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)

Tumor angiogenesis is associated with tumor progression and aggressiveness in a number of malignancies, and vascular endothelial growth factor (VEGF) is considered as a leading candidate in this process. The aim of the present study was to investigate the role of VEGF immunohistochemical expression and tumor angiogenesis in predicting local recurrence in surgically treated lip SCC. We performed a retrospective analysis of 50 patients with lip SCC in order to investigate whether VEGF immunohistochemical expression and tumor angiogenesis correlate with clinicopathologic parameters and outcome. Tumor angiogenesis was estimated by determining microvessel density (MVD) with the use of CD34 antibody. Our results showed that VEGF was strongly correlated with tumor invasion towards the surgical margin. There was also a significant association of high VEGF expression with a higher incidence of local recurrence (p < 0.001). We suggest that VEGF expression may be used as an index to distinguish patients with higher risk of relapse.
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PMID:Immunohistochemical expression of vascular endothelial growth factor correlates with positive surgical margins and recurrence in T1 and T2 squamous cell carcinoma (SCC) of the lower lip. 1538 Jan 73

Cyclooxygenase-2 (COX-2) is well established to play an important role in the tumorigenesis of a variety of human cancers; however, the function of COX-2 in the development of esophageal squamous cell carcinoma (ESCC) remains less clear. Here, we determined, first, the pattern of COX-2 expression in normal esophageal mucosa, dysplasia, carcinoma in situ (CIS) and invasive SCC. Immunohistochemical analysis showed that, while COX-2 was weakly expressed, if at all, in normal squamous epithelium, strong COX-2 expression was detected as early as the stage of dysplasia and frequently in 20 of 26 (77%) CIS and 86 of 111 (77%) invasive SCC. Upregulation of COX-2 in ESCC was found to be significantly associated with tumor progression (R = 0.493, P < 0.01). Further, treatment of human ESCC cell lines (KYSE450 and KYSE510) with NS-398, a COX-2 specific chemical inhibitor, suppressed the production of prostaglandin E2 (PGE2) and induced cell growth inhibition, cell cycle arrest at the G1-S checkpoint, and the expression of cyclin-dependent kinase inhibitors p21waf1/cip1 and p27kip1. Finally, knockdown expression of COX-2 in KYSE450 cells by a specific COX-2 siRNA dramatically inhibited PGE2 production, cell growth and, more importantly, colony formation and tumorigenesis in nude mice. Together, this study suggested that COX-2 may be involved in an early stage of squamous cell carcinogenesis of the esophagus and has a non-redundant role in the regulation of cellular proliferation and tumorigenesis of esophageal epithelial cells.
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PMID:Significance of COX-2 expression in human esophageal squamous cell carcinoma. 1635 17

Tumors of the oral cavity are highly vascularized malignancies. Disruption of neovascular networks was shown to limit the access of nutrients and oxygen to tumor cells and inhibit tumor progression. Here, we evaluated the effect of the activation of an artificial death switch (iCaspase-9) expressed in neovascular endothelial cells on the progression of oral tumors. We used biodegradable scaffolds to co-implant human dermal microvascular endothelial cells stably expressing iCaspase-9 (HDMEC-iCasp9) with oral cancer cells expressing luciferase (OSCC3-luc or UM-SCC-17B-luc) in immunodeficient mice. Alternatively, untransduced HDMEC were co-implanted with oral cancer cells, and a transcriptionaly targeted adenovirus (Ad-VEGFR2-iCasp-9) was injected locally to deliver iCaspase-9 to neovascular endothelial cells. In vivo bioluminescence demonstrated that tumor progression was inhibited, and immunohistochemistry showed that microvessel density was decreased, when iCaspase-9 was activated in tumor-associated microvessels. We conclude that activation of iCaspase-9 in neovascular endothelial cells is sufficient to inhibit the progression of xenografted oral tumors.
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PMID:Activation of iCaspase-9 in neovessels inhibits oral tumor progression. 1663 57

Telomerase activation and telomere maintenance are essential for cell immortalization and represent a rate-limiting step in cancer progression. The E6 oncoprotein of high-risk human papillomavirus (HPV) is known to activate telomerase, but its expression in CIN lesions and its prognostic value in cervical cancer (CC) are still incompletely understood. As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for hTERT (telomerase reverse transcriptase), and tested for HPV using PCR with three primer sets (MY09/11, GP5(+)/GP6(+), SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV after cone treatment. Expression of hTERT was increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 18.81; 95% CI 8.48-41.69; P = 0.0001). Positive hTERT expression was 90% specific indicator of CIN, with 98.7% PPV, but suffers from low sensitivity (57.5%) and NPV (14.3%). hTERT expression was also significantly associated to HR-HPV with OR 3.38 (95% CI 1.90-6.02; P = 0.0001), but this association was confounded by the histological grade (Mantel-Haenszel common OR = 1.83; 95% CI 0.92-3.79; P = 0.086). Expression of hTERT did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in cervical cancer in univariate or multivariate survival analysis. It was concluded that up-regulation of hTERT was closely associated with HR-HPV, due to activation by the E6 oncoprotein. hTERT is a late marker of cervical carcinogenesis, significantly associated with progression to CIN3. Theoretically, a combination of hTERT assay (showing high SP and PPV) with another test showing high SE and high NPV (e.g. Hybrid Capture 2 for HPV), should provide an ideal screening tool capable of high-performance detection of CIN lesions.
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PMID:Upregulation of telomerase (hTERT) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus, virus persistence, or disease outcome in cervical cancer. 1704 57

Head and neck squamous cell cancers (HNSCC) are particularly aggressive and are resistant to many forms of treatment. Ceramide metabolism has been shown to play an important role in cancer progression and cancer resistance to therapy in many tumor models, including HNSCC. Here, we study the role of the ceramide-metabolizing enzyme acid ceramidase (AC) in therapeutic responses in HNSCC. First, we show that AC is over-expressed in 70% of head and neck squamous cell tumors compared with normal tissues, suggesting that this enzyme may play an important role in facilitating HNSCC growth. Next, comparison of three HNSCC cell lines with low, medium, and high levels of AC reveals an inverse correlation between the levels of AC and their response to exogenous C-6-ceramide. Furthermore, over-expression of AC in SCC-1 cells increased resistance to Fas-induced cell killing. Conversely, down-regulation of AC using specific AC small interfering RNA (siRNA) sensitized the SCC-1 cancer cell line to Fas-induced apoptosis. Finally, we show that the AC inhibitor LCL 204 can sensitize HNSCC cell lines to Fas-induced apoptosis both in vitro and in a xenograft model in vivo, suggesting that the combination of FasL gene therapy and LCL 204 may become a new treatment option for advanced-stage head and neck cancer.
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PMID:Role of acid ceramidase in resistance to FasL: therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy. 1742 10

Focal adhesion kinase (FAK) is considered intimately involved in cancer progression. Our previous research has demonstrated that overexpression of FAK is an early and frequent event in squamous cell carcinomas of the supraglottic larynx, and it is associated with the presence of metastases in cervical lymph nodes. The purpose of this study was to examine the functional role of FAK in the progression of head and neck squamous cell carcinomas (HNSCC). To this end, expression of FAK-related nonkinase (FRNK) or small interfering RNA (siRNA) against FAK was used to disrupt the FAK-induced signal transduction pathways in the HNSCC-derived SCC40 and SCC38 cell lines. Similar phenotypic effects were observed with the two methodological approaches in both cell lines. Decreased cell attachment, motility and invasion were induced by FRNK and FAK siRNA, whereas cell proliferation was not impaired. In addition, increased cell invasion was observed upon FAK overexpression in SCC cells. FRNK expression resulted in a downregulation of MMP-2 and MMP-9 expression. Interestingly, MMP-2 overexpression in FRNK-expressing cells rescued FRNK inhibition of cell invasion. This is the first demonstration of a direct rescue of impaired cell invasion by the re-expression of MMP-2 in a tumour cell type with decreased expression of functional FAK. Collectively, these data reported here support the conclusion that FAK enhances invasion of HNSCC by promoting both increased cell motility and MMP-2 production, thus providing new insights into possible therapeutic intervention strategies.
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PMID:Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression. 1834 46

Antiangiogenic therapies have shown varying results partly because each tumor type secretes a distinct panel of angiogenic factors to sustain its own microvascular network. In addition, recent evidence demonstrated that tumors develop resistance to antiangiogenic therapy by turning on alternate angiogenic pathways when one pathway is therapeutically inhibited. Here, we test the hypothesis that expression of a caspase-based artificial death switch in tumor-associated endothelial cells will disrupt tumor blood vessels and slow down tumor progression irrespective of tumor type. Adenoviral vectors expressing inducible Caspase-9 (iCaspase-9) under transcriptional regulation with the endothelial cell-specific vascular endothelial growth factor receptor-2 (VEGFR2) promoter (Ad-hVEGFR2-iCaspase-9) induced apoptosis of proliferating human dermal microvascular endothelial cells (HDMECs), but not human tumor cells (UM-SCC-17B, head and neck squamous cell carcinoma; HepG2, hepatocellular carcinoma; PC-3, prostate adenocarcinoma; SLK, Kaposi's sarcoma; MCF-7, breast adenocarcinoma). Notably, apoptosis was dependent upon activation of iCaspase-9 with the dimerizer drug AP20187. Local delivery of Ad-hVEGFR2-iCaspase-9 followed by intraperitoneal injection of AP20187 ablated tumor microvessels and inhibited xenografted tumor growth in all tumor models evaluated here. We conclude that a cancer gene therapy strategy based on a transcriptionally targeted viral vector expressing an inducible caspase allows for selective and controlled ablation of microvessels of histopathologically diverse tumor types.
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PMID:Cancer gene therapy with iCaspase-9 transcriptionally targeted to tumor endothelial cells. 1856 14

Mast cells (MCs) display a diversity of roles that may contribute to the stromal microenvironment alterations during tumor progression. The aim of this study was to investigate MC populations expressing tryptase and c-kit in lip squamous cell carcinoma (lip SCC) (n=37), actinic cheilitis (AC) (n=15) and normal lip mucosa (control) (n=6), as well as their relationship with microscopic parameters (collagen degeneration, elastin changes, angiogenesis and proliferative index). Tryptase, c-kit, CD31 and Ki-67 expressions were analyzed by means of immunohistochemistry and collagen and elastic fibers were visualized with Picrosirus and Verhoeff's stain, respectively. The numbers of tryptase+ MC were significantly higher in lip SCC when compared with control (P=0.01), while a similar density of these cells was observed in AC and lip SCC (P=0.09). The density of c-kit+ MC was similar in all groups examined (P=0.65). MC migration (c-kit+/Tryptase+ relationship) was 69% in lip SCC, 60% in AC and 100% in control. The number of CD31+ blood vessels was significantly higher in the lip SCC when compared with control and AC (P<0.01). The increase of MCs and angiogenesis in lip SCC may reflect an important modification in the tumor microenvironment during squamous photo-carcinogenesis.
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PMID:Density and migration of mast cells in lip squamous cell carcinoma and actinic cheilitis. 1922 48

Oral and oro-pharyngeal squamous cell carcinomas (OSCC) exhibit surface breach, and recent studies have demonstrated bacterial contamination of primary and metastatic OSCC. Increasing concentrations of inflammatory products, such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF), correlate with, and contribute to, cancer progression, but their regulation in OSCC is poorly understood. We hypothesized that monocyte-lineage cells and bacterial contamination may contribute important inflammatory products that can support OSCC progression. We found that relative to non-specific chronic mucositis, oral carcinoma-in-situ/superficially-invasive OSCC contained more monocyte-lineage cells. In vitro, we used lipopolysaccharide (LPS) to model bacterial contamination, and evaluated the effects of oral and oropharyngeal (O)SCC-monocyte interactions and of LPS on OSCC cells and on the production of IL-6 and VEGF. OSCC cell lines varied in constitutive cytokine and chemokine production, and OSCC-monocyte interactions in the absence of LPS stimulated IL-6 and VEGF occasionally, while LPS-OSCC-monocyte interactions were always strongly stimulatory. Importantly, LPS independently stimulated some OSCC lines to secrete monocyte-dendritic cell chemoattractants CCL2 and/or CCL20, as well as IL-6 and/or VEGF. While very little constitutive Y705-STAT3 phosphorylation (pY705-STAT3) was detectable in HNSCC lines, IL-6 rapidly induced pY705-STAT3 in OSCC lines that produced little IL-6 constitutively. Supernatants from LPS-OSCC-monocyte co-cultures always rapidly and strongly activated STAT3, which was partly due to IL-6. We conclude that monocytes and microbial contamination have the potential to contribute to OSCC progression, as STAT3 activation in OSCC cells depends on soluble factors, which are consistently available through LPS-OSCC-monocyte interactions.
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PMID:Lipopolysaccharide-squamous cell carcinoma-monocyte interactions induce cancer-supporting factors leading to rapid STAT3 activation. 1960 82

The ability of cells to modulate interactions with each other and the substrate is essential for epithelial tissue remodeling during processes such as wound healing and tumor progression. However, despite strides made in the field of proteomics, proteins involved in adhesion have been difficult to study. Here, we report a method for the enrichment and analysis of proteins associated with the basal surface of the cell and its underlying matrix. The enrichment involves deroofing the cells with 20 mM ammonium hydroxide and the removal of cytosolic and organellar proteins by stringent water wash. Proteomic profiling was achieved by LC-FTMS, which allowed comparison of differentially expressed or shared proteins under different cell states. First, we analyzed and compared the basal cell components of mouse keratinocytes lacking the cell-cell junction molecule plakoglobin with their control counterparts. Changes in the molecules involved in motility and invasion were detected in plakoglobin-deficient cells, including decreased detection of fibronectin, integrin beta(4), and FAT tumor suppressor. Second, we assessed the differences in basal cell components between two human oral squamous cell carcinoma lines originating from different sites in the oral cavity (CAL33 and UM-SCC-1). The data show differences between the two lines in the type and abundance of proteins specific to cell adhesion, migration, and angiogenesis. Therefore, the method described here has the potential to serve as a platform to assess proteomic changes in basal cell components including extracellular and adhesion-specific proteins involved in wound healing, cancer, and chronic and acquired adhesion-related disorders.
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PMID:Detection of differentially expressed basal cell proteins by mass spectrometry. 1995 77


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