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)

Attachment of tumor cells to the endothelium (EC) under flow conditions is critical for the migration of tumor cells out of the vascular system to establish metastases. Innate immune system processes can potentially promote tumor progression through inflammation dependant mechanisms. White blood cells, neutrophils (PMN) in particular, are being studied to better understand how the host immune system affects cancer cell adhesion and subsequent migration and metastasis. Melanoma cell interaction with the EC is distinct from PMN-EC adhesion in the circulation. We found PMN increased melanoma cell extravasation, which involved initial PMN tethering on the EC, subsequent PMN capture of melanoma cells and maintaining close proximity to the EC. LFA-1 (CD11a/CD18 integrin) influenced the capture phase of PMN binding to both melanoma cells and the endothelium, while Mac-1 (CD11b/CD18 integrin) affected prolonged PMN-melanoma aggregation. Blocking E-selectin or ICAM-1 (intercellular adhesion molecule) on the endothelium or ICAM-1 on the melanoma surface reduced PMN-facilitated melanoma extravasation. Results indicated a novel finding that PMN-facilitated melanoma cell arrest on the EC could be modulated by endogenously produced interleukin-8 (IL-8). Functional blocking of the IL-8 receptors (CXCR1 and CXCR2) on PMN, or neutralizing soluble IL-8 in cell suspensions, significantly decreased the level of Mac-1 up-regulation on PMN while communicating with melanoma cells and reduced melanoma extravasation. These results provide new evidence for the complex role of hemodynamic forces, secreted chemokines, and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the endothelium in the microcirculation, which are significant in fostering new approaches to cancer treatment through anti-inflammatory therapeutics.
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PMID:Melanoma cell extravasation under flow conditions is modulated by leukocytes and endogenously produced interleukin 8. 1670 76

E- cadherin is a member of the cadherin superfamily known as the main mediator of the cell- cell calcium dependent adhesion interactions. Research evidence also yields to this adhesion molecule an important role in carcinogenesis and tumor progression. This review focuses on the differential expression of E- cadherin in the various anatomic sites of the human body where HNSCC arises. Controversies in the results of various studies are discussed and possible prospects for application of all this developing knowledge to prognosis and therapy of the disease are briefly mentioned.
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PMID:Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC). 1676 12

Interactions between the neural cell adhesion molecules NCAM and N-cadherin with the fibroblast growth factor receptor (FGFR) are important for a number of developmental events and have also been implicated in tumor progression. The factors regulating these interactions are not known. We have used co-immunoprecipitation and co-clustering paradigms to show that both adhesion molecules can interact with the 3Ig IIIC isoform of the FGFR1 in a number of cell types. Interestingly, whereas the interaction can be seen over most of the cell surface, it is not seen at points of cell-cell contact where the adhesion molecules accumulate at stable junctions. We also demonstrate for the first time that all of the major isoforms of NCAM can interact with the FGFR. Using deletion mutagenesis we have found that the adhesion molecule/FGFR interaction can withstand the removal of most of any one of the FGFR immunoglobulin-like domains (D1-D3). In contrast, the FGFR interaction with N-cadherin and NCAM (but not FGF) is absolutely dependant on the presence of the acid box motif that can be found in the linker region between D1 and D2. As this motif can be spliced out of all four FGFRs, it suggests that this is one mechanism that can regulate the interaction of the receptor with different ligand classes.
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PMID:The fibroblast growth factor receptor acid box is essential for interactions with N-cadherin and all of the major isoforms of neural cell adhesion molecule. 1700 51

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. We recently reported that induction of a chemoresistant phenotype in the PDAC cell line PT45-P1 by long-term chemotherapy involves an increased interleukin 1 beta (IL1beta)-dependent secretion of nitric oxide (NO) accounting for efficient caspase inhibition. In the present study, we elucidated the involvement of L1CAM, an adhesion molecule previously found in other malignancies, in this NO-dependent chemoresistance. Chemoresistant PT45-P1res cells, but not chemosensitive parental PT45-P1 cells, express high levels of L1CAM in an ILbeta-dependent fashion. PT45-P1res cells subjected to short interfering RNA (siRNA)-mediated L1CAM knock-down exhibited reduced inducible nitric oxide synthase expression and NO secretion, as well as a significant increase of anti-cancer drug-induced caspase activation, an effect reversed by the NO donor S-nitroso-N-acetyl-D,L-penicillamine. Conversely, overexpression of L1CAM in PT45-P1 cells conferred anti-apoptotic protection to anti-cancer drug treatment. Interestingly, L1CAM ectodomain shedding, in example, by ADAM10, as reported for other L1CAM-related activities, seemed to be dispensable for anti-apoptotic protection by L1CAM. Neither the shedded L1CAM ectodomain was detected in chemoresistant L1CAM-expressing PT45-P1 cells nor did the administration of various metalloproteinase inhibitors affect L1CAM-dependent chemoresistance. Immunohistochemical analysis revealed L1CAM expression in 80% of pancreatic cancer specimens, supporting a potential role of L1CAM in the malignancy of this tumor. These findings substantiate our understanding of the molecular mechanisms leading to chemoresistance in PDAC cells and indicate the importance of L1CAM in this scenario.
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PMID:Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells. 1708 12

ADAM-17 (a disintegrin and metalloproteinase 17) is a membrane-anchored protein, which can cleave the ectodomain in a variety of transmembrane proteins. In the in vitro experiments with tumor cells, ADAM-17 is reported to cleave CD44, an adhesion molecule that interacts with hyaluronic acid, to promote tumor cell migration. In the present study, we examined ADAM-17 expression and CD44 cleavage in specimens from 50 patients diagnosed to have oral squamous cell carcinoma (SCC). Each specimen was divided into two pieces, one was studied by immunohistochemistry and the other was subjected to a Western blot. By coordinating the results of both analyses, ADAM-17 expression was evaluated to be high in 23 cases (46%). When CD44 cleavage was also studied by immunohistochemical staining as well as with Western blotting, CD44 cleavage was judged to be positive in 29 cases (58%). When the ADAM-17 expression level was compared with the CD44 cleavage state, most of the cases expressing high levels of ADAM-17 (87%) showed positive CD44 cleavage. The level of ADAM-17 expression was significantly correlated to the nodal metastasis and local recurrence in oral SCC. Our findings suggest that ADAM-17 is involved in CD44 cleavage and contributes to tumor progression in oral SCC.
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PMID:ADAM-17 associated with CD44 cleavage and metastasis in oral squamous cell carcinoma. 1718 Jun 79

Inflammation can play a regulatory role in cancer progression and metastasis. Previously, we have shown that metastatic tumor cells entering the liver trigger a proinflammatory response involving Kupffer cell-mediated release of tumor necrosis factor-alpha and the up-regulation of vascular endothelial cell adhesion receptors, such as E-selectin. Here, we analyzed spatio-temporal aspects of the ensuing tumor-endothelial cell interaction using human colorectal carcinoma CX-1 and murine carcinoma H-59 cells and a combination of immunohistochemistry, confocal microscopy, and three-dimensional reconstruction. E-selectin expression was evident mainly on sinusoidal vessels by 6 and 10 hours, respectively, following H-59 and CX-1 inoculation, and this corresponded to a stabilization of the number of tumor cells within the sinuses. Tumor cells arrested in E-selectin(+) vessels and appeared to flatten and traverse the vessel lining, away from sites of intense E-selectin staining. This process was evident by 8 (H-59) and 12 (CX-1) hours after inoculation, coincided with increased endothelial vascular cell adhesion molecule-1 expression, and involved tumor cell attachment in areas of intense vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 expression. Nonmetastatic (human) MIP-101 and (murine) M-27 cells induced a weaker response and could not be seen to extravasate. The results show that metastatic tumor cells can alter the hepatic microvasculature and use newly expressed endothelial cell receptors to arrest and extravasate.
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PMID:The host inflammatory response promotes liver metastasis by increasing tumor cell arrest and extravasation. 1745 81

Cell adhesion is a basic count in inter- and intra-cellular communication and plays an important role in tumor progression. This study was conducted to investigate the serum levels of intercellular adhesion molecule (ICAM-1) and E-selectin in patients with advanced stage non-small cell lung cancer (NSCLC) and the relationships with known prognostic parameters and therapy. These serum factors were measured of 57 NSCLC patients pathologically verified before and after chemotherapy in comparison with 24 healthy controls by using ELISA method. Serum levels of ICAM-1 were increased significantly in NSCLC patients compared with the healthy controls (P = 0.006). However, serum E-selectin levels were not significantly different from healthy control groups (0.643). No statistically significant relationships were found between investigated all serum parameters and various characteristics of patients, and the diseases such as stage and tumor burden. Likewise, we also found no correlation between serum ICAM-1 and E-selectin (P = 0.78). We found that serum ICAM-1 levels were decreased owing to the chemotherapy effect, independently from chemotherapy response. However, serum E-selectin levels were not changed by the chemotherapy effect. The median survival of all patients was 11.9 months and 1-year survival rate was 47.6%. We found that patients performance status (P = 0.013), age (P = 0.015), and weight loss (P = 0.007) were prognostic factors for survival. Serum E-selectin levels showed a trend (P = 0.08) related to worse prognosis, however serum ICAM-1 levels were determined as ineffective on survival (P = 0.11). Multivariate analysis revealed that only weight loss (P = 0.005) and E-selectin levels (P = 0.002) remained as an independent prognostic factor for survival in patients with advanced NSCLC. In conclusion, our data suggest that higher serum ICAM-1 can be useful for diagnosis while E-selectin levels have prognostic significance and could be a potential prognostic factor in NSCLC patients.
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PMID:Serum levels of intercellular adhesion molecule ICAM-1 and E-selectin in advanced stage non-small cell lung cancer. 1800 89

Emerging evidence indicates that chronic inflammation plays an important role in prostate carcinogenesis. Yet to date the precise molecular and cellular mechanisms linking inflammation to carcinogenesis remains unclear. The purpose of this study was to determine the local contribution of prostate epithelial cells to the inflammatory process. We characterized the inflammatory response elicited directly by prostate epithelial cells using an in vitro culture system in which androgen-dependent LNCaP prostate cancer epithelial cells were exposed to conditioned media from LPS-activated THP-1 macrophages. Upon exposure to activated macrophage conditioned media, LNCaP cells elicited a local proinflammatory response, as evidenced by NFkappaB activation, and the production of proinflammatory cytokines TNFalpha, IL-1beta, and IL-6. Furthermore, we observed a significant upregulation of the adhesion molecule VCAM-1 and nuclear estrogen receptor alpha (ERalpha) two biomarkers that correlate with tumor immune evasion and tumor progression. Our results suggest that prostate epithelial cells may play a significant role in sustaining and amplifying the inflammation process through NFkappaB activation and local production of proinflammatory cytokines that results in the recruitment and activation of additional immune cells in the prostate. At the same time, increased expression of VCAM-1 and ERalpha in prostate epithelial cells upon exposure to inflammatory conditions highlights the potential link between chronic inflammation and its involvement in promoting prostate cancer carcinogenesis.
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PMID:Induction of proinflammatory response in prostate cancer epithelial cells by activated macrophages. 1904 Nov 75

The mammary epithelium is thought to be stabilized by cell-cell adhesion mediated mainly by E-cadherin (E-cad). Here, we show that another cadherin, retinal cadherin (R-cad), is critical for maintenance of the epithelial phenotype. R-cad is expressed in nontransformed mammary epithelium but absent from tumorigenic cell lines. In vivo, R-cad was prominently expressed in the epithelium of both ducts and lobules. In human breast cancer, R-cad was down-regulated with tumor progression, with high expression in ductal carcinoma in situ and reduced expression in invasive duct carcinomas. By comparison, E-cad expression persisted in invasive breast tumors and cell lines where R-cad was lost. Consistent with these findings, R-cad knockdown in normal mammary epithelium stimulated invasiveness and disrupted formation of acini despite continued E-cad expression. Conversely, R-cad overexpression in aggressive cell lines induced glandular morphogenesis and inhibited invasiveness, tumor formation, and lung colonization. R-cad also suppressed the matrix metalloproteinase 1 (MMP1), MMP2, and cyclooxygenase 2 gene expression associated with pulmonary metastasis. The data suggest that R-cad is an adhesion molecule of the mammary epithelium, which acts as a critical regulator of the normal phenotype. As a result, R-cad loss contributes to epithelial suppression and metastatic progression.
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PMID:Loss of retinal cadherin facilitates mammary tumor progression and metastasis. 1949 Dec 71

Vascular inflammation is a pivotal factor of a variety of diseases, such as atherosclerosis and tumor progression. The present study was designed to examine the anti-inflammatory effect of ethanol extract of Gastrodia elata rhizome (EGE) in primary cultured human umbilical vein endothelial cells (HUVEC). Pretreatment of cells with EGE attenuated TNF-alpha-induced increase in expression levels of cell adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Real time qRT-PCR also showed that EGE decreased the mRNA expression levels of ICAM-1, VCAM-1, E-selectin as well as macrophage chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8). In addition, EGE significantly inhibited TNF-alpha-induced increase in monocyte adhesion of HUVEC in a dose-dependent manner. Furthermore, EGE significantly inhibited TNF-alpha-induced intracellular reactive oxygen species (ROS) production and p65 NF-kappaB activation by preventing IkappaB-alpha phosphorylation. In conclusion, the present data suggest that EGE could suppress TNF-alpha-induced vascular inflammatory process via inhibition of oxidative stress and NF-kappaB activation in HUVEC.
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PMID:Anti-inflammatory effect of Gastrodia elata rhizome in human umbilical vein endothelial cells. 1950 81


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