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PubMedDate not supplied

Bone morphogenetic protein-2 suppresses invasiveness of TSU-Pr1 cells with the inhibition of MMP-9 secretion.

Bone morphogenetic protein (BMP), which is a member of the transforming growth factor beta (TGF-beta) superfamily, has powerful osteoinductive effects and various biological activities in a variety of cells. The effect of BMP-2 on the human carcinoma cell line TSU-Pr1 was examined. BMP-2 was found to inhibit the migration and invasiveness, but not the proliferation, of TSU-Pr1 cells. Gel zymography for matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) detection revealed that BMP-2 down-regulated the activity of MMP-9, but not of MMP-2 or uPA. BMP-2 also reduced the secretion of MMP-9 into the culture media, but did not affect the secretion of MMP-2, Timp-1, Timp-2 or Timp-3. These results suggest that BMP-2 inhibits migration and decreases MMP-9 secretion to suppress the invasiveness of TSU-Pr1 cells. This is the first report of a role for BMP signaling in reducing the invasiveness of cancer cells.

Bone Morphogenetic Protein 2↗
PubMedDate not supplied

Comparison of ID8 MOSE and VEGF-modified ID8 cell lines in an immunocompetent animal model for human ovarian cancer.

Attempts to develop novel immunotherapeutic mouse models have been hampered by the lack of an adequate in vivo system. This study was performed to establish an immunocompetent mouse model for the testing of immunotherapy concepts. The in vivo system was based on a svngeneic mouse ovarian surface epithelium (MOSE) cancer, physiologically and biologically closely resembling human epithelial ovarian cancer. In addition, a more aggressive variant containing a mutated form of vascular epithelial growth factor was also evaluated. The growth patterns of these ovarian cancer cells in mice were compared to the established, highly aggressive 4T1 breast cancer model. A clinically-relevant tool for the study of different growth patterns in ovarian cancer, with potential significance for the development of novel immunological methods, was successfully developed.

Animals↗
PubMed2005

Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition.

Previous experiments with PTK787/ZK222584, a specific inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, using irradiated human FaDu squamous cell carcinoma in nude mice, suggested that radiation-damaged tumor vessels are more sensitive to VEGFR inhibition. To test this hypothesis, the tumor transplantation site (i.e., the right hind leg of nude mice) was irradiated 10 days before transplantation of FaDu to induce radiation damage in the host tissue. FaDu tumors vascularized by radiation-damaged blood vessels appeared later, grew at a slower rate, and showed more necrosis and a smaller vessel area per central tumor section than controls. PTK787/ZK222584 at a daily dose of 50 mg/kg body weight had no impact on growth of control tumors. In contrast, tumors vascularized by radiation-damaged vessels responded to PTK787/ZK222584 with longer latency and slower growth rate than controls, and a trend toward further increase in necrosis, indicating that irradiated tumor vessels are more susceptible to VEGFR inhibition than unirradiated vessels. Although not proving causality, expression analysis of VEGF and VEGFR2 shows that enhanced sensitivity of irradiated vessels to a specific inhibitor of VEGFR tyrosine kinases correlates with increased expression of the molecular target.

Animals↗
PubMed2006

Ectopic activity of fibroblast growth factor receptor 1 in hepatocytes accelerates hepatocarcinogenesis by driving proliferation and vascular endothelial growth factor-induced angiogenesis.

Fibroblast growth factor (FGF) signaling mediates cell-to-cell communication in development and organ homeostasis in adults. Of the four FGF receptor (FGFR) tyrosine kinases, only FGFR4 is expressed in mature hepatocytes. Although FGFR1 is expressed by hepatic cell progenitors and adult nonparenchymal cells, ectopic expression is commonly observed in hepatoma cells. Here, we determined whether ectopic FGFR1 is a cause or consequence of hepatocellular carcinoma by targeting a constitutively active human FGFR1 to mouse hepatocytes. Livers of transgenic mice exhibited accelerated regeneration after partial hepatectomy but no signs of neoplastic or preneoplastic abnormalities for up to 18 months. However, in diethylnitrosamine-treated mice, the chronic FGFR1 activity promoted an incidence of 44% adenomas at 4 months and 38% hepatocellular carcinoma at 8 months. No adenoma or hepatocellular carcinoma was observed in diethylnitrosamine-treated wild-type (WT) livers at 4 or 8 months, respectively. At 10 and 12 months, tumor-bearing livers in transgenic mice were twice the size of those in WT animals. Isolated hepatoma cells from the transgenic tumors exhibited a growth advantage in culture. Advanced hepatocellular carcinoma in the transgenic livers exhibited a reduced rate of necrosis. This was accompanied by a mean microvessel density of 2.7 times that of WT tumors and a markedly higher level of vascular endothelial growth factor. In cooperation with an initiator, the persistent activity of ectopic FGFR1 in hepatocytes is a strong promoter of hepatocellular carcinoma by driving cell proliferation at early stages and promoting neoangiogenesis at late stages of progression.

Animals↗
PubMed2005

Angiogenesis inhibition by vascular endothelial growth factor receptor-2 blockade reduces stromal matrix metalloproteinase expression, normalizes stromal tissue, and reverts epithelial tumor phenotype in surface heterotransplants.

Inhibition of vascular endothelial growth factor (VEGF) signaling, a key regulator of tumor angiogenesis, through blockade of VEGF receptor (VEGFR)-2 by the monoclonal antibody DC101 inhibits angiogenesis, tumor growth, and invasion. In a surface xenotransplant assay on nude mice using a high-grade malignant squamous cell carcinoma cell line (A-5RT3), we show that DC101 causes vessel regression and normalization as well as stromal maturation resulting in a reversion to a noninvasive tumor phenotype. Vessel regression is followed by down-regulation of expression of both VEGFR-2 and VEGFR-1 on endothelial cells and increased association of alpha-smooth muscle actin-positive cells with small vessels indicating their normalization, which was further supported by a regular ultrastructure. The phenotypic regression of an invasive carcinoma to a well-demarcated dysplastic squamous epithelium is accentuated by the establishment of a clearly structured epithelial basement membrane and the accumulation of collagen bundles in the stabilized connective tissue. This normalization of the tumor-stroma border coincided with down-regulated expression of the stromal matrix metalloproteinases 9 and 13, which supposedly resulted in attenuated turnover of extracellular matrix components permitting their structural organization. Thus, in this mouse model of a human squamous cell carcinoma cell line, blockade of VEGF signaling resulted in the reversion of the epithelial tumor phenotype through stromal normalization, further substantiating the crucial role of stromal microenvironment in regulating the tumor phenotype.

Animals↗
PubMed2006

A mechanism-based combination therapy reduces local tumor growth and metastasis in an orthotopic model of prostate cancer.

Therapy-induced stimulation of angiogenic molecules can promote tumor angiogenesis leading to enhanced tumor growth and cancer metastasis. Several standard and emerging therapies, such as radiation and photodynamic therapy (PDT), can induce angiogenic molecules, thus limiting their effectiveness. PDT is approved for the treatment of several cancers; however, its induction of vascular endothelial growth factor (VEGF) creates conditions favorable to enhanced tumor growth and metastasis, therefore mitigating its cytotoxic and antivascular effects. This is the first report showing that subcurative PDT in an orthotopic model of prostate cancer (LNCaP) increases not only VEGF secretion (2.1-fold) but also the fraction of animals with lymph node metastases. PDT followed by administration of an antiangiogenic agent, TNP-470, abolished this increase and reduced local tumor growth. On the other hand, administration of TNP-470 before PDT was less effective at local tumor control. In addition, animals in all groups, except in the PDT + TNP-470 group, had a weight loss of >3 g at the time of sacrifice; the weight of the animals in the PDT + TNP-470 group did not change. The significant reduction (P < 0.05) in tumor weight and volume observed between the PDT + TNP-470 group and the control group suggests that the combination of PDT and antiangiogenic treatment administered in the appropriate sequence was not only more effective at controlling local tumor growth and metastases but also reduced disease-related toxicities. Such molecular response-based combinations merit further investigations as they enhance both monotherapies and lead to improved treatment outcomes.

Angiogenesis Inhibitors↗
PubMed2006

Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding.

Hypoxia-inducible factor-alpha (Hif-alpha) plays an important role in tumor growth by increasing resistance to apoptosis and the production of angiogenic factors, such as vascular endothelial growth factor (VEGF). Therefore, Hif-alpha is an attractive target for development of novel cancer therapeutics. We have generated Chinese hamster ovary cells, which stably express luciferase reporter construct under the control of a hypoxia response element to screen 15,000 compounds. We identified 40 compounds that inhibited hypoxic up-regulation of luciferase, and the top 30 compounds were further screened in a secondary assay using MDA-468 breast cancer cell line. Eight compounds were shown to inhibit VEGF expression in hypoxic cells at subtoxic concentrations. Three top putative Hif inhibitors, DJ12, DJ15, and DJ30, were chosen for further analysis. Transient transfection of cells with hypoxia-regulated luciferase reporter plasmids further validated that these compounds inhibit hypoxia up-regulated genes. All three compounds failed to inhibit Hif-1alpha protein levels but they did inhibit induction of downstream targets of Hif-alpha under hypoxia. Two of the three compounds were cell type specific, whereas compound DJ12 inhibited VEGF at subtoxic levels in breast cancer cell lines MDA-468 and ZR-75, melanoma cell line MDA-435, and pVHL mutant renal cancer cell lines RCC4 and 786-0. Compound DJ12 down-regulated mRNA of downstream targets of Hif-alpha, and significantly inhibited Hif-1alpha transactivation activity by blocking Hif-1alpha hypoxia response element-DNA binding. Our cell-based approach and deconvolution of the inhibitory effect of DJ12 has identified a novel compound that targets the hypoxia pathway by inhibiting Hif-alpha-inducible transcription.

Animals↗
PubMed2006

Functional thyrotropin receptor attenuates malignant phenotype of follicular thyroid cancer cells.

Thyrotropin (TSH) is a thyroid-specific growth factor inducing differentiated function and growth of thyrocytes in vitro. In thyroid cancer, loss of TSH-receptor (TSHR) expression is a sign of de-differentiation and is believed to contribute to the malignant phenotype. The present studies aimed to determine the in vitro and in vivo effects of functioning TSHR in the follicular thyroid cancer cell line HTC, a subclone of FTC133 cells, lacking endogenous expression of TSHR, and HTCtshr+ cells transfected with human TSHR-cDNA. HTCtshr+ cells grew faster in vitro (doubling time 1.15 vs 1.56 d, p < 0.05) and TSH caused a dose-dependent growth response. Adhesion to and invasion through reconstituted basement membrane were reduced in HTCtshr+ cells, but when stimulated with TSH increased to levels comparable to naïve HTC cells. In vivo, tumor latency was 11 d for naïve HTC as compared to 21 d for HTCtshr+ xenografts. Smaller tumor volumes were registered for HTCtshr+ cells (250 +/- 217 vs 869 +/- 427 mm3, p < 0.05). Angiogenesis, as determined by vascular surface density (VSD) of experimental tumors, was enhanced in naïve HTC tumors (VSD 0.87 +/- 0.1 microm-1 vs 0.55 +/- 0.2 microm-1 in HTCtshr+, p < 0.05). VEGF secretion was more pronounced in naïve HTC cells stimulated with EGF, than in HTCtshr+ cells stimulated with either TSH or EGF. In conclusion, regained expression of functional TSHR in the follicular thyroid cancer cell line HTC alters in vitro features commonly associated with the malignant phenotype. Smaller tumors and reduced angiogenesis of xenotransplanted HTC cells with functioning TSHR suggest a less aggressive in vivo phenotype. The present data highlight the pivotal role of TSHR to affect transformed thyrocytes in vitro and in vivo. They also suggest a role for EGF as a modulator of angiogenesis in thyrocytes devoid of TSHR.

Adenocarcinoma, Follicular↗
PubMed2006

Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1.

Hypoxia-inducible factor-1 (HIF-1) has a central role in cellular responses to hypoxia, including the transcriptional activation of a number of genes involved in angiogenesis in tumors. We found that curcumin, a natural, biologically active compound isolated from the commonly used spice turmeric, significantly decreases hypoxia-induced HIF-1alpha protein levels in HepG2 hepatocellular carcinoma cells. Moreover, curcumin suppressed the transcriptional activity of HIF-1 under hypoxia, leading to a decrease in the expression of vascular endothelial growth factor (VEGF), a major HIF-1 target angiogenic factor. Curcumin also blocked hypoxia-stimulated angiogenesis in vitro and down-regulated HIF-1alpha and VEGF expression in vascular endothelial cells. These findings suggest that curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1alpha-mediated angiogenesis.

Cell Growth Processes↗
PubMed2004

Functional genomics of cell elongation in developing cotton fibers.

Cotton fibers are single-celled seed trichomes of major economic importance. Factors that regulate the rate and duration of cell expansion control fiber morphology and important agronomic traits. For genetic characterization of rapid cell elongation in cotton fibers, approximately 14,000 unique genes were assembled from 46,603 expressed sequence tags (ESTs) from developmentally staged fiber cDNAs of a cultivated diploid species ( Gossypium arboreum L.). Conservatively, the fiber transcriptome represents 35-40% of the genes in the cotton genome. In silico expression analysis revealed that rapidly elongating fiber cells exhibit significant metabolic activity, with the bulk of gene transcripts, represented by three major functional groups - cell wall structure and biogenesis, the cytoskeleton and energy/carbohydrate metabolism. Oligonucleotide microarrays revealed dynamic changes in gene expression between primary and secondary cell wall biogenesis showing that fiber genes in the dbEST are highly stage-specific for cell expansion - a conclusion supported by the absence of known secondary cell wall-specific genes from our fiber dbEST. During the developmental switch from primary to secondary cell wall syntheses, 2553 "expansion-associated" fiber genes are significantly down regulated. Genes (81) significantly up-regulated during secondary cell wall synthesis are involved in cell wall biogenesis and energy/carbohydrate metabolism, which is consistent with the stage of cellulose synthesis during secondary cell wall modification in developing fibers. This work provides the first in-depth view of the genetic complexity of the transcriptome of an expanding cell, and lays the groundwork for studying fundamental biological processes in plant biology with applications in agricultural biotechnology.

Cell Growth Processes↗
PubMed2005

Down-regulation of Cx43 by retroviral delivery of small interfering RNA promotes an aggressive breast cancer cell phenotype.

Connexins are gap junction proteins that assemble into channels that mediate direct intercellular communication. Connexins are well-documented tumor suppressors and are thought to regulate both cell growth and differentiation. As previously reported, most human breast tumors and cell lines down-regulate gap junctions or have defective gap junctional intercellular communication. Furthermore, overexpression of connexins in breast cancer cells inhibits tumor growth in vivo. In this study, we hypothesize that controlled Cx43 down-regulation would induce breast tumor cells to acquire a more aggressive phenotype. Here we report that Cx43 was down-regulated in both normal rat kidney (NRK) cells and human breast cancer cell lines (MDA-MB-231 and Hs578T) by transfection with chemically synthesized small interfering RNA (siRNA) or short hairpin RNA generated from a retroviral infection. Furthermore, we show that retroviral delivery and expression of siRNA directed to different coding regions of Cx43 resulted in differential levels of Cx43 silencing and impaired gap junctional intercellular communication. Cx43-silenced Hs578T cells grew faster and were more migratory. Finally, Western blot analysis revealed that down-regulation of Cx43 resulted in decreased expression of thrombospondin-1, an antiangiogenesis molecule, and increased expression of vascular endothelial growth factor. Taken together, these results suggest that Cx43 is required for maintaining cell differentiation and the regulation of molecules important in angiogenesis.

Animals↗
PubMed2006

The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells.

Transforming growth factor beta (TGF-beta) can act as suppressor and promoter of cancer progression. Intracellular Smad proteins (i.e., receptor regulated Smads and common mediator Smad4) play a pivotal role in mediating antimitogenic and proapoptotic effects of TGF-beta, but their function in TGF-beta-induced invasion and metastasis is unclear. Here, we have investigated the role of Smad4 in a cellular and mouse model for TGF-beta-induced breast cancer progression. Consistent with its tumor suppressor function, specific silencing of Smad4 in NMuMG mammary gland epithelial cells using small hairpin RNA (shRNA)-expressing RNAi vectors strongly mitigated TGF-beta-induced growth inhibition and apoptosis. Smad4 knockdown also potently inhibited TGF-beta-induced epithelial to mesenchymal transition of NMuMG cells as measured by morphologic transformation from epithelial to fibroblast-like cells, formation of stress fibers, inhibition of E-cadherin expression, and gain of expression of various mesenchymal markers. Furthermore, we show that knockdown of Smad4 in MDA-MB-231 breast cancer cells strongly inhibited the frequency of bone metastasis in nude mice by 75% and significantly increased metastasis-free survival. Communication of MDA-MB-231 cells with the bone microenvironment, which is needed for optimal tumor cell growth and metastasis, may be affected in Smad4 knockdown cells as TGF-beta-induced expression of interleukin 11 was attenuated on Smad4 knockdown. Taken together, our results show that Smad4 plays an important role in both tumor suppression and progression of breast cancer cells.

Animals↗
PubMed2004

Overexpression of estrogen receptor-alpha in the endometrial carcinoma cell line Ishikawa: inhibition of growth and angiogenic factors.

BACKGROUND: A high level of estrogen receptor-alpha (ER-alpha) is believed to be favorable in the prognosis and treatment of endometrial, ovarian, and breast cancer. High levels of ER-alpha have been shown to inhibit the growth and invasive, metastatic potential of breast cancer cell lines. To bring about these inhibitory effects, ER-alpha probably acts through other cellular factors involved in the regulation of cell growth. OBJECTIVE: To investigate the role of high levels ER-alpha in growth inhibition of endometrial cancer cells. METHODS: A human ER-alpha cDNA was stably overexpressed in an endometrial cancer cell line, namely, Ishikawa. ER-alpha-overexpressing, parent, and control Ishikawa cells were grown in vitro and their growth rates were compared by cell count. ER-alpha-overexpressing and parent Ishikawa cells were also grown in vitro as tumors in a chicken chorioallantoic membrane (CAM) model, and tumor growth and angiogenesis was measured. Finally, levels of angiogenesis-modulating factors, nitric oxide synthase (NOS), and vascular endothelial growth factor (VEGF) were examined in relation to ER overexpression. RESULTS: The growth of Ishikawa cells was found inhibited in culture as well as in the CAM model. Angiogenesis of CAM tumors was also found inhibited in ER-overexpressing cells. Angiogenic factor VEGF was inhibited whereas the activity of NOS was found elevated following ER overexpression. CONCLUSION: Our work on the Ishikawa cell line indicates that high levels of ER-alpha in endometrial cancer may inhibit cancer growth by modulating angiogenic factors, thereby limiting the blood supply to the growing tumor. Our results support the earlier data from other groups that have shown a positive correlation between high ER content and better prognosis of endometrial cancers.

Animals↗
PubMed2005

Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo.

Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in approximately 70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo. Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G1 and G2, and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the effect of perifosine in combination with temozolomide. We observed an enhanced effect when both were used in culture. With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice. Animal studies showed that perifosine and temozolomide combination therapy was more effective than temozolomide treatment alone (P < 0.01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic.

Animals↗
PubMed2005

Gene therapeutic exploration: retrovirus-mediated soluble vascular endothelial growth factor receptor-2 (sFLK-1) inhibits the tumorigenicity of S180, MCF-7, and B16 cells in vivo.

Inhibition of tumor angiogenesis is an anticancer strategy in which neovasculature is targeted because tumor progression relies on neovascularization. The soluble, truncated form of vascular endothelial growth factor receptor-2 (VEGFR-2), sFLK-1, is a well-known inhibitor of endothelial cells. This kind of soluble receptor retains its high-affinity binding to VEGF, but cannot work with the receptor tyrosine transphosphorylation and activation of downstream signal transduction to induce endothelial proliferation due to the lack of the tyrosine kinase domain. Therefore, we tried to use this sFLK-1 as an inhibitor for malignant tumor gene therapy. In this study we transferred a soluble VEGFR-2 (sFLK-1) from embryo mouse liver by RT-PCR to PA317 cells through retroviral vector (pLXSN) and obtained stable expression. NIH3T3 cells were used for measuring the virus titer. The virus titer in this experiment was 2 x 10(7) CFU/ml. After 7 days of preparing subcutaneous tumor models bearing S180, MCF-7, and B16 cells in mice, respectively, 2 x 10(7) PFU of recombinant retroviruses were injected locally into the tumors the treatment groups. After treatment, the tumor size and weight were significantly smaller than that of control (p < 0.05). After autopsy, the metastasic focus numbers in the treatment groups were also less than control groups. We also measured VEGFR-2 expression in tumor tissues by Western blot to check if sFLK-1 had been integrated into the cells of tumor tissues. Expression in the treatment groups was significantly greater than that of control groups (p < 0.001). Microvessel density (MVD) and proliferative cell nuclear antigen (PCNA) were investigated to determine whether the Re-sFLK-1 fragment had the ability to inhibit tumor angiogenesis and proliferation in mice bearing S180 and MCF-7 cells. The results showed that MVD and PCNA in th e treatment groups werelower than in control groups. There were significant difference between treatment groups and control groups (p < 0.0001). The results indicated that retroviral-mediated sFLK-1 gene therapy in animal tumor models has significant therapeutic effect.

Animals↗
PubMed2005

Root responses to soil physical conditions; growth dynamics from field to cell.

Root growth in the field is often slowed by a combination of soil physical stresses, including mechanical impedance, water stress, and oxygen deficiency. The stresses operating may vary continually, depending on the location of the root in the soil profile, the prevailing soil water conditions, and the degree to which the soil has been compacted. The dynamics of root growth responses are considered in this paper, together with the cellular responses that underlie them. Certain root responses facilitate elongation in hard soil, for example, increased sloughing of border cells and exudation from the root cap decreases friction; and thickening of the root relieves stress in front of the root apex and decreases buckling. Whole root systems may also grow preferentially in loose versus dense soil, but this response depends on genotype and the spatial arrangement of loose and compact soil with respect to the main root axes. Decreased root elongation is often accompanied by a decrease in both cell flux and axial cell extension, and recent computer-based models are increasing our understanding of these processes. In the case of mechanical impedance, large changes in cell shape occur, giving rise to shorter fatter cells. There is still uncertainty about many aspects of this response, including the changes in cell walls that control axial versus radial extension, and the degree to which the epidermis, cortex, and stele control root elongation. Optical flow techniques enable tracking of root surfaces with time to yield estimates of two-dimensional velocity fields. It is demonstrated that these techniques can be applied successfully to time-lapse sequences of confocal microscope images of living roots, in order to determine velocity fields and strain rates of groups of cells. In combination with new molecular approaches this provides a promising way of investigating and modelling the mechanisms controlling growth perturbations in response to environmental stresses.

Acclimatization↗
PubMed2005

Erythropoietin disrupts hypoxia-inducible factor signaling in ovarian cancer cells.

OBJECTIVE: The objective of this study was to evaluate the effects of recombinant erythropoietin (EPO) on HIF-1alpha induced angiogenic pathways in ovarian cancer cells. METHODS: Using Western blots and both quantitative and non-quantitative RT-PCR, HIF-1alpha protein and VEGF transcription levels were assessed. Cell growth was measured using flow cytometry. RESULTS: EPO treatment decreased hypoxia-induced HIF-1alpha protein levels and VEGF transcription, with no effect on cell growth. Inhibition of HIF-1alpha signaling by EPO was also observed in MCF-7 breast cancer cells. CONCLUSION: These novel findings suggest that EPO may exhibit anti-angiogenic properties, thus encouraging further exploration of signaling pathways between EPO and HIF-1alpha.

Cell Growth Processes↗
PubMed2005

Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors.

Activating mutations of the B-RAF gene are observed in >60% of human melanomas. Approximately 90% of these mutations occur in the activation segment of the kinase domain as a single-base substitution that converts a valine to glutamic acid at codon 599 (V599E) in exon 15. This mutation causes activation of the kinase as well as downstream effectors of the mitogen-activated protein kinase-signaling cascade, leading to melanoma tumor development by an as yet unknown mechanism. In this study, we have identified the role of (V599E)B-Raf in melanoma tumor development by characterizing the mechanism by which this mutant protein promotes melanoma tumorigenesis. Small interfering RNA targeted against B-Raf or a Raf kinase inhibitor (BAY 43-9006) was used to reduce expression and/or activity of (V599E)B-Raf in melanoma tumors. This inhibition led to reduced activity of the mitogen-activated protein kinase-signaling cascade and inhibited tumor development in animals. Targeted reduction of mutant (V599E)B-Raf expression (activity) in melanoma cells before tumor formation inhibited tumorigenesis by reducing the growth potential of melanoma cells. In contrast, reduction of mutant (V599E)B-Raf activity in preexisting tumors prevented further vascular development mediated through decreased vascular endothelial growth factor secretion, subsequently increasing apoptosis in tumors. These effects in combination with reduced proliferative capacity halted growth, but did not shrink the size of preexisting melanoma tumors. Thus, these studies identify the mechanistic underpinnings by which mutant (V599E)B-RAF promotes melanoma development and show the effectiveness of targeting this protein to inhibit melanoma tumor growth.

Animals↗