Growth factor regulation of secreted matrix metalloproteinase and plasminogen activators in prostate cancer cells, normal prostate fibroblasts and normal osteoblasts

Forbes, Katie; Webb, M A; Sehgal, Inder

doi:10.1038/sj.pcan.4500640

Cited by 13 publications

(10 citation statements)

References 41 publications

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“…This complex process requires proliferation, migration, and structural modification of endothelial cells, which are regulated by pro-angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) ( 3 ). Further, either alone or in combination, these two factors stimulate proteases and plasminogen activators in tumor tissues to degrade the basement membrane, which promotes tumor metastasis and endothelial cells recruitment for neovascularization ( 4 ). In addition, bFGF and VEGFA can synchronize platelet-derived growth factor (PDGF) and its receptor synergistically to facilitate blood vessel formation by modulating their expression and activation ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

et al. 2020

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Tumor angiogenesis is dependent on growth factors, and inhibition of their pathways is one of the promising strategies in cancer therapy. However, resistance to single pathway has been a great concern in clinical trials so that it necessitates multiple targetable factors for developing tumor angiogenesis inhibitors. Moreover, the strategy of Fc fusion protein is an attractive platform for novel peptide agents, which gains increasing importance with FDA approval because of better immunogenicity and stability. Here, we applied the Fc fusion protein concept to bFGF/VEGFA pathways and designed a multi-epitope Peptibody with immunogenic peptides derived from human bFGF and VEGFA sequences. Immunization with Peptibody could elicit high-titer anti-bFGF and anti-VEGFA antibodies, activate T cells, and induce Th1/Th2-type cytokines. In in vitro experiments, the isolated anti-Peptibody antibody inhibited the proliferation and migration of A549 cells and human umbilical vein endothelial cells (HUVECs) by decreasing the MAPK/Akt/mTOR signal pathways. In the murine tumor model, pre-immunization with Peptibody suppressed the tumor growth and neovascularization of lung cancer by decreasing the production of bFGF/VEGFA/PDGF, the MAPK/Akt/mTOR signal pathways, and the activation of suppressive cells in tumor sites. Further, the biological characterizations of the recombinant Peptibody were investigated systematically, including protein primary structure, secondary structure, stability, and toxicity. Collectively, the results highlighted the strategy of bFGF/VEGFA pathways and Fc fusion protein in suppressing tumor progression and angiogenesis, which emphasized the potential of multiple targetable factors for producing enduring clinical responses in tumor patients.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

et al. 2020

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“…Compared to control HMFs, treated with HMF cell conditioned media (HMFCM), HMFs treated with 102 cell conditioned media (102CM) exhibited significantly increased levels of several genes that have been previously associated with activated fibroblasts present in inflammatory situations and CAFs: MMP-1, MMP-3, IL-8, and SDF-1 (3, 8, 18, 45, 46) (Figure 2A). Notably, these genes also promote breast cancer invasion and metastasis (13, 36, 43, 47).…”

Section: Resultsmentioning

confidence: 99%

CXCR4 and Matrix Metalloproteinase-1 Are Elevated in Breast Carcinoma–Associated Fibroblasts and in Normal Mammary Fibroblasts Exposed to Factors Secreted by Breast Cancer Cells

Eck

Côté

Winkelman

et al. 2009

Molecular Cancer Research

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The complex molecular communications that occur between neoplastic and stromal cells within the tumor microenvironment play an integral role in breast cancer pathogenesis. Carcinoma-associated fibroblasts (CAF) produce tumor-enhancing factors and have been strongly implicated in breast cancer development. Similar to the way in which tumors have been compared with "wounds that never heal," CAFs have been equated to activated fibroblasts, which are present in inflammatory environments, in which they aid in wound healing through tissue remodeling and repair. Matrix metalloproteinase-1 (MMP-1) and G protein-coupled receptor, CXCR4, are elevated in these activated fibroblasts, in which they facilitate angiogenesis and matrix degradation, processes that are also vital to breast cancer metastasis. In this study, we investigated MMP-1 and CXCR4 expression in normal human mammary fibroblasts (HMF) exposed to soluble breast cancer factors. Historically, elevated CXCR4 expression is associated with breast cancer cells. However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype. To confirm the clinical relevancy of our findings, we analyzed CAFs obtained from primary breast cancers. These cells also displayed elevated MMP-1 and CXCR4 levels compared with counterpart fibroblasts, and were more invasive and migratory. Together, our data suggest that soluble breast cancer factors initiate the transdifferentiation of normal HMFs to tumor-promoting CAFs, and that through the induction of MMP-1 and CXCR4 levels, these cells exhibit an invasive and migratory phenotype. (Mol Cancer Res 2009;7(7):1033-44)

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“…This result indicates that adding VEGF neutralizing antibody does not play an important role in the cell invasion during hypoxia. However, using conditioned medium from GA treated hypoxic cells 25 led to a significant decrease in cell invasion in comparison to the wells in which HCM was used (19.6072.60, and 73.2078.49 cells per field, respectively). These data suggest that a decrease in HIF1a leads to a decrease in cell invasion.…”

Section: Inhibition Of Hif-1a By Geldanamycin O Alqawi Et Almentioning

confidence: 86%

“…However, they kept their cells in hypoxia for 24 h. Other studies have demonstrated that VEGF can upregulate MMP-9 via its activation of VEGF receptors in different cell lines. 25,41 They showed an increase in VEGF protein due to VEGF cDNA transfection resulted in an increase in MMP-2 protein. So the upregulation of MMP-2 and MMP-9 by hypoxia or VEGF may be cell type specific, and VEGF or hypoxia in DU-145 cells may not regulate MMP-2 and MMP-9.…”

Section: Inhibition Of Hif-1a By Geldanamycinmentioning

confidence: 99%

Effects of geldanamycin on HIF-1α mediated angiogenesis and invasion in prostate cancer cells

Alqawi

Moghaddas

Singh

2006

Prostate Cancer Prostatic Dis

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Geldanamycin (GA), a benzoquinone ansamycin, is a naturally occurring inhibitor of heat shock protein (Hsp90), which regulates the transcription activity of hypoxia-inducible factor 1 (HIF-1a). Under hypoxia, HIF-1a is activated in tumor cells, and induces the transcription of vascular endothelial growth factor (VEGF), which is the prime regulator for angiogenesis. VEGF promotes the formation of new blood vessels by stimulating endothelial cell division and migration. This eventually forms a vascular network that allows for tumor growth and metastasis. In this study, we used GA to inhibit HIF-1a transcription function. Human prostate cancer DU-145 cells were incubated in a hypoxic chamber at 1% O 2 and 371C for different durations. Both mRNA and protein levels of HIF-1a and VEGF were upregulated under hypoxic conditions. We demonstrated that GA treatment of hypoxic DU-145 cells abolished the induction of HIF-1a protein in a time-dependent manner and decreased VEGF mRNA and its protein levels. The transient transfection of DU-145 cells with luciferase reporter gene construct (5HRE/hCMVmp-luc) showed that the transcriptional activity of HIF-1a was significantly induced in response to hypoxia, but inhibited by GA. In addition, using conditioned medium from GA-treated hypoxic cells led to a significant decrease in cell invasion in comparison with using conditioned medium from nontreated hypoxic cells. These data provide evidence for the important role of GA in inhibition of angiogenesis and also invasion mediated by HIF-1a in prostate cancer cells.

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Growth factor regulation of secreted matrix metalloproteinase and plasminogen activators in prostate cancer cells, normal prostate fibroblasts and normal osteoblasts

Cited by 13 publications

References 41 publications

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

CXCR4 and Matrix Metalloproteinase-1 Are Elevated in Breast Carcinoma–Associated Fibroblasts and in Normal Mammary Fibroblasts Exposed to Factors Secreted by Breast Cancer Cells

Effects of geldanamycin on HIF-1α mediated angiogenesis and invasion in prostate cancer cells

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