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)

The mechanisms of hypercalcemia were assessed in 15 patients with humoral hypercalcemia of malignancy (HHM) who had tumors at various stages of progression. In patients with early tumors, bone biopsies were generally normal and the hypercalcemia was due to an elevation in renal tubular resorption of calcium. Conversely, osteoclastic resorption was markedly increased in patients with advanced tumors, particularly those in whom the biopsies were obtained postmortem. Osteoclast surface (Oc.S) correlated positively with the stage of tumor progression (r = 0.80, p less than 0.002), degree of immobility (r = 0.87, p less than 0.002), and level of urinary cyclic AMP excretion (r = 0.60, p less than 0.02). When compared with a group of ambulant patients with primary hyperparathyroidism (HPT), osteoblast surface (Ob.S%) in HHM was depressed (median and range): 1.2% (0-11.6%) versus 5.3% (1.1-32.0%) (p less than 0.001). However, a relatively low Ob.S (4%) and raised Oc.S (43.5%) were also seen in an immobilized patient with severe HPT. These data suggest that the PTH-related peptides currently invoked in the pathogenesis of HHM may initially cause hypercalcemia by enhancing renal tubular calcium resorption. The increase in osteoclastic activity and depression of osteoblastic activity that subsequently occurs is probably due to the combined effects of immobilization and higher circulating levels of PTHrP on the skeleton. However, the release of other bone-resorbing factors by the tumor, which have a depressant effect on osteoblastic activity, remains possible.
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PMID:Contrasting mechanisms of hypercalcemia in patients with early and advanced humoral hypercalcemia of malignancy. 271 73

Subcutaneous adipose tissue was examined in 77 patients with breast cancer, 61 patients with lung cancer and in a control group of 23 male and 27 female with non-tumor pathology; the weight and age of controls matched those of cancer patients. The obesity in breast cancer patients was of the hypertrophic type, and of combined type (hypertrophic-hyperplastic) in patients who were more than 50% overweight. The increased level of adipose tissue in lung cancer patients was mostly due to the larger size of adipocytes. The concentration of unsaturated fatty acids in adipose tissue in breast cancer patients was in direct correlation with the level of this tissue and adipocyte size, while, in lung cancer group, this correlation was reversed. There was no inverse correlation between the size and c-AMP level of adipocytes in both cancer groups. Resistance to the inhibitory effect of glucose on lipolysis occurring in adipose tissue was more frequent in cancer patients than in controls. Antilipolytic effect of insulin in subcutaneous adipose tissue of breast cancer patients was less pronounced than in lung cancer group. Liposynthetic activity in adipose tissue was identical in all study groups. Lipolytic activity in adipose tissue was enhanced in both cancer groups, but in the breast cancer group it was in direct correlation with overweight, while in lung cancer patients--with the degree of tumor progression.
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PMID:[Morphometric and biochemical peculiarities of fatty tissue in patients with cancer of the breast and lung]. 630 31

MUC18/MCAM is a melanoma-associated cell adhesion molecule that is also occasionally found on carcinomas and other tumor types. On melanomas, MUC18 expression increases with tumor progression and is found on more than 70% of metastatic lesions. To investigate the regulation of MUC18 expression, cell lines of diverse tissue origin were exposed to cytokines, regulators of intracellular cyclic AMP (cAMP), and to phorbol ester. MUC18 expression could not be induced in negative cell lines and could only be modulated by changes in cAMP levels or by exposure to phorbol ester in positive cells. An increase in intracellular cAMP led to an up-regulation in cell surface MUC18 that was maximal at 48 h. Increased MUC18 mRNA levels were observed as soon as 4 h and were 3-fold higher than in control cells by 48 h. Exposure of the cells to phorbol ester reduced MUC18 surface expression to background levels by 24 h. This downregulation was associated with decreased mRNA levels that were apparent at 8 h. By 24 h, steady-state levels of MUC18 mRNA had been reduced by 58%. Whereas similar changes in MUC18 surface expression were observed in MUC18-expressing glioma and carcinoma cell lines, melanoma cells were more resistant to the MUC18-modulating effects of cAMP analogues and phorbol ester. These observations suggest that the strong MUC18 expression observed in advanced melanomas may reflect disturbances in the normal regulation of this molecule.
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PMID:Phorbol ester and cyclic AMP-mediated regulation of the melanoma-associated cell adhesion molecule MUC18/MCAM. 861 75

Spatially-regulated P-cadherin expression is crucial for maintaining the normal epidermal architecture. P-cadherin expression in cutaneous squamous-cell carcinomas (SCC) is altered, and may participate in tumor progression. We therefore investigated how P-cadherin expression was regulated in a cultured cutaneous SCC cell line (DJM-1). At low calcium concentration (0.05 mM), DJM-1 cells expressed P-cadherin weakly in the cytoplasm. At a higher calcium concentration, P-cadherin was promptly translocated to the cell surface within 30 min, gradually increased on the cell surface for up to 48 hr, and was continuously expressed for at least 7 days. During this time course, the total amount of P-cadherin protein had increased, whereas the steady-state mRNA levels for P-cadherin had not changed. The inhibition of protein synthesis by cycloheximide, but not the inhibition of gene transcription by actinomycin-D, completely suppressed the expression of P-cadherin. The effect of calcium was inhibited by tyrphostins but not by H-7, cholera toxin, or dibutylic cyclic AMP. Increments in the extracellular calcium concentration did not mobilize the intracellular calcium pool, and were accompanied by the tyrosine phosphorylation of a 62-kDa protein. In addition, DJM-1 cells expressed mRNA for a calcium-sensing receptor originally demonstrated in the parathyroid gland. The results suggest an unique mechanism for regulating P-cadherin gene expression in DJM-1 cells by extracellular calcium, which stimulates the de novo synthesis of P-cadherin at the translational level through protein tyrosine phosphorylation.
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PMID:Human squamous-cell-carcinoma cell line (DJM-1) cells synthesize P-cadherin molecules via an elevation of extracellular calcium: calcium regulates P-cadherin-gene expression at the translational level via protein tyrosine phosphorylation. 935 92

Cell motility is an essential component of tumor progression and metastasis. A number of factors, both autocrine and paracrine, have been found to influence cell motility. In the present study, adenosine and adenine nucleotides directly stimulated chemotaxis of A2058 melanoma cells in the absence of exogenous factors. Three adenosine receptor agonists stimulated motility in the melanoma cells and two adenosine receptor antagonists strongly inhibited the chemotactic response to both adenosine and AMP. The chemotactic stimulation by adenosine and AMP was pertussis toxin sensitive. Otherwise unresponsive Chinese hamster ovary cells which were transfected with the adenosine A1 receptor cDNA acquired the direct, pertussis toxin sensitive, chemotactic response to adenosine, and this response was inhibited by adenosine receptor antagonists. These findings demonstrate that adenosine and adenine nucleotides are capable of stimulating chemotaxis of tumor cells mediated through an adenosine receptor, probably of the A1 subtype. The possibility of antimetastatic therapies based on inhibition of adenosine receptor activity is raised.
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PMID:Adenosine receptor mediates motility in human melanoma cells. 961 7

Neuroendocrine (NE) cells occur as scattered foci within prostatic adenocarcinoma, similar to their distribution within ductal epithelial cells of the normal prostate. However, the density of NE cells is often greater in prostate carcinomas than in normal tissue, and the frequency of NE cells correlates with tumor grade, loss of androgen sensitivity, autocrine/paracrine activity, and poor prognosis. Although NE cells are nonmitotic, proliferating cells are found in direct proximity to them, suggesting that NE cells provide paracrine stimuli for surrounding carcinoma cells. In vitro, differentiation of the LNCaP and PC3M prostatic tumor cell lines to a NE phenotype can be induced by dibutyryl cyclic AMP (cAMP), suggesting that physiological agents that increase intracellular concentrations of cAMP might regulate NE differentiation in vivo. Indeed, we demonstrate in this report that LNCaP cells acquire NE characteristics in response to treatment with physiological and pharmacological agents that elevate intracellular cAMP, agents such as epinephrine, isoproterenol, forskolin, and dibutyryl cAMP. The androgen-independent LNCaP-derived cell line C4-2 also responded to these agents, indicating that cells representing later stages of tumor progression are also capable of differentiation. The NE phenotype in this study was monitored by the appearance of dense core granules in the cytoplasm, the extension of neuron-like processes, loss of mitogenic activity, and expression of the NE markers neuron-specific enolase, parathyroid hormone-related peptide, neurotensin, serotonin, and chromogranin A. However, contrary to previous reports, we observed rapid loss of the NE phenotype in both LNCaP and C4-2 cells upon withdrawal of inducing agents. Withdrawal also resulted in a rapid, dramatic increase in tyrosine kinase and mitogen-activated protein kinase activities, suggesting that activation of these intracellular signaling enzymes may be important for reentry into the cell cycle. Together, these results indicate that chronic cAMP-mediated signaling is required to block proliferation of prostate tumor cells and to induce NE differentiation.
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PMID:Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible: implications for prostate cancer progression. 1044 1

Protein kinase Calpha (PKCalpha) is a phospholipid-dependent protein-serine/threonine kinase that plays a major role in intracellular signaling pathways associated with transformation and tumor progression. Glioblastoma multiforme (GBM) and GBM cell lines exhibit increased levels of PKCalpha compared to normal brain tissue that relates to their proliferative and invasive potential. To investigate the transcriptional regulation of PKCalpha, the 5'-flanking sequence of the human PKCalpha gene was cloned and its promoter activity assessed in U-87 GBM cells. This sequence contained a TATA-less promoter region and a single transcription start site within an initiator sequence. Basal promoter activity was restricted to a region spanning -227 to +77 relative to the transcription start site. DNase I footprinting revealed multiple activator protein-2 (AP-2) binding sites and one Sp1 binding site within this region, and point mutations of two AP-2 elements resulted in a loss of DNA binding and transcriptional activation. Overexpression of Sp1 in either U-87 or insect cells increased transcription from the -227/+77 promoter region, whereas overexpression of AP-2 increased transcription only in insect cells. Cis activation of the promoter in U-87 cells was increased by phorbol esters but not by cyclic AMP or phosphatidylinositol 3-kinase inhibitors. These results provide evidence that cis activation of the basal promoter of the human PKCalpha gene occurs through an AP-2-dependent, phorbol ester-responsive pathway, which suggests an autoregulatory manner of transcription in GBM.
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PMID:Modulation of the human protein kinase C alpha gene promoter by activator protein-2. 1226 29

Tumor microenvironment controls the selection of malignant cells capable of surviving in stressful and hypoxic conditions. The transcription factor, cyclic AMP-responsive element binding (CREB) protein, activated by multiple extracellular signals, modulates cellular response by regulating the expression of a multitude of genes. Previously, we have demonstrated that two cystein residues, at the DNA binding domain of CREB, mediate activation of CREB-dependent gene expression at normoxia and hypoxia. The construction of a dominant-positive CREB mutant, insensitive to hypoxia cue (substitution of two cystein residues at position 300 and 310 with serine in the DNA binding domain) and of a dominant negative CREB mutant (addition of a mutation in serine(133)), enabled a direct assessment, in vitro and in vivo, of the role of CREB in tumor progression. In this work, we demonstrate both in vitro and in vivo that CREB controls hepatocellular carcinoma growth, supports angiogenesis, and renders resistance to apoptosis. Along with the identification, by DNA microarray, of the CREB-regulated genes in normoxia and hypoxia, this work demonstrates for the first time that in parallel to other hypoxia responsive mechanisms, CREB plays an important role in hepatocellular carcinoma tumor progression.
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PMID:A pivotal role of cyclic AMP-responsive element binding protein in tumor progression. 1497 73

Cyclooxygenase-derived prostaglandin E(2) (PGE(2)) stimulates tumor progression by modulating several proneoplastic pathways. The mechanisms by which PGE(2) promotes tumor growth and metastasis through stimulation of cell migration, invasion, and angiogenesis have been fairly well characterized. Much less is known, however, about the molecular mechanisms responsible for the immunosuppressive effects of PGE(2). We identified PGE(2) target genes and subsequently studied their biologic role in colorectal cancer cells. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE(2) treatment of LS174T colon cancer cells. Analysis of PGE(2)-mediated activation of the DAF promoter employing 5'-deletion luciferase constructs suggests that regulation occurs at the transcriptional level via a cyclic AMP/protein kinase A-dependent pathway. Nonsteroidal anti-inflammatory drugs blocked DAF expression in HCA-7 colon cancer cells, which could be restored by the addition of exogenous PGE(2). Finally, we observed an increase in DAF expression in the intestinal mucosa of Apc(Min+/-) mice treated with PGE(2) in vivo. In summary, these results indicate a novel immunosuppressive role for PGE(2) in the development of colorectal carcinomas.
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PMID:Prostaglandin E2 regulates the complement inhibitor CD55/decay-accelerating factor in colorectal cancer. 1552 8

Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.
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PMID:Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. 1686 52


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