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)

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor first identified as being activated by hypoxia but also in normoxic conditions by insulin and IGF-2. It is able to induce the expression of glycolytic genes and hence the ATP production, it also regulates the expression of the angiogenic factor VEGF and stimulates erythropoiesis via EPO production. HIF-1 is a protein necessary for the normal embryonic and cardiovascular system development, but seems to be also involved in cancer progression and apoptosis. Thus, it appears that HIF-1 plays a central role in normal cellular functions and in tissue metabolism but it is also involved in pathological evolutions raising its interest as a therapeutic target. In this review, we summarize the dual role of HIF-1 as a major component of the embryo development, as well as an element of tumor progression and of anoxia-induced apoptosis.
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PMID:Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review). 1067 65

Thioredoxin (Trx) and Trx reductase (TrxR) are redox-active proteins that participate in multiple cellular events, including growth promotion, apoptosis, and cytoprotection. Studies on overexpression of Trx and TrxR in human cancers have indicated a role of these proteins in tumor development. In this study, we analyzed the expression of TrxR in peripheral blood cells, tumor-transformed leukemia, and melanoma cells and found, in addition to abundant plasma membrane localization, that TrxR was released from these cells. Secretory cells were observed at the single cell level using a sensitive enzyme-linked immunospot assay. The release was inducible, and physiological stimulation of human monocytes by IFN-gamma, lipopolysaccharide, and interleukin 1alpha significantly increased the number of TrxR-secreting cells (P = 0.004). Secretion of TrxR followed the classical Golgi pathway, and it was confirmed by metabolic labeling using [35S]methionine and [35S]cysteine. TrxR was also detected for the first time in fresh healthy blood donor plasma (n = 21; median concentration, 18.0 ng/ml), with biological activity as determined by insulin reduction assay. These results highlight the role of extracellular Trx and TrxR during inflammation and tumor progression. Released Trx, with its active site motif containing amino acids Cys-X-X-Cys, was recently shown to have chemoattractant properties beside its previously described antioxidant and cocytokine activities. Regeneration of oxidized Trx requires available TrxR outside the cell, the presence and induction of which is described in this paper for normal and transformed cells.
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PMID:Thioredoxin reductase, a redox-active selenoprotein, is secreted by normal and neoplastic cells: presence in human plasma. 1078 96

We hypothesized that the tolerance for nutrient deprivation as well as angiogenesis might be an important factor for tumor progression under hypovascular conditions. When normal human fibroblasts were subjected to extreme nutrient starvation by culturing in a medium without serum, glucose, and amino acids, cells died within 24 h. When substituted with liver cancer cell lines HepG2, Hep3B, HLE, and HuH-7, cell death occurred within 36 h. In contrast, four of six pancreas cancer cell lines, PANC-1, AsPC-1, BxPC-1, and KP-3, survived for remarkably longer periods; >50% of the cells survived, even after starvation for 48 h. Among three gastric cancer cell lines, MKN28, MKN45, and MKN74, only the most poorly differentiated MKN45 cells survived >36 h. More than 50% of the cells in colon cancer cell lines SW480, WiDr, and DLD-1 survived after 36 h, and the most undifferentiated SW480 cell line survived longest. We examined the possible involvement of PKB/Akt expression in the survival of various cell lines under nutrient starvation conditions. High expression of PKB/Akt was found to be associated with tolerance for nutrient starvation. When Akt antisense RNA expression vectors were introduced into PANC-1 cells, the tolerance was partially but significantly diminished by vectors for Akt1 and Akt2 but not Akt3. Because elimination of the tolerance might serve as a new strategy for cancer therapy, several compounds were tested for this purpose, and troglitazone, an insulin sensitizer, as well as LY294002, a phosphatidylinositol 3-kinase inhibitor, were found to kill PANC-1 cells only under nutrient starvation conditions.
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PMID:Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. 1108 46

Cellular binding of receptor-recognized forms of alpha2-macroglobulin (alpha2M*) is mediated by the low-density lipoprotein receptor related protein (LRP) and the alpha2M signaling receptor (alpha2MSR). In nonmalignant cells, ligation of alpha2MSR promotes DNA synthesis and cellular proliferation. Here, we report that insulin treatment of highly metastatic 1-LN human prostate carcinoma selectively increases alpha2MSR expression and binding of alpha2M* to 1-LN cells. alpha2M* induces transient increases in intracellular calcium and inositol 1,4,5-trisphosphate in insulin-treated 1-LN cells, consistent with activation of alpha2MSR. Inhibition of signaling cascades activated by insulin blocks upregulation of alpha2MSR. By contrast, alpha2M* does not bind to nor induce intracellular signaling in PC-3 cells, even though 1-LN cells were subcloned from PC-3 cells. We suggest that alpha2M* behaves like a growth factor in these highly malignant cells. The 1-LN metastatic phenotype may result, in part, from aberrant expression of alpha2MSR, indicating the possible involvement of alpha2M* in tumor progression.
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PMID:Selective upregulated expression of the alpha2-macroglobulin signaling receptor in highly metastatic 1-LN prostate carcinoma cells. 1109 86

Pancreatic cancer has an incidence of approximately 8 to 10 cases per 100,000 citizens in Western industrialized countries, and the incidence has been increasing throughout the last decades. Insensitivity to antigrowth and apoptotic signals as well as self-sufficiency in growth signals are hallmarks of malignant growth. Pancreatic cancers often exhibit alterations in growth inhibitory pathways such as Smad4 mutations and Smad6 and Smad7 overexpression, and evade apoptosis through p53 mutations and aberrant expression of apoptosis regulating genes. In addition, in pancreatic cancer a variety of growth factors are expressed at increased levels. For example, the concomitant presence of the EGF-receptor and its ligands EGF, TGF-alpha, and/or amphiregulin is associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection. Furthermore, a number of other growth factors and their receptors, such as fibroblast growth factors, nerve growth factor, platelet-derived growth factors, and insulin-like growth factors and their respective receptors are expressed at increased levels in pancreatic cancer and are thought to contribute to its malignant phenotype. Taken together, the disturbance of growth inhibitory and apoptotic pathways and the abundance of growth promoting factors give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival prognosis.
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PMID:Growth factors and their receptors in pancreatic cancer. 1113 19

PTEN/MMAC1/TEP1 (PTEN) is a tumor suppressor gene that is mutated in a variety of advanced and metastatic cancers, strongly suggests that PTEN alteration is possibly involved in the tumor progression and formation of metastases. However, the roles of PTEN in tumor growth and metastasis and its functional mechanisms are not fully understood. We evaluated the tumor suppressor function of PTEN gene on tumor growth and metastasis in vitro and in vivo. Our results of in vitro soft agar assay and in vivo PTEN-expressing tumor cell growth showed that PTEN inhibited the tumorigenicity of B16F10 melanoma cells. Anti-metastatic function of PTEN was also revealed by experimental pulmonary metastatic animal model. For the further insight into the mechanisms underlying the PTEN-mediated inhibition of tumor metastasis, we have examined the role of PTEN on the secretion of matrix metalloproteinases (MMPs), insulin-like growth factors (IGFs) and the expression of secretory and cellular vascular endothelial growth factor (VEGF) proteins that have been described to contribute to the metastasis of tumor. PTEN significantly lowered MMPs and IGFs secretion and also expression of secretory and cellular VEGF proteins. These results suggest that PTEN tumor suppressor protein inhibits tumorigenicity and metastasis through regulation of MMP, IGFs, and VEGF expression.
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PMID:Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene. 1159 33

The serine/threonine protein kinase PKB (also known as Akt) is thought to be a key mediator of signal transduction processes. The identification of PKB substrates and the role PKB phosphorylation plays in regulating these molecules have been a major focus of research in recent years. A recently developed motif-profile scoring algorithm that can be used to scan the genome for potential PKB substrates is therefore a useful tool, although additional considerations, such as the evolutionary conservation of the phosphorylation site, must also be taken into account. Recent evidence indicates that PKB plays a key role in cancer progression by stimulating cell proliferation and inhibiting apoptosis and is also probably a key mediator of insulin signalling. These findings indicate that PKB is likely to be a hot drug target for the treatment of cancer, diabetes and stroke. There are, however, a number of pitfalls of methodologies currently employed to study PKB function, and therefore caution should be used in interpretation of such experiments.
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PMID:PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? 1168 94

Carcinomas that develop in the pancreatic islets of transgenic mice expressing the SV40 T-antigens (Tag) under transcriptional control of the rat insulin II promoter (RIP) progress through well-characterized stages that are similar to aspects of human tumor progression, including hyperplastic growth, increased angiogenesis and reduced apoptosis. The latter two stages have been associated with recurrent loss of heterozygosity (LOH) and reduced genome copy number on chromosomes 9 (LOH9) and 16 (LOH16), aberrations which we believe contribute to these phenotypes. Earlier analyses localized LOH9 to approximately 3 Mb and LOH16 to approximately 30 Mb (both syntenic with human 3q21-q25) but were limited by low throughput and a lack of informative polymorphic markers. Here we show that comparative genomic hybridization to DNA microarrays (array CGH) overcomes these limitations by allowing efficient, genome-wide analyses of relative genome copy number. The CGH arrays used in these experiments carried BACs distributed at 2-20-MB intervals across the mouse genome and at higher density in regions of interest. Using array CGH, we further narrowed the loci for LOH9 and LOH16 and defined new or previously unappreciated recurrent regions of copy-number decrease on chromosomes 6, 8 and 14 (syntenic with human chromosomes 12p11-p13, 16q24.3 and 13q11-q32, respectively) and regions of copy-number increase on chromosomes 2 and 4 (syntenic to human chromosomes 20q13.2 and 1p32-p36, respectively). Our analyses of human genome sequences syntenic to these regions suggest that CYP24, PFDN4, STMN1, CDKN1B, PPP2R3 and FSTL1 are candidate oncogenes or tumor-suppressor genes. We also show that irradiation and genetic background influence the spectrum of aberrations present in these tumors.
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PMID:Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas. 1169 78

The pivotal role of vascular endothelial growth factor (VEGF-A) in the regulation of angiogenesis, in particular in the onset and maintenance of tumor angiogenesis, has been demonstrated repeatedly in experimental model systems and, more recently, in clinical trials. Experimental evidence has also suggested that up-regulated expression of VEGF-A may cooperate with other genetic or epigenetic changes to induce or accelerate tumor progression to invasive and metastatic cancers. Here we report the generation of transgenic mouse lines that express human VEGF-A165 under the control of the rat insulin promoter in the beta cells of pancreatic islets of Langerhans (Rip1VEGF-A). These mice do not exhibit detectable changes in islet development, vascularization, or physiology. Intercrosses of these mice with a transgenic mouse model of pancreatic beta cell carcinogenesis (Rip1Tag2) result in an earlier onset of tumor angiogenesis and with it accelerated tumor growth and mortality. The transition from benign tumors (adenoma) to malignant tumors (carcinoma) is modestly accelerated; however, tumor metastases are not observed. Our findings indicate that in beta-cell tumorigenesis, overexpression of VEGF-A165 accelerates the onset of tumor angiogenesis and with it tumor progression but is not sufficient to induce tumor metastasis.
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PMID:Overexpression of vascular endothelial growth factor-A165 enhances tumor angiogenesis but not metastasis during beta-cell carcinogenesis. 1180 16

Glioblastomas rarely metastasize outside the CNS. We biologically characterized a case of secondary glioblastoma associated with extracranial progression and distant metastasis. A 42-year-old male patient was subjected to craniotomy for a left temporal tumor (astrocytoma grade II) and subsequently underwent another 3 craniotomies due to tumor recurrences. At the third craniotomy, extracranial progression was noted, and the tumor was classified as a glioblastoma. In order to pinpoint the genes expressed differentially in the intracranial primary tumor and the metastatic tumors, we used cDNA microarray. The patterns of gene expression in these 2 samples were highly similar, suggesting that the mechanism of metastasis was direct infiltration of tumor cells into extracranial blood vessels. Insulin-like growth factor binding protein-2 was overexpressed in both primary and metastatic tumors. Immunohistochemical studies of DNA-dependent protein kinase, which participates in the repair of DNA, was strongly positive in the samples obtained at the first and second operations, but the positive rates were markedly reduced in the specimens obtained at the third and fourth operations. These results suggest that insulin-like growth factor binding protein-2 and deficiency of DNA-dependent protein kinase proteins promoted tumor progression in the present case.
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PMID:Biologic characterization of a secondary glioblastoma with extracranial progression and systemic metastasis. 1262 29


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