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)

MUC1/sec is a secreted form of the glycoprotein mucin 1 (MUC1). To characterize the role that MUC1 and MUC1/sec have in tumor progression, these genes were expressed in DA-3 mammary tumor cells. DA-3 cells and DA-3 cells expressing the transmembrane MUC1 gene (DA-3/TM) grow with similar kinetics in BALB/c mice. Surprisingly, DA-3 cells expressing and secreting MUC1/sec (DA-3/sec) fail to form tumors in vivo. The mechanism of rejection was evaluated using mice deficient in constituents of the immune system. All mice lacking IFN-gamma, NK, NKT, or macrophages formed DA-3/sec tumors that regressed shortly after implantation. However, progressively growing DA-3/sec tumors developed in mice devoid of T lymphocytes. The importance of T lymphocytes in the rejection of DA-3/sec tumors was further supported by detection of DA-3-specific CTL in mice challenged with the DA-3/sec tumor. Recruitment of appropriate APC and effector cells is an important first step in the tumor clearance. Indeed, DA-3/sec cells or cell supernatants recruited 3-4 times as many macrophages as DA-3/TM cells in vivo, suggesting that a secreted chemotactic product is produced from DA-3/sec cells. RNA and protein analysis of DA-3/sec cells revealed that several genes are up-regulated by MUC1/sec expression, including MCP-1 (CCL-2). These results suggest DA-3/sec cells are capable of recruiting immune cells, and that rejection of DA-3/sec tumors, although aided by cells of the innate immune response, is ultimately due to T cell-mediated events.
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PMID:MUC1/sec-expressing tumors are rejected in vivo by a T cell-dependent mechanism and secrete high levels of CCL2. 1526 1

Pleomorphic malignant fibrous histiocytoma (MFH) is occasionally associated with inflammatory paraneoplastic syndrome (PNS). Recently, we reported that interleukin (IL)-6, one of the candidate cytokines, which induces such systemic inflammatory reaction, may be a tumor-associated factor involved in the pathogenesis and its clinical manifestations of MFH. In the local microenvironment, tumor-induced inflammatory reaction may play a role favoring tumor progression. To clarify the biological relevance of IL-6 in MFH, we established a human MFH cell line, named MIPS-2, derived from a resected specimen of a patient presenting with PNS. In this patient, the serum IL-6 level ran parallel to the disease course: elevated serum IL-6 concentration normalized immediately after radical surgery, and re-elevation occurred on tumor recurrence. MIPS-2 presented pleomorphic appearance, severe nuclear abnormalities with prominent nucleoli, and tumorigenesis in nude mice. MIPS-2 expressed IL-6, IL-6 receptor (IL-6R), and glycoprotein 130 (gp130) but lacked the soluble form of IL-6R (sIL-6R), as determined by flow cytometry and reverse transcriptase-polymerase chain reaction analyses. Stimulation of MIPS-2 with IL-6 combined with exogenous sIL-6R induced phosphorylation of both signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK), decreased cell proliferation, attenuated invasion, and induced morphological changes. Collectively, these data suggested that the IL-6/sIL-6R signaling pathway plays a pivotal role for proliferation, invasion, and morphology of MFH via STAT3 and MAPK pathway as autocrine and/or paracrine manner, and proposed the therapeutic potential for the use of both anti-growth factor and proinflammatory cytokine-targeting strategies to combat devastating MFH.
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PMID:Interleukin-6/soluble interleukin-6 receptor signaling attenuates proliferation and invasion, and induces morphological changes of a newly established pleomorphic malignant fibrous histiocytoma cell line. 1527 21

Prostate tumor cells preferentially adhere to bone marrow endothelial cells (BMECs) compared with endothelial linings from other tissue microvessels, implicating the importance of BMEC adhesion in the predilection of prostate tumor metastasis to bone. E (endothelial)-selectin, which functions as an initiator of leukocyte adhesion to target tissue endothelium, is constitutively expressed on BMECs, suggesting that prostate tumor cells could use this adhesive mechanism to initiate their migration into bone. In this report, we demonstrate for the first time that human bone-metastatic prostate tumor cells roll on human BMECs under physiological flow conditions. We show that these dynamic adhesive interactions are dependent on the expression of BMEC E-selectin and sialylated glycoconjugates on bone-metastatic prostate tumor cells. We also establish the importance of both glycoprotein(s) and glycosphingolipid structures displaying sialyl Lewis X epitopes as potential E-selectin ligands on bone-metastatic prostate tumor cells. Coexpression of sialylated glycoproteins and glycolipids on bone-metastatic prostate tumor cells triggers robust E-selectin binding activity, which is identical to that observed on human hematopoietic progenitor cells. By Western blot analysis, we identify candidate E-selectin glycoprotein ligand(s); distinct sialyl Lewis X (or HECA-452 antigen)-bearing membrane proteins were resolved at M(r) 130,000 and M(r) 220,000 as well as others ranging from M(r) 100,000 to M(r) 220,000. Immunohistochemical analysis of HECA-452 antigen expression on normal prostate tissue and on low- and high-grade prostate adenocarcinoma shows that HECA-452 antigen expression is directly associated with prostate tumor progression and may indicate acquisition of E-selectin ligand expression. These findings provide novel insight into potential adhesive mechanisms promoting hematogenous dissemination of prostate tumor cells into bone.
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PMID:Rolling of human bone-metastatic prostate tumor cells on human bone marrow endothelium under shear flow is mediated by E-selectin. 1528 32

Transforming growth factor (TGF)-beta1 is associated with tumor progression and resistance to chemotherapy in established cancers, as well as host immune suppression. Here, we show that the serum glycoprotein alpha2-HS-glycoprotein (AHSG) blocks TGF-beta1 binding to cell surface receptors, suppresses TGF-beta signal transduction, and inhibits TGF-beta-induced epithelial-mesenchymal transition, suggesting that AHSG may play a role in tumor progression. In 66 consecutive sporadic human colorectal cancer specimens, we observed a 3-fold depletion of ASHG in tumor compared with normal tissue, whereas levels of other abundant plasma proteins, albumin and transferrin, were equivalent. Using the Multiple intestinal neoplasia/+ (Min/+) mouse model of intestinal tumorigenesis, we found twice as many intestinal polyps overall, twice as many large polyps (>3 mm diameter), and more progression to invasive adenocarcinoma in Min/+ Ahsg-/- mice than in littermates expressing Ahsg. Phosphorylated Smad2 was more abundant in the intestinal mucosa and tumors of Min/+ mice lacking Ahsg, demonstrating increased TGF-beta signaling in vivo. Furthermore, TGF-beta-mediated suppression of immune cell function was exaggerated in Ahsg-/- animals, as shown by inhibition of macrophage activation and reduction in 12-O-tetradecanoylphorbol 13-acetate-induced cutaneous inflammation. Reconstitution of Ahsg-/- mice with bovine Ahsg suppressed endogenous TGF-beta-dependent signaling to wild-type levels, suggesting that therapeutic enhancement of AHSG levels may benefit patients whose tumors are driven by TGF-beta.
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PMID:alpha2HS-glycoprotein, an antagonist of transforming growth factor beta in vivo, inhibits intestinal tumor progression. 1537 47

CD26/Dipeptidyl Peptidase IV (DPPIV) is a 110-kDa glycoprotein that is expressed on numerous cell types and has multiple biological functions. A key facet of CD26/DPPIV biology is its enzymatic activity and its physical and functional interaction with other molecules. The substrates of CD26/DPPIV are proline-containing peptides and include growth factors, chemokines, neuropeptides, and vasoactive peptides. DPPIV plays an important role in immune regulation, signal transduction, and apoptosis. Furthermore, CD26 appears to play an important role in tumor progression. In the present review, we summarize key aspects of CD26/DPPIV involvement in tumor biology and its potential role in cancer development and behavior.
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PMID:CD26/dipeptidyl peptidase IV and its role in cancer. 1537 76

A number of genes are implicated in the initiation and progression of osteosarcoma; however, cytogenetic and comparative genomic hybridization studies indicate the involvement of additional unidentified genes. An examination of gene expression profiles in 22 high-grade osteosarcoma tumor specimens from 15 patients (including paired primary and metastatic samples from five patients) indicated that von Willebrand factor (vWF) mRNA expression may increase during tumor progression. vWF, a large glycoprotein previously considered to be expressed exclusively by endothelial cells and megakaryocytes, is involved in platelet aggregation and adhesion to the subendothelial matrix, processes critical to hematogenous tumor cell metastasis to the lung. Analysis of paired primary and metastatic osteosarcoma tumor samples from 10 patients revealed an increase in vWF gene expression in metastases (P=0.005). Immunohistochemistry showed that, in addition to the endothelial cells, vWF protein was also detected in osteosarcoma cells in vivo in 13 of 29 tumor specimens as well as in SAOS2, an osteosarcoma cell line. The tumor cell staining correlated positively with high vWF expression in the sample (P=0.006). Although vascular endothelial cells contribute to the vWF mRNA detected in the tumor samples, there was neither any correlation between vascular density (VD) and vWF mRNA expression nor between VD and clinical outcome. These findings suggest that vWF expression is deregulated in osteosarcoma tumors, potentially contributing to metastasis.
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PMID:von Willebrand factor expression in osteosarcoma metastasis. 1546 17

Expression of B7-H1, a costimulating glycoprotein in the B7 family, is normally restricted to macrophage-lineage cells, providing a potential costimulatory signal source for regulation of T cell activation. In contrast, aberrant expression of B7-H1 by tumor cells has been implicated in impairment of T cell function and survival, resulting in defective host antitumoral immunity. The relationship between tumor-associated B7-H1 and clinical cancer progression is unknown. Herein, we report B7-H1 expression by both renal cell carcinoma (RCC) tumors of the kidney and RCC tumor-infiltrating lymphocytes. In addition, our analysis of 196 clinical specimens reveals that patients harboring high intratumoral expression levels of B7-H1, contributed by tumor cells alone, lymphocytes alone, or tumor and/or lymphocytes combined, exhibit aggressive tumors and are at markedly increased risk of death from RCC. In fact, patients with high tumor and/or lymphocyte B7-H1 levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of B7-H1 expression (risk ratio 4.53; 95% confidence interval 1.94-10.56; P < 0.001.) Thus, our study suggests a previously undescribed mechanism whereby RCC may impair host immunity to foster tumor progression. B7-H1 may prove useful as a prognostic variable for RCC patients both pre- and posttreatment. In addition, B7-H1 may represent a promising target to facilitate more favorable responses in patients who require immunotherapy for treatment of advanced RCC.
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PMID:Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. 1556 34

The secreted clusterin/apolipoprotein J (CLU) protein form is a ubiquitously expressed heterodimeric glycoprotein which is differentially regulated in many severe physiological disturbance states including cell death, ageing, cancer progression, and various neurological diseases. Despite extensive efforts CLU function remains an enigma, the main cause being the intriguingly distinct and usually opposed functions in various cell types and tissues. In the current report we investigated the effects of CLU on cellular growth and survival in three human osteosarcoma (OS) cell lines, namely KH OS, Sa OS, and U-2 OS that express very low, moderate, and high endogenous steady-state CLU amounts, respectively. We found that exposure of these established OS cell lines or primary OS cells to genotoxic stress results in CLU gene induction at distinct levels that correlate negatively to CLU endogenous amounts. Following CLU-forced overexpression by means of an artificial transgene, we found that although extracellular CLU inhibits cell death in all three OS cell lines, intracellular CLU has different effects on cellular proliferation and survival in these cell lines. Transgenic KH OS cell lines adapted to moderate intracellular CLU levels were growth-retarded and became resistant to genotoxic and oxidative stress. In contrast, transgenic Sa OS and U2 OS cell lines adapted to high intracellular CLU amounts were sensitive to genotoxic and oxidative stress. In these two cell lines, the proapoptotic CLU function could be rescued by caspase inhibition. To monitor the immediate effects of heterologous CLU overexpression prior to cell adaptation, we performed transient transfections in all three OS cell lines. We found that induction of high intracellular CLU amounts increases spontaneous apoptosis in KH OS cells and reduces DNA synthesis in all three cell lines assayed. On the basis of these novel findings we propose that although extracellular CLU as well as intracellular CLU at low/moderate levels is cytoprotective, CLU may become highly cytostatic and/or cytotoxic if it accumulates intracellularly in high amounts either by direct synthesis or by uptake from the extracellular milieu.
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PMID:Differential effects of clusterin/apolipoprotein J on cellular growth and survival. 1564 46

Continued progress in breast cancer immunotherapy, in particular breast cancer vaccines, depends on the identification of target molecules aberrantly expressed on breast cancer cells. Many different approaches to antigen discovery, including the recent developments in genomics and proteomics, have favored identification of protein tumor antigens. While some of these molecules provide important peptide epitopes recognized by T cells and antibodies, they represent only a small minority of potential targets. Considering that the majority of the cell proteins and therefore tumor cell proteins are glycosylated, tumor glycopeptides represent more important tumor-specific targets. Protein glycosylation is known to be dysregulated in cancer cells, leading to the accumulation of tumor-specific glycoproteins actively involved in tumor progression and metastasis. In addition to understanding the glycobiology of tumor cells and identifying tumor-specific glycoprotein antigens, better understanding is required of how the innate and the adaptive immune systems handle processing, presentation and recognition of glycoprotein antigens. We discuss here some of the new therapeutic strategies for exploiting abnormal glycosylation pathways in tumors and using defined carbohydrate and/or glycoprotein tumor antigens in active specific immunotherapy of breast cancer.
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PMID:Glycoprotein tumor antigens for immunotherapy of breast cancer. 1568 9

The mucin-type glycoprotein podoplanin is specifically expressed by lymphatic but not blood vascular endothelial cells in culture and in tumor-associated lymphangiogenesis, and podoplanin deficiency results in congenital lymphedema and impaired lymphatic vascular patterning. However, research into the biological importance of podoplanin has been hampered by the lack of a generally available antibody against the human protein, and its expression in normal tissues and in human malignancies has remained unclear. We generated a human podoplanin-Fc fusion protein and found that the commercially available mouse monoclonal antibody D2-40 specifically recognized human podoplanin, as assessed by enzyme-linked immunosorbent assay and Western blot analyses. We found that, in addition to lymphatic endothelium, podoplanin was also expressed by peritoneal mesothelial cells, osteocytes, glandular myoepithelial cells, ependymal cells, and by stromal reticular cells and follicular dendritic cells of lymphoid organs. These findings were confirmed in normal mouse tissues with anti-podoplanin antibody 8.1.1. Podoplanin was also strongly expressed by granulosa cells in normal ovarian follicles, and by ovarian dysgerminomas and granulosa cell tumors. Although podoplanin was primarily absent from normal human epidermis, its expression was strongly induced in 22 of 28 squamous cell carcinomas studied. These findings suggest a potential role of podoplanin in tumor progression, and they also identify the first commercially available antibody for the specific staining of a defined lymphatic marker in archival human tissue sections, thereby enabling more widespread studies of tumor lymphangiogenesis in human cancers.
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PMID:Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. 1574 2


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