Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatoma-derived growth factor (HDGF) is highly expressed in tumor cells, and stimulates their proliferation. In the present study, we investigated the role of HDGF in tumorigenesis and elucidated the mechanism of action. Stable transfectants of NIH3T3 cells overexpressing HDGF did not show significant anchorage-independent growth in soft agar assay. However, these stable transfectants overexpressing HDGF generated sarcomatous tumors in nude mice. These tumors were red-colored macroscopically, and histologically showed a rich vascularity. Immunohistochemical analysis using CD31 antibody showed new vessel formation. Recombinant HDGF stimulated proliferation of human umbilical vein endothelial cells in a dose-dependent manner, and stimulated tubule formation. Furthermore, vascular endothelial growth factor (VEGF) was detected immunohistochemically in the tumor tissues. Transient expression of HDGF induced both VEGF gene and protein expression as demonstrated by a reporter assay using VEGF gene promoter. The administration of anti-VEGF neutralizing antibody significantly suppressed, but did not block, the tumor growth of HDGF-overexpressing cells in nude mice. Thus, these findings suggested that HDGF-induced tumor formation in vivo involves induction of VEGF as well as direct angiogenic activity.
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PMID:Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor. 1466 17

Ovarian cancer is believed to develop from the ovarian surface epithelium through the accumulation of aberrations of oncogenes and/or tumor suppressor genes. However, it is unclear how the gene abnormalities are involved in ovarian carcinogenesis. To elucidate the process, we transfected genes reported to show their abnormalities in human ovarian cancers into human ovarian surface epithelial cells. Immortalization of the cells was achieved by the transfection of SV40 large T antigen (LT) and human telomerase reverse transcriptase (hTERT); however, the resultant cells showed no tumorigenesis. Additional transfection of either c-erbB-2 or mutant Ha-ras into the immortalized cells showed the anchorage-independent growth and tumorigenesis in mice with the incidence of 50% and 40%, respectively. Histologically, all the tumours were undifferentiated. In association with the tumorigenesis, the cells expressing c-erbB-2 or mutant Ha-ras demonstrated increased vascular endothelial growth factor secretion under hypoxia and enhanced resistance to apoptosis compared with the immortalized cells. Collectively, the introduction of either c-erbB-2 or mutant Ha-ras in the cells, which were efficiently immortalized by the transfection of LT and hTERT, showed tumorigenicity, suggesting that c-erbB-2 or mutant Ha-ras genes might be involved in ovarian carcinogenesis.
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PMID:C-erbB-2 or mutant Ha-ras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro. 1467 9

Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C>T) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C>T homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1alpha (HIF-1alpha), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, VHL 598C>T homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P <.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL syndrome were not found, suggesting that overexpression of HIF-1alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in VHL 598C>T homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.
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PMID:Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. 1472 98

We aimed to evaluate the prognostic significance of microvessel density (MVD), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGFbeta), as well as to find out the relationship between MVD, and VEGF and TGFbeta in epithelial ovarian cancer (EOC). Surgical specimens of 47 patients with stage I-IV primary EOC, who underwent extended surgical staging according to FIGO, were investigated. Five- micro m thick tissue sections were immunostained with antibody to factor VIII-related antigen, and MVD was assessed at three separate areas of x200 magnification. Expressions for VEGF and TGFbeta were evaluated by immunohistochemical staining using related monoclonal antibodies. Results were correlated with clinicopathologic factors and survival. We did not find any correlation between MVD and clinicopathologic factors, or patient survival. Similarly, there was no association between the degree of VEGF staining and survival or clinicopathologic factors, except preoperative ascites volume, which was higher in patients showing moderate and intense VEGF staining than those with weak VEGF staining (P = 0.052). The expression of TGFbeta was inversely correlated with preoperative CA-125 levels (P < 0.05). Furthermore, there was no correlation between MVD and the staining intensity of VEGF or TGFbeta. In conclusion, angiogenesis does not appear as a prognostic factor in EOC. We suggest that VEGF is an important mediator of ascites formation, and that TGFbeta, which is supposed to have tissue-specific actions in tumorigenesis, may have growth-inhibitory functions in EOC.
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PMID:Prognostic significance of tumor angiogenesis in epithelial ovarian cancer: in association with transforming growth factor beta and vascular endothelial growth factor. 1476 33

PC cell-derived growth factor, also known as progranulin, is an M(r) 88,000 growth factor (referred as PCDGF/GP88) overexpressed in human breast cancer. Antisense inhibition of PCDGF/GP88 expression in MDA-MB-468 cells inhibited tumor formation in nude mice. In estrogen receptor-positive cells, PCDGF/GP88 was expressed in response to estradiol and shown to mediate its mitogenic effect. Pathologic studies indicated that PCDGF/GP88 was expressed in 80% of invasive ductal carcinomas in correlation with parameters of poor prognosis. In the present article, the relationship between PCDGF/GP88 expression and tamoxifen resistance was examined in MCF-7 cells. PCDGF/GP88 overexpression rendered MCF-7 cells able to proliferate in the absence of estrogen and in the presence of tamoxifen. The PCDGF/GP88-overexpressing cells formed tumors in ovariectomized nude mice in the absence of estradiol and in its presence, in contrast to MCF-7 cells. Tumor growth of the overexpressing cells was increased significantly when the mice were treated with tamoxifen. PCDGF/GP88 blocked tamoxifen-induced apoptosis by preventing down-regulation of bcl-2 expression and poly(ADP-ribose) polymerase cleavage. In addition, PCDGF/GP88-overexpressing cells presented higher level of the angiogenic factors vascular endothelial growth factor and angiopoietin-1 than MCF-7 control cells. Tamoxifen treatment additionally increased the level of vascular endothelial growth factor. These studies suggest that PCDGF/GP88 plays a critical role in breast cancer tumorigenesis and in the transition to estrogen independence and tamoxifen resistance, a hallmark of poor prognosis. On the basis of the in vivo studies, it is postulated that tamoxifen treatment of patients with estrogen receptor-positive breast tumors overexpressing PCDGF/GP88 could have adverse clinical consequences.
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PMID:PC cell-derived growth factor mediates tamoxifen resistance and promotes tumor growth of human breast cancer cells. 1499 34

Akt signaling is involved in tumorigenesis via a number of different mechanisms that result in increased proliferation and decreased apoptosis. Previous data have demonstrated that Akt-mediated signaling is functionally involved in keratinocyte transformation. This work investigates the involvement of angiogenesis as a mediator of tumorigenesis in Akt-transformed keratinocytes. Tumors produced by subcutaneous injection of the latter showed increased angiogenic profiles associated with increased vascular endothelial growth factor (VEGF) protein levels. However, in contrast to v-ras(Ha)-transformed keratinocytes, VEGF mRNA levels were not increased. The induction of VEGF protein by Akt is associated with increased phosphorylation and thus activation of p70S6K and eIF4E-binding protein 1, leading to increased VEGF translation. In addition, we observed increased metaloproteinases 2 and 9 expression, but not thrombospondin 1, in tumors derived from Akt-transformed keratinocytes. Collectively, these results demonstrate that Akt is an important mediator of angiogenesis in malignant keratinocytes through a post-transcriptional mechanism.
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PMID:Akt mediates an angiogenic switch in transformed keratinocytes. 1500 36

Angiogenesis, which plays a key role in the development of astrocytic gliomas, depends on the local balance between various molecules that induce and inhibit neovascularization. Whereas recent experimental studies have indicated that cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) regulate angiogenesis by modulating vascular endothelial growth factor (VEGF) production, little is known about the relationships among expression of these markers, angiogenesis, and clinical outcome in astrocytic glioma cases. We therefore examined immunohistochemical expression of COX-2, iNOS, and VEGF in 51 high-grade astrocytomas including 31 glioblastomas (grade IV) and 20 anaplastic astrocytomas (grade III), 49 low-grade astrocytomas (grade II), and 43 reactive astrogliosis specimens, and determined the relationship with microvessel density (MVD) and prognostic significance. Stepwise increase of immunoreactive scores for COX-2, iNOS, and VEGF was found from astrogliosis, through low-grade to high-grade astrocytoma. The COX-2 expression strongly correlated with iNOS, VEGF, and high MVD, both overall and in all tumors, whereas iNOS expression was weakly associated with VEGF and high MVD. Univariate analysis revealed a significant association between COX-2 overexpression and a poor outcome. The findings for COX-2 and VEGF-related angiogenesis raise the possibility that the COX-2 pathway may contribute to astrocytic tumorigenesis by promoting new vessel formation with prognostic implications.
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PMID:Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance. 1508 99

The contribution of the mRNA cap-binding protein, eIF-4E, to malignant transformation and progression has been illuminated over the past decade. eIF-4E overexpression has been demonstrated in human tumors of the breast, head and neck, colon, prostate, bladder, cervix and lung, and has been related to disease progression. Overexpression of eIF-4E in experimental models dramatically alters cellular morphology, enhances proliferation and induces cellular transformation, tumorigenesis and metastasis. Conversely, blocking eIF-4E function by expression of antisense RNA, or overexpression of the inhibitory eIF-4E binding proteins (4E-BPs), suppresses cellular transformation, tumor growth, tumor invasiveness and metastasis. Although eIF-4E regulates the recruitment of mRNA to ribosomes, and thereby globally regulates cap-dependent protein synthesis, eIF-4E contributes to malignancy by selectively enabling the translation of a limited pool of mRNAs--those that generally encode key proteins involved in cellular growth, angiogenesis, survival and malignancy (e.g. cyclin D1, c-myc, vascular endothelial growth factor, matrix metalloprotease 9). A deeper understanding of the role of eIF-4E in regulating the translation of the diverse gene products involved in all aspects of malignancy will improve the capacity to exploit eIF-4E as a therapeutic target and as a marker for human cancer progression.
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PMID:eIF-4E expression and its role in malignancies and metastases. 1509 68

The antioxidant N-acetyl-cysteine (NAC) has been shown to be chemopreventive in clinical studies, and in recent studies, has shown promise in preventing tumor progression. Although the effects of NAC on tumorigenesis have been associated with decreased angiogenesis, the mechanism of the anti-angiogenic activity has not been determined. In the following study, we describe a novel mechanism whereby NAC therapy blocks MDA-MB-435 breast carcinoma cell proliferation and metastasis in an in vivo tumorigenic model. Athymic nude mice bearing MDA-MB-435 xenografts were treated with systemic NAC daily for 8 weeks. NAC treatment resulted in endothelial cell apoptosis and reduction of microvascular density within the core of the tumor leading to significant tumor cell apoptosis/necrosis. Angiostatin accumulated in tumors from NAC-treated but not control animals. Additional studies using a vascular endothelial growth factor-dependent chicken chorioallantoic membrane angiogenic assay recapitulated NAC-induced endothelial apoptosis and coordinate production of angiostatin, a potent endothelial apoptotic factor. In vitro studies showed angiostatin was formed in endothelial cultures in a vascular endothelial growth factor- and NAC-dependent manner, a process that requires endothelial cell surface plasminogen activation. These results suggest that systemic NAC therapy promotes anti-angiogenesis through angiostatin production, resulting in endothelial apoptosis and vascular collapse in the tumor.
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PMID:N-acetyl-cysteine promotes angiostatin production and vascular collapse in an orthotopic model of breast cancer. 1511 15

Previous experiments have shown that a vascular endothelial growth factor (VEGF)-DT385 toxin conjugate inhibits endothelial cell proliferation, angiogenesis and solid tumor growth in a xenotransplant model system. Here, we report that VEGF-DT385 toxin conjugate effectively inhibits spontaneous tumorigenesis. The C3(1)/SV40 TAg transgenic mouse model of mammary gland carcinogenesis was used to determine the effectiveness of VEGF-DT385 toxin conjugate in delaying the onset of disease and the development of solid tumors. Animals were treated daily with conjugate for a period of 7 days. Therapy was initiated at week 14 of development before any visible adenocarcinomas were evident. Treatment of mice with VEGF-DT385 toxin conjugate significantly delayed the onset of tumorigenesis and inhibited solid tumor growth by more than 92%. Furthermore, conjugate treated animals showed less than twice the number of tumor nodules when compared to control mice. Finally, this vascular targeting agent significantly increased survival time of animals by 5 weeks. VEGF-DT385 toxin conjugate resulted in temporary weight loss and no long-lasting toxicity was seen. More importantly, using this established tumor model, VEGF-DT385 toxin conjugate appeared to be as effective as a similar treatment schedule with recombinant human endostatin. Our results suggest that VEGF-DT385 toxin conjugate is a potent inhibitor of mammary adenocarcinoma growth and might be useful in breast cancer therapy.
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PMID:VEGF-DT385 toxin conjugate inhibits mammary adenocarcinoma development in a transgenic mouse model of spontaneous tumorigenesis. 1511 74


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