Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial-stromal interactions are important not only in growth, development, and functional cytodifferentiation of the prostate but also in derangements of prostate gland such as BPH and prostate carcinoma. This chapter explores the roles of epithelium and stroma during this delicate process and highlights the role and mutual influence of each on the other. It also examines the importance of ECM in mediating the effects of androgens and drawn attention to estrogen and genetic factors in the process. During this process of epithelial-stromal interaction, growth factors play a central role in mediating the interactions. This chapter focuses on the role of several growth factors including epidermal growth factor, fibroblast growth factor, transforming growth factor alpha, transforming growth factor beta, insulin-like growth factor-1, vascular endothelial growth factor, nerve growth factor, platelet-derived growth factor, and hepatocyte growth factor. This chapter emphasizes the importance of epithelial-stromal interactions in tumorigenesis and highlights the switch of paracrine to autocrine mode during the process of carcinogenesis.
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PMID:Growth factors and epithelial-stromal interactions in prostate cancer development. 1087 77

All-trans-retinoic acid (RA) and other retinoids modulate cell growth and differentiation, generally favoring terminal cell differentiation and inhibiting carcinogenesis. Retinoids are also reported to inhibit angiogenesis and endothelial cell migration, actions that are also anti-carcinogenic. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine secreted by many tumors. It renders microvessels hyperpermeable to plasma and stimulates endothelial cell migration and division. To investigate further the mechanisms by which RA inhibits angiogenesis, we evaluated the effects of RA on VPF/VEGF-induced angiogenesis and microvascular permeability. RA selectively inhibited the angiogenic response induced by VPF/VEGF, but not that induced by fibroblast growth factor-2 (FGF-2), in the CAM assay. RA and two of its isomers also inhibited the vascular permeabilizing effect of VPF/VEGF but not that induced by histamine. The vascular permeabilization induced by VPF/VEGF and blocked by RA takes place within 1-15 min, too short a time frame for RA to act by modulating transcription through classic retinoid receptors. RA also inhibited VPF/VEGF-induced phosphorylation of PLC-gamma and synthesis of cGMP but actually increased VPF/VEGF binding to cultured endothelial cells. Taken together, these findings indicate that RA selectively blocks VPF/VEGF-induced microvascular permeability and angiogenesis and also identify VPF/VEGF as a major target of RA action. The selectivity of RA's action suggests that other, RA-independent pathways must exist for the angiogenesis induced by FGF-2 and the vascular permeabilizing effect of histamine.
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PMID:Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade. 1096 85

We previously demonstrated that cyclooxygenase-2 (COX-2) was predominantly expressed in macrophages of sporadic human colonic adenomas; however, the role of COX-2-expressing cells during colon carcinogenesis has not yet been elucidated. In the present study, we showed the effect of PGE, on vascular endothelial growth factor (VEGF) production by PMA-differentiated U937 cells, a human macrophage model (H-Mac), and by human colon cancer cells T84. PGE1 dramatically induced VEGF production by H-Mac, but not that by T84. PGE1 significantly increased intracellular cAMP formation by H-Mac, but only modestly increased that by T84. 8-bromo-cAMP and cholera toxin also increased VEGF production by H-Mac. In contrast, neither of these agents modulated VEGF production by T84. EP2 and EP4 (PGE specific receptors) mRNA was expressed in both cells. PG dramatically increased VEGF production by activated macrophages, but not by cancer cells, through a specific PGE receptor-mediated process. These findings suggest that PGs produced by COX-2-expressing macrophages induce VEGF production by macrophages, but not by cancer cells, in an autocrine fashion.
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PMID:Effect of prostaglandin E1 on vascular endothelial growth factor production by human macrophages and colon cancer cells. 1096 22

During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic, releasing VEGF. MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect. Our results show that MMP-9 is a component of the angiogenic switch.
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PMID:Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. 1102 65

Both carcinogenesis and wound healing proceed through stages of proliferation and tissue remodeling. Here, using either a model of multistage epidermal carcinogenesis in K14-HPV16 transgenic mice or creation of full-thickness back wounds in nontransgenic mice, we determined patterns of expression of hypoxia inducible factor (HIF)-1alpha, and three targets of the heterodimeric transcription factor HIF-1, glucose transporter (GLUT)-1, phosphoglycerate kinase (PGK)-1, and vascular endothelial growth factor (VEGF) in skin. Neither HIF-1alpha, GLUT-1, PGK-1, nor VEGF mRNA was detectable in unwounded nontransgenic skin. In epidermal carcinogenesis, HIF-1alpha, GLUT-1, PGK-1, and VEGF mRNAs were just detectable in early-stage hyperplasia, markedly increased in high-grade epidermal chest dysplasias, and further increased in invasive squamous carcinomas. In neoplastic skin, HIF-1alpha, GLUT-1, and PGK-1 mRNAs localized in the basal and immediate suprabasal epidermal layers, whereas VEGF mRNA was predominantly expressed in the more superior spinous and granular epidermal layers. Immediately after wounding, HIF-1alpha, GLUT-1, and PGK-1 mRNAs were detectable in basal keratinocytes at the wound edge. Expression of all three genes increased to maximum levels in reepithelializing basal keratinocytes and then diminished to near undetectable levels after wound epithelialization. Although VEGF mRNA similarly increased and decreased during wound healing, its expression pattern was more punctate; the most intense hybridization signals were detected in the upper spinous and granular layers of reepithelializing keratinocytes and in dermal cells morphologically similar to macrophages. These data suggest stage-specific and spatio-temporal control of HIF-1alpha and HIF-1 target gene expression in both multistage epithelial carcinogenesis and wound healing.
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PMID:Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. 1108 44

Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF receptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and inhibited tumor angiogenesis in an ex vivo bioassay, in which endothelial cells were cocultured with angiogenic tumor biopsies in a collagen gel. Moreover, AdsFGFR repressed tumor angiogenesis and hence tumor growth in vivo in allograft transplantation experiments. Whereas adenoviral expression of a soluble form of VEGF receptor 1 (AdsFlt) predominantly affected the initiation of tumor angiogenesis, soluble FGF receptor (sFGFR) appeared to impair the maintenance of tumor angiogenesis. The combination of sFGFR and soluble Flt exhibited a synergistic effect in the repression of tumor growth. Finally, i.v. injection of AdsFGFR resulted in a dramatic repression of tumor growth in a transgenic mouse model of pancreatic beta cell carcinogenesis. Similar to control infections with AdsFlt, tumor-associated vessel density was decreased, indicating that the expression of sFGFR impaired tumor angiogenesis. These data indicate that FGFs play a critical role in tumor angiogenesis.
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PMID:Fibroblast growth factors are required for efficient tumor angiogenesis. 1115 26

Thyroid nodule genesis may be considered as an amplification of thyroid heterogeneity due to genetic and/or epigenetic mechanisms. We classified the thyroid nodules in five types with distinct histological features: hyperplastic, neoplastic, colloid, cystic and thyroiditic nodules. Hyperplastic: Thyrocyte proliferation is under the control of TSH but several other paracrine and autocrine factors are secreted by follicular cells, the stromal apparatus and the lymphocytes, which are implicated in initiation and perpetuation of thyroid hyperplasia. Growth occurs mainly through TSHR, cAMP and PKA. Constitutive cAMP overproduction has been shown to be due to point mutation of the TSHR or Gs protein, producing overgrowth and hyperfunction. Neoplastic: Several activated oncogenes have been identified in thyroid malignancies. Oncogenes relevant to the thyroid carcinogenesis are: mutated TSHR and gsp (constitutive activation of cAMP); TRK (receptor for NGF); RET/PTC (phosphorylation of tyrosine kinase receptor)--an isoform of this oncogene is induced by radiation: ras (it encodes Gs proteins transducing mitogenic signals); and c-MET (receptor for hepatocyte growth factor). The evolution of a differentiated thyroid cancer towards an undifferentiated cancer is due to a mutation of a family of proteins (i.e., p53), which acts as a brake, preventing the genomic instability of cancer. It is suggested that a tumor initiates by RET or ras and possibly progresses--as a result of additional mutations and by p53 mutation--to anaplastic carcinoma. Colloid: Flattening of the epithelium and dilatation of follicles containing viscous material--made up by a concentrated solution of thyroglobulin (hTg)--is the characteristic of the colloid nodule. A defect of intraluminal reabsorption of hTg has been suggested but not proven. Experimentally, a load of iodine is able to change thyroid hyperplasia to a colloid feature; however, a load of iodine is rarely found in the clinical history of patients. A new clue to the pathogenesis comes from the finding that a relevant part of the colloid (10-20%) is made up of insoluble globules, where hTg is compacted in a polymeric form. It is suggested that stocking hTg into globules is defective in colloid nodules, leading to enormous enlargement of the follicle. Cystic: It is estimated that between 15 and 40% of thyroid nodules are partly or entirely cystic. The 'true cyst' is rare; most of the so-called cystic nodules are 'pseudocysts', which follow necrosis and colliquation. Necrosis issues as an imbalance between growth and the precisely regulated process of angiogenesis. More recently, the VEGF/VPF has been found to be at the origin of recent and recurrent cysts. Immunotoxic and apoptotic mechanisms have also been suggested. Chemical analysis of cystic fluid showed a 'denatured' and 'serum-like' pattern suggesting different mechanisms in the pathogenesis of the pseudocystic thyroid nodules. Thyroiditic: Nodular lymphocytic thyroiditis (NLT) includes two different entities: 1) lymphocyte thyroiditis growing as a nodule in a hyperplastic or normal gland, and 2) lymphocyte thyroiditis associated in the same nodule with other nodular diseases of the thyroid: papillary thyroid carcinoma and lymphoma have been found to be associated to chronic lymphocytic thyroiditis.
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PMID:Pathogenesis of thyroid nodules: histological classification? 1123 84

Germline mutations of the von Hippel-Lindau tumor suppressor gene (VHL) in humans causes a hereditary cancer syndrome characterized by the development of retinal and central nervous system hemangioblastomas. Other tumors associated with von Hippel-Lindau disease include clear cell renal carcinomas and pheochromocytomas. Tumor development in this setting is due to functional loss of the remaining wild-type VHL allele. Biallelic VHL inactivation is also common in nonhereditary hemangioblastomas and clear cell renal carcinomas, in keeping with Knudson's 2-Hit Model of carcinogenesis. The VHL gene product, pVHL, is a component of an E3 ubiquitin ligase that targets the alpha subunits of the HIF (hypoxia-inducible factor) transcription factor for destruction in the presence of oxygen. Consequently, tumor cells lacking pVHL overproduce the products of HIF target genes such as vascular endothelial growth factor and transforming growth factor alpha. pVHL has been implicated in a variety of processes that are central to carcinogenesis including cell-cycle control, differentiation, extracellular matrix formation and turnover, and angiogenesis.
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PMID:The von Hippel-Lindau tumor suppressor gene. 1123 28

Angiogenesis is essential for tumour growth and metastasis. The induction of tumour vascularization is mediated by the release of angiogenic peptides. Among these factors, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) are thought to be the most important. Previous experimental studies indicate that the process of apoptosis, the programme of cell death, may be related to angiogenesis in head and neck carcinogenesis. Therefore, cryostat sections of 49 head and neck squamous cell carcinomas (HNSCC) were investigated immunohistochemically for pro-apoptotic factors caspase-3 and Fas ligand (FasL) using a standard streptavidin-biotin complex procedure. Expression of bFGF, VEGF and MMP-9 served as angiogenic markers. Additionally, intratumoral microvascular density (MVD) was counted by immunostaining of endothelial cells using anti-vWF antibody. Comparing the expression of apoptotic and angiogenic factors, a statistically significant inverse correlation of caspase-3 expression and VEGF and MMP-9 expression was found. Concerning FasL, the correlation of its expression with expression of VEGF, bFGF and MMP-9 was inversely correlated. With respect to vWF-immunostaining, statistical analysis gave a clear inverse correlation between the tumour vascularity and the expression of FasL (p = 0.0008) and caspase-3 (p = 0.0068). Our results suggest that HNSCC tumour angiogenesis contributes to a reduction of apoptosis in tumour cells. This may be explained by the activation of pro-apoptotic factors caused by hypoxia.
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PMID:Inverse correlation of apoptotic and angiogenic markers in squamous cell carcinoma of the head and neck. 1129 65

The expression of a primary initiator of tumor angiogenic responses, vascular endothelial growth factor (VEGF), may be induced by nitric oxide (NO) in carcinoma cells. However, the net impact of NO on carcinogenesis remains unclear, because manipulation of NO levels has been shown to either stimulate or inhibit tumor growth. We have investigated the relationship between inducible NO synthase (NOS II), VEGF expression, and growth of B16-F1 melanoma over 14 days in wild-type (NOS II+/+) mice and in those in which the gene for NOS II has been deleted (NOS II-/-). B16-F1 tumor growth was measured as wet weight of the excised tissue. Tumor NOS II and VEGF localization were evaluated by immunohistochemistry, and VEGF mRNA levels were measured by Northern blot analysis. In NOS II+/+ mice inoculated with B16-F1 melanoma cells, macroscopic tumors were always observed at 14 days; however, 22% of NOS II-/- mice had no detectable tumor mass. Immunoreactive NOS II was detected in tumor cells of tumors grown in NOS II+/+ but not in NOS II-/- mice. Although immunoreactive VEGF was detected in the granules of tumor-associated mast cells from both NOS II+/+ and NOS II-/- mice, VEGF mRNA expression in tumors from NOS II-/- was half that in NOS II+/+ mice. Neither NOS II inhibition, exogenous NO, nor peroxynitrite influenced DNA synthesis in culture B16-F1 melanoma cells. The NO donor did not alter either VEGF mRNA levels or degranulation in cultures of the mast cell line RBL-2H3, but peroxynitrite increased both VEGF mRNA expression and degranulation. We conclude that host expression of NOS II contributes to induction of NOS II in the tumor and to melanoma growth in vivo, possibly by regulating the amount and availability of VEGF.
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PMID:Nitric oxide synthase II gene disruption: implications for tumor growth and vascular endothelial growth factor production. 1130 6


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