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)

Adenocarcinoma of the pancreas is an extremely malignant neoplasm with a particular propensity to spread to the liver. In an effort to combine chemotherapy with high-dose local irradiation plus a modest dose of irradiation to suspected (subclinical) hepatic metastasis, patients with unresectable pancreatic carcinomas with no known distant metastasis were treated on a prospective multi-institutional Radiation Therapy Oncology Group (RTOG) Phase I/II trial. High total dose continuous radiation therapy to the pancreas (6120 cGy in 34 fractions over 7 weeks) and simultaneous prophylactic hepatic irradiation (PHI, 2340 cGy in 13 fractions for the last 2.5 weeks) were combined with administration of 5-fluorouracil 1000 mg/m2/day (maximum, 1500 mg) by intravenous continuous infusion for 5 days starting on day 1 and repeated on day 30 for 5 days, followed by a dose of 600 mg/m2 as a weekly bolus injection starting during week 9 for 6 months. In 18 months, 81 patients were enrolled in the study; 79 were evaluable with a minimum potential follow-up of 8.2 months. The patients ranged in age from 32 to 75 years (median, 64 years). Karnofsky performance status was 80 to 100 in 74% of patients. The tumor was confined to the head of the pancreas in 72% of patients. The planned radiation therapy for the pancreas was completed in 87% of patients, 80% received the planned PHI, and 85% completed the first two cycles of chemotherapy. Seventy-five percent of patients completed both treatments according to the protocol. Most patients who did not complete both treatments had tumor progression or refused additional therapy. During all cycles of chemotherapy and radiation therapy, 2 patients died of complications (Grade 5, 1 hepatic and 1 infection), 9 had life-threatening reactions (Grade 4, 7 hematologic, 1 neurologic, and 1 mucositis), and 31 patients had severe effects (Grade 3) according to the RTOG toxicity scale. Overall hepatic metastasis was documented in 32% (13% as the first site of failure), persistent or progressive pancreatic tumor was evident in 73%, and abdominal and extra-abdominal spread were reported in 27% and 8% of patients, respectively. Eighty percent (63 patients) died (median survival, 8.4 months). Although this study suggests that PHI may reduce the frequency of hepatic metastasis, failure to control the primary tumor and intraabdominal spread remain overwhelming.
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PMID:High-dose local irradiation plus prophylactic hepatic irradiation and chemotherapy for inoperable adenocarcinoma of the pancreas. A preliminary report of a multi-institutional trial (Radiation Therapy Oncology Group Protocol 8801). 157 12

A recently established model for local breast cancer recurrence using the 13762NF rat mammary adenocarcinoma was used to evaluate biologic and biochemical properties related to clinical outcome for this class of tumors. Sublines isolated from local tumor regrowths following surgical resection differed from each other and from the 'parental' cell lines for multiple phenotypes, including metastatic propensity. Local recurrence- and primary tumor-derived sublines were examined by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), lectin binding to electrophoretically separated proteins, and lactoperoxidase-catalyzed cell surface iodination; and differential protein patterns were compared to tumor progression and metastatic potential. 2D-PAGE revealed several quantitatively different spots which correlated with lung colonization potential. In particular, quantities of an apparently unique, non-cell-surface protein, P50.9 (Mr approximately 50,900, pI approximately 7.3) correlated inversely with metastatic propensity, suggesting that it may be associated with, among other possibilities, the negative regulation of the metastatic phenotype. P50.9 was unrelated to four similarly sized metastasis-associated proteins--tumor autocrine motility factor; the rat analog of tumor suppressor, p53; rat cytokeratin 14 or procathepsin D--as determined by amino acid analysis. A major wheat germ agglutinin binding sialoglycoprotein, gp93 (Mr approximately 93,000), was present in smaller amounts as cells were passaged in vivo and re-established as in vitro cultures [MTF7 greater than 'primary' tumor-derived lines (sc1, sc3) much greater than local recurrence-derived lines (LR1, LR1a, LR3, LR4, LR5, LR6)]. Besides cell surface glycoprotein losses, two of six local recurrence-derived sublines expressed a wheat germ agglutinin-binding sialoglycoprotein, gp110 (Mr approximately 110,000), previously undetected on any of the other cell lines including the parental populations. gp110 was found in LR3 and LR6 which were relatively highly metastatic; however, correlation with metastatic potential failed because gp110 was not present on the metastatic parental cell line, MTF7. These results demonstrate specific quantitative and qualitative protein differences associated with the selection of locally recurrent mammary tumors.
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PMID:Tumor progression- and metastasis-associated proteins identified using a model of locally recurrent rat mammary adenocarcinomas. 222 68

To date, the structure of the autocrine motility factor (AMF), a tumor-secreted cytokine which stimulates cell migration in vitro and metastasis in vivo, is unknown. Here, AMF secreted by Gc-4 PF murine fibrosarcoma into a protein-free conditioned media was isolated, purified, and microsequenced. The results demonstrate that AMF is the previously cloned cytokine and enzyme designated as neuroleukin, and phosphohexose isomerase (PHI), which has been independently implicated in cell motility, and to be a cancer progression marker. PHI catalyzes isomerization of glucose 6-phosphate to fructose 6-phosphate and is specific for both sugars. Murine AMF exhibits the enzymatic properties of PHI and rabbit heart PHI-stimulated mouse fibrosarcoma cells' motility similar to those of the endogenous AMF. Specific PHI inhibitors (carbohydrate phosphates) inhibited enzymatic activity and AMF-induced cell motility.
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PMID:Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. 867 49

Urothelial carcinomas are heterogeneous diseases with an aggressive clinical potential. To date, the most used prognostic factors for bladder carcinomas are grade and stage, which are based on histopathological parameters that are often not reliable in predicting a clinical outcome. Here, we evaluated the clinical outcome of 100 patients with urothelial carcinomas with follow-up information for more than 2 years after surgery in relation to the expression of two cell surface antigens, ie, E-cadherin and autocrine motility factor receptor (AMF-R, gp78). Frozen bladder tissues were serially cut, stained either with hematoxylin and eosin for grading, with the anti-gp78 antibodies, or with anti-E-cadherin antibodies to determine level of expression. Of 63 patients presented at the time of diagnosis with pathological loss of E-cadherin associated with increased gp78 expression, 39 (62%) succumbed to tumor progression or death. Of 37 patients with normal E-cadherin and gp78 expression positive and negative, respectively, 36 (97%) had favorable disease outcomes (P < 0.0001). The results suggest that in bladder carcinomas abnormal expression of both E-cadherin and gp78 results in a poor disease outcome, independent of tumor stage and grade.
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PMID:Improved prognosis assessment for patients with bladder carcinoma. 917 85

Motility factors, e.g. SF/HGF (scatter factor/hepatocyte growth factor) or AMF (autocrine motility factor) can influence the migration of tumor cells in vitro and may facilitate invasive growth and metastases in vivo. The production of motility factors was studied in cell lines derived from human cholangiocarcinomas. Culture supernatants from 5 different cholangiocarcinoma cell lines (EGI-1, RPMI 7451, MZ CHA-1, MZ CHA-2 and MZ CHA-3) were analyzed in scatter assays with NRK and MDCK cells as indicator cells which react with cellular migration in the presence of motility factors. Culture supernatants from 4 of the 5 cell lines investigated induced migration of the indicator cells thus demonstrating the production of motility factors. Three of the cell lines (MZ CHA-1, MZ CHA-2, RPMI 7451) produced a factor with a molecular weight ranging between 50 and 100 kDa, EGI-1 cells secreted a factor with a molecular weight >100 kDa. None of the factors was identical to HGF as demonstrated by the lacking reactivity in a HGF specific ELISA and by the inability to induce scattering of HPAF indicator cells like HGF. Similar to SF/HGF, the activity of the EGI-1 factor was inhibited by the proteoglycan heparin and stimulated the chemotactic cell migration, but in contrast to SF/HGF it could not induce invasive growth of NRK cells. The production of scatter factors could be involved in tumor progression and formation of metastases of cholangiocarcinomas.
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PMID:Motility factors identified in supernatants of human cholangiocarcinoma cell lines. 1129 63

Autocrine motility factor receptor (AMF-R) has been shown to play an important role in tumor cell migration, invasion and metastasis. We have detected AMF-R expression in tissue specimens from patients with non-small-cell lung cancer (NSCLC) and have assessed their clinical characteristics. Using RT-PCR and immunohistochemistry, we quantified the expression of AMF-R in 47 patients with NSCLC who underwent curative tumor resection, to investigate the relationship between AMF-R expression and clinicopathologic factors and prognosis. RT-PCR results agreed well with the immunohistochemic results (p < 0.0001). In 47 NSCLC patients, 34 (72.3%) samples were evaluated as having high AMF-R gene expression. AMF-R gene expression was significantly associated with lymph node metastasis and stage (p = 0.0295 for lymph node metastasis, p = 0.0152 for stage). The overall survival rate for patients with high AMF-R gene-expressing tumors was significantly worse than for those whose tumors had low AMF-R expression (p = 0.0029). Multivariate analysis also showed that AMF-R gene expression was significantly related to survival (p = 0.0165). These data indicate that AMF-R may contribute to tumor progression and that AMF-R gene expression can serve as a useful prognostic marker in NSCLC.
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PMID:Significance of autocrine motility factor receptor gene expression as a prognostic factor in non-small-cell lung cancer. 1166 22

Phosphoglucose isomerase (PGI; EC 5.3.1.9) is a cytosolic housekeeping enzyme of the sugar metabolism pathways that plays a key role in both glycolysis and gluconeogenesis. PGI is a multifunctional dimeric protein that extracellularly acts as a cytokine with properties that include autocrine motility factor (AMF)-eliciting mitogenic, motogenic, and differentiation functions, and PGI has been implicated in tumor progression and metastasis. Little is known of the biochemical regulation of PGI/AMF activities, although it is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2); however, the physiological significance of this phosphorylation is unknown. Thus, by site-directed mutagenesis, we substituted Ser(185) with aspartic acid (S185D) or glutamic acid (S185E), which introduces a negative charge and conformational changes that mimic phosphorylation. A Ser-to-Ala mutant protein (S185A) was generated to abolish phosphorylation. Biochemical analyses revealed that the phosphorylation mutant proteins of PGI exhibited decreased enzymatic activity, whereas the S185A mutant PGI protein retained full enzymatic activity. PGI phosphorylation by CK2 also led to down-regulation of enzymatic activity. Furthermore, CK2 knockdown by RNA interference was associated with up-regulation of cellular PGI enzymatic activity. The three recombinant mutant proteins exhibited indistinguishable cytokine activity and receptor-binding affinities compared with the wild-type protein. In both in vitro and in vivo assays, the wild-type and S185A mutant proteins underwent active species dimerization, whereas both the S185D and S185E mutant proteins also formed tetramers. These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity. The process by which phosphorylation modulates the enzymatic activity of PGI thus has an important implication for the understanding of the biological regulation of this key glucose metabolism-regulating enzyme.
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PMID:Differential regulation of phosphoglucose isomerase/autocrine motility factor activities by protein kinase CK2 phosphorylation. 1563 53

Phosphoglucose isomerase (PGI; EC 5.3.1.9) is a housekeeping cytosolic enzyme of the sugar metabolism pathways that plays a key role in glycolysis and gluconeogenesis. PGI is a multifunctional dimeric protein that extracellularly acts as a cytokine with properties that include autocrine motility factor (AMF) eliciting mitogenic, motogenic, differentiation functions and has been implicated in tumor progression and metastasis. Since metastasis is regulated in part by hypoxia, which induces the transcription of metastasis-associated genes and anaerobic glycolic metabolism, we questioned whether hypoxia also regulates the expression level of tumor cells' PGI/AMF. We establish here that in the human breast carcinoma BT-549 cells hypoxia enhanced expression of the transcription factor hypoxia-inducible factor (HIF)-1, which in turn led to the up-regulation of PGI/AMF expression and was specifically inhibited by inhibitors of the phosphatidylinositol 3'-kinase signaling pathway. In addition, the hypoxia induction of PGI/AMF expression was suppressed by inhibitors of vascular endothelial growth factor (VEGF) or VEGF receptors, suggesting that hypoxia-inducible VEGF regulates the PGI/AMF expression. Hypoxia also enhanced cancer cell motility, and these effects were strongly inhibited by the PGI/AMF, VEGF, or VEGF receptor inhibitors. The results presented here suggest that under hypoxic conditions the expression of PGI/AMF is regulated in part by the HIF pathway, which in turn increases the flow of the glycolytic cascade leading to an increased anaerobic energy generation; thus, inhibition of PGI/AMF expression and activities may provide a new therapeutic modality for treatment of hypoxic tumors.
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PMID:Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. 1612 9

Phosphoglucose isomerase (PGI) is one of the glycolytic enzymes and is a multifunctional enzyme that functions in glucose metabolism inside the cell while acting as a cytokine outside the cell, with properties that include autocrine motility factor (AMF) regulating tumor cell motility. Although there are many studies indicating that PGI/AMF has been implicated in progression of metastasis, no direct studies of the significance of exogenous PGI/AMF on tumor progression have been reported. Here, we report on the mesenchymal-to-epithelial transition (MET), which is the reverse phenomenon of the epithelial-to-mesenchymal transition that is associated with loss of cell polarity, loss of epithelia markers, and enhancement of cell motility essential for tumor cell invasion and metastasis. Mesenchymal human fibrosarcoma HT1080 cells, which have naturally high levels of endogenous and exogenous PGI/AMF, were stably transfected with PGI/AMF small interfering RNA (siRNA). The siRNA targeting human PGI/AMF down-regulated the endogenous PGI/AMF expression and completely extinguished the secretion of PGI/AMF in a human fibrosarcoma HT1080, whereas the control siRNA showed no effects. The PGI/AMF siRNA caused cells to change shape dramatically and inhibited cell motility and invasion markedly. Suppression of PGI/AMF led to a contact-dependent inhibition of cell growth. Those PGI/AMF siRNA-transfected cells showed epithelial phenotype. Furthermore, tumor cells with PGI/AMF deficiency lost their abilities to form tumor mass. This study identifies that MET in HT1080 human lung fibrosarcoma cells was initiated by down-regulation of the housekeeping gene product/cytokine PGI/AMF, and the results depicted here suggest a novel therapeutic target/modality for mesenchymal cancers.
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PMID:Down-regulation of phosphoglucose isomerase/autocrine motility factor results in mesenchymal-to-epithelial transition of human lung fibrosarcoma cells. 1748 35

Phosphoglucose isomerase (PGI; EC 5.3.1.9) is a ubiquitous cytosolic enzyme essential for glycolysis and gluconeogenesis. PGI is a multifunctional dimeric protein that extracellularly acts as a cytokine [autocrine motility factor (AMF)] eliciting mitogenic, motogenic, and differentiation functions through binding to its cell surface receptor gp78/AMF receptor (AMFR). AMFR contains a seven-transmembrane domain with RING-H2 and leucine zipper motifs showing ubiquitin protein ligase (E3) activity and is exposed on the endoplasmic reticulum surface. Augmented expressions of both PGI/AMF and AMFR have been implicated in tumor progression and metastasis, and an intracellular binding partner of PGI/AMF is expected to regulate in part its diverse biological functions. Thus, we screened a cDNA library using a yeast two-hybrid system to search for interacting protein(s) and report on the finding of poly(ADP-ribose) polymerase-14 (PARP-14) to be a binding partner with PGI/AMF. PARP-14-PGI/AMF interaction was confirmed by coimmunoprecipitation and immunolocalization. We also report that PGI/AMF degradation is mainly regulated by the ubiquitin-lysosome system and RNA interference experiments revealed that PARP-14 inhibits PGI/AMF ubiquitination, thus contributing to its stabilization and secretion. This newly characterized PARP-14 protein should assist in understanding the regulation of PGI/AMF intracellular function(s) and may provide a new therapeutic target for inhibition of PGI/AMF inducing tumor cell migration and invasion during metastasis.
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PMID:Regulation of phosphoglucose isomerase/autocrine motility factor activities by the poly(ADP-ribose) polymerase family-14. 1787 8


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