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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One event that accompanies glioma progression is the upregulation of angiogenesis. Low-grade gliomas are moderately vascularized tumors whereas high-grade gliomas show prominent microvascular proliferations and areas of high vascular density. To analyze the molecular mechanisms underlying glioma angiogenesis, we studied the expression of vascular endothelial growth factor (VEGF) and its tyrosine kinase receptors VEGFR-1 and VEGFR-2 during normal brain development and glioma-induced angiogenesis. Our results suggest a paracrine control of angiogenesis and endothelial cell proliferation that is tightly regulated and transient in the embryonic brain, switched off in the normal adult brain, and turned on in tumor cells (VEGF) and the host vasculature (VEGFR-1 and -2) during tumor progression. It is unknown how VEGF and VEGF receptors are upregulated during glioma angiogenesis, but there is recent evidence that VEGF as well as endogenous inhibitors of angiogenesis could be under control of the tumor suppressor genes p53 and VHL.
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PMID:Angiogenesis in malignant gliomas. 858 68

Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA-methyltransferase (DNA-MTase) activity. Each component of this "methylation imbalance" may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may well be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.
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PMID:Alterations in DNA methylation: a fundamental aspect of neoplasia. 933 76

Seventy malignant, premalignant and histologically normal biopsies from 7 oesophagogastrectomy specimens of adenocarcinomas of the lower oesophagus and gastroesophageal junction were analysed for loss of heterozygosity (LOH) at 9 known or putative gene loci. LOH was detected in 20 of 27 (74%) malignant biopsies, 4 of 7 (57%) biopsies of dysplasia, 2 of 12 (25%) biopsies of histologically normal oesophagus adjacent to adenocarcinoma, and in 2 of 14 (14%) biopsies of histologically normal stomach adjacent to adenocarcinoma. LOH at the VHL, APC, CDKN2 and DCC tumour suppressor and MSH3 mismatch repair gene loci can be detected in histologically normal tissue and in adjacent adenocarcinoma, and are potential markers of early neoplastic progression.
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PMID:Histological and molecular mapping of adenocarcinoma of the oesophagus and gastroesophageal junction: loss of heterozygosity occurs in histologically normal epithelium in the oesophagus and stomach. 1076 62

We here review the literature on genetics related to pheochromocytoma. About 10 percent of these neuroendocrine tumors are hereditary and are most often associated with multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease, and neurofibromatosis type 1 (NF 1). Hereditary tumor syndromes such as the aforementioned ones, are ideal to study the molecular pathogenesis of tumorigenesis as opposed to sporadic tumors in which genetic alterations often merely represent epigenetic tumor progression phenomena. Recent advances in molecular genetics, especially of RET, VHL, NF1, and SDHD, helped better understand the pathogenesis of pheochromocytoma. In this paper, we not only summarize key points of genetic discoveries related to pheochromocytoma, but also report in table format all known RET germline mutations related to pheochromocytoma.
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PMID:Genetic aspects of pheochromocytoma. 1130 96

Tumor suppressor proteins control the proliferation and survival of normal cells; consequently, their inactivation by gene mutations can initiate or drive cancer progression. Most tumor suppressors have been identified by genetic screening, and in many cases their function and regulation are poorly understood. Ten such proteins were recently shown to contain nuclear transport signals that facilitate their "shuttling" between the nucleus and cytoplasm. This type of dynamic intracellular movement not only regulates protein localization, but also often impacts on function. Here, we review the pathways by which tumor suppressors such as APC, p53, VHL, and BRCA1 cross the nuclear envelope and the impact of regulated nuclear import/export on protein function.
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PMID:Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. 1253 92

Little is known about the clinical significance at the frequent association of 3p loss with 5q gain/loss in conventional renal cell carcinoma (RCC). We analyzed the clinical significance of copy number gain and loss at 5q21 approximately q23 combined with allelic loss of 3p25 (including the VHL gene). Fifty RCCs were examined by dual-color fluorescence in situ hybridization with DNA probes for D3Z1 (3cen), cCI3-865 (3p25.1 approximately p25.3), D5S23 (5p15.2), cCI5-243 (5q21.2 approximately q21.3), and cCI5-215 (5q22.3 approximately q23.2). In patients who had 3p loss, there was a significant association of loss at 5q22.3 approximately q23.2 with large tumors (>7 cm) and high-grade tumors (both P < 0.05), whereas gain at 5q22.3 approximately q23.2 was associated with low-grade tumors (P < 0.05). There was also a significant association loss at 5q21.2 approximately q21.3 high-grade tumors in patients with 3p loss (P < 0.05). Patients with 3p loss and gain at 5q22.3 approximately q23.2 had a significantly better disease-specific survival than those who had 3p loss without such gain (P < 0.05). Allelic loss of 3p25 including the VHL gene is thought to be an immediate event in the development of conventional RCC. Copy number gains or losses of 5q21 approximately q23 are thought to be events that lead to tumor progression although the clinical significance of either gains or losses is not well known.
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PMID:Allelic loss of 3p25 associated with alterations of 5q22.3 approximately q23.2 may affect the prognosis of conventional renal cell carcinoma. 1594 69

In endochondral bone development chondrocytes undergo well-ordered and controlled phases of proliferation, hypertrophic differentiation, mineralization of the surrounding matrix, death, blood vessel invasion, and finally replacement of cartilage with bone. The chondrocytic growth plate is a unique mesenchymal tissue, as it is avascular but it requires blood vessel invasion, i.e. the angiogenic switch, in order to be replaced by bone. We have recently provided evidence that the growth plate is hypoxic during fetal development. Adaptation to hypoxia is a critical event in numerous pathological settings, such as tumor progression and survival of tissues in which blood flow has been suddenly interrupted. One of the hallmarks of the response to hypoxia is activation of the transcription factor HIF-1alpha. The von Hippel Lindau tumor suppressor protein VHL is a component of a ubiquitin ligase promoting proteolysis of HIF-1alpha. By using a genetic approach, we have demonstrated the essential role of the hypoxia/VHL/HIF-1alpha pathway in endochondral bone development. Hypoxia-dependent up regulation of HIF-1alpha transcriptional activity is critical for survival of hypoxic chondrocyte, and it shapes up the fetal growth plate by inhibiting chondrocyte proliferation, increasing matrix accumulation and probably modulating cell size. The findings overall highlight the usefulness of studying fetal growth plate development as a model to address issues such as adaptation of normal tissues to hypoxia, survival of hypoxic cells, and regulation of the angiogenic switch. They also demonstrate a crucial role of hypoxia and HIF-1alpha in development and differentiation.
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PMID:Hypoxia and HIF-1 alpha in chondrogenesis. 1614 91

One hundred fifty-four consecutive patients with pheochromocytoma (PC, n=137) or paraganglioma (PG, n=17) were treated at our unit. Twenty patients had MEN 2, 15 VRD, and 1 VHL tumors. Twelve had malignant tumors and were classified according to mode of presentation: (1) Distant metastases (n=4); three underwent surgical debulking (with chemotherapy in one); and three had 131I-MIBG therapy. Within 4 years two patients died of tumor progression. (2) Locally advanced disease (n=4), all resected for cure. (3) Malignancy disclosed during follow-up after adrenalectomy with "benign" histopathology (n=4). All patients in groups 2 and 3 developed recurrence 9 (1-17) years after primary surgery; four underwent resection, one remains tumor-free. The others were treated chronically with phenoxybenzamine, combined with 131I-MIBG in one. These eight patients were observed 20 (5-35) years after primary surgery and 11 (1-19) years after recurrence. This series is population-based and may better reflect the natural history of malignant PC/PG than the series from national referral centers. Active surgical treatment and phenoxybenzamine resulted in low tumor-related mortality in groups 2 and 3; five patients died 8-30 years after diagnosis, four of PC/PG (three from group 2 and one from group 3) and one of other causes. We propose tumor uptake studies (MIBG- and octreotide scintigraphy) in patients with nonresectable metastases; to select individual radionuclide therapy data on the expression of CA-transporters/somatostatin receptors may be helpful. To diagnose PC/PG early, screening of adrenal incidentalomas has been suggested. In a regional population-based prospective study, 503 incidentalomas were reported during 18 months, but only one patient with PG was identified.
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PMID:Malignant pheochromocytoma in a population-based study: survival and clinical results. 1710 19

In this age of targeted therapy, identification of molecular pathways that are deregulated in cancer will not only elucidate underlying tumorigenic mechanisms, but may also help to determine the classes of drugs that are used for treatment. In kidney cancer, a spectrum of histological subtypes exists that are characterized both by distinct molecular signatures and increasingly by distinct molecular pathways that are deregulated in each subtype. For example, the VHL/hypoxia pathway is well-known to be deregulated in clear cell renal cell carcinoma (RCC) whereas in papillary RCC activation of the HGF/Met pathway has been implicated. Additional molecular pathways, many not yet identified, may also be involved in the development of the different histologic subtypes. Moreover, differences in pathway activation may reflect differences in tumor progression and response to treatment. In this article, we describe an oncogenomic approach, based on integrative analysis of gene expression profiling data. In this approach, gene expression data is used to identify both cytogenetic abnormalities and molecular pathways that are deregulated in RCC. Ideally, predicted pathway abnormalities can be linked to predicted cytogenetic abnormalities to identify likely candidate genes. Although further cellular and functional studies are warranted to validate the computational models, development of such models in RCC have the potential to open up new avenues of molecular research and may have significant diagnostic and therapeutic implications.
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PMID:Identification of deregulated oncogenic pathways in renal cell carcinoma: an integrated oncogenomic approach based on gene expression profiling. 1732 20

Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis. ECM is predominantly collagen, and the imino acids (Pro and HyPro) comprise 25% of collagen residues. The final step in collagen degradation is catalyzed by prolidase, the obligate peptidase for imidodipeptides with Pro and HyPro in the carboxyl terminus. Defective wound healing in patients with inherited prolidase deficiency is associated with histologic features of angiopathy suggesting that prolidase may play a role in angiogenesis. Because HIF-1 alpha is central to angiogenesis, we considered that prolidase may modulate this pathway. To test this hypothesis, we made expression constructs of human prolidase and obtained stable transfectants in colorectal cancer cells (RKO). Overexpression of prolidase resulted in increased nuclear hypoxia inducible factor (HIF-1 alpha) levels and elevated expression of HIF-1-dependent gene products, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). The activation of HIF-1-dependent transcription was shown by prolidase-dependent activation of hypoxia response element (HRE)-luciferase expression. We used an oxygen-dependent degradation domain (ODD)-luciferase reporter construct as a surrogate for HIF-1 alpha as an in situ prolyl-hydroxylase assay. Since this reporter is degraded by VHL-dependent mechanisms, the increased levels of luciferase observed with prolidase expression reflected the decreased HIF-1 alpha prolyl hydroxylase activity. Additionally, the differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1 alpha levels. These findings show that metabolism of imidodipeptides by prolidase plays a previously unrecognized role in angiogenic signaling.
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PMID:Extracellular matrix and HIF-1 signaling: the role of prolidase. 1799 10


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