of IL-10 to maintain CTL function could be enhanced by the depletion of CD4(+) T cells. This suggests that IL-10 mediates contrasting effects on both CD4(+) and CD8(+) T cells that result in either immune dampening or immune potentiation in situ, respectively. Appreciation of this dichotomy in IL-10 immunobiology may allow for the design of more effective cancer vaccines designed to activate and maintain specific CD8(+) T-cell effector function in situ.
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PMID:Interleukin-10 promotes the maintenance of antitumor CD8(+) T-cell effector function in situ. 1156 1

CD44 is a cell-surface molecule that has been shown to have several splicing isoforms. In various human tumors, such as primary colon and breast tumors, and their metastases, alterations of CD44 isoform expression have been reported. The present study was performed to investigate CD44 alternative transcript splicing in gynecologic malignancies. We performed reverse transcriptase polymerase chain reaction (RT-PCR) analysis of CD44 splice variant expression on mRNA transcripts from ovarian carcinomas (six primary and 15 metastatic tumors) from 21 patients and from cervical carcinomas (25 primary and two metastatic tumors) from 25 patients. We also performed this analysis on five different ovarian carcinoma cell lines established from ascitic fluid and primary tumors, and two cervical carcinoma cell lines. We included eight normal female genital tissue specimens and one additional placenta specimen in our RT-PCR analysis for comparison with CD44 expression of carcinomas. The CD44H isoform was amplified in all of the specimens. None of eight normal tissue specimens, including myometrium and ovary, expressed CD44R1 transcripts. But the CD44R1 transcript was expressed in 2/6 (33.3%) primary ovarian carcinomas and in 7/15 (46.6%) metastatic ovarian carcinomas. In cervical carcinoma, 13/25 (52.0%) primary tumors and 2/2 (100.0%) metastatic tumors expressed CD44R1. The CD44R1 transcript was expressed increasingly during ovarian and cervical tumor progression (P = 0.026 and P = 0.002, respectively). In conclusion, the frequency of CD44R1 transcript expression increased during ovarian and cervical carcinoma progression, and analysis of CD44 splice variants may be useful in detecting primary and metastatic gynecologic malignancies.
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PMID:Expression of the CD44 adhesion molecule in primary and metastatic gynecologic malignancies and their cell lines. 1157 76

In this study we initially examined the interaction between CD44v3 (a hyaluronan (HA) receptor) and Vav2 (a guanine nucleotide exchange factor) in human ovarian tumor cells (SK-OV-3.ipl cell line). Immunological data indicate that both CD44v3 and Vav2 are expressed in SK-OV-3.ipl cells and that these two proteins are physically linked as a complex in vivo. By using recombinant fragments of Vav2 and in vitro binding assays, we have detected a specific binding interaction between the SH3-SH2-SH3 domain of Vav2 and the cytoplasmic domain of CD44. In addition, we have observed that the binding of HA to CD44v3 activates Vav2-mediated Rac1 signaling leading to ovarian tumor cell migration. Further analyses indicate that the adaptor molecule, growth factor receptor-bound protein 2 (Grb2) that is bound to p185(HER2) (an oncogene product), is also associated with the CD44v3-Vav2 complex. HA binding to SK-OV-3.ipl cells promotes recruitment of both Grb2 and p185(HER2) to the CD44v3-Vav2 complex leading to Ras activation and ovarian tumor cell growth. In order to determine the role of Grb2 in CD44v3 signaling, we have transfected SK-OV-3.ipl cells with Grb2 mutant cDNAs (e.g. Delta N-Grb2 that has a deletion in the amino-terminal SH3 domain or Delta C-Grb2 that has a deletion in the carboxyl-terminal SH3 domain). Our results clearly indicate that the SH3 domain deletion mutants of Grb2 (i.e. the Delta N-Grb2 (and to a lesser extent the Delta C-Grb2) mutant) not only block their association with p185(HER2) but also significantly impair their binding to the CD44v3-Vav2 complex and inhibit HA/CD44v3-induced ovarian tumor cell behaviors. Taken together, these findings strongly suggest that the interaction of CD44v3-Vav2 with Grb2-p185(HER2) plays an important role in the co-activation of both Rac1 and Ras signaling that is required for HA-mediated human ovarian tumor progression.
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PMID:Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth. 1160 75


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