scholarly journals Differential Regulation of Tumor Angiogenesis by Distinct ErbB Homo- and Heterodimers

2002 ◽  
Vol 13 (11) ◽  
pp. 4029-4044 ◽  
Author(s):  
Lily Yen ◽  
Naciba Benlimame ◽  
Zeng-Rong Nie ◽  
Dingzhang Xiao ◽  
Taiqi Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mutational Analysis ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Extracellular Signal ◽  
Erbb Receptor Family

Interactions between cancer cells and their microenvironment are critical for the development and progression of solid tumors. This study is the first to examine the role of all members of the ErbB tyrosine kinase receptors (epidermal growth factor receptor [EGFR], ErbB-2, ErbB-3, or ErbB-4), expressed singly or as paired receptor combinations, in the regulation of angiogenesis both in vitro and in vivo. Comparison of all receptor combinations reveals that EGFR/ErbB-2 and ErbB-2/ErbB-3 heterodimers are the most potent inducers of vascular endothelial growth factor (VEGF) mRNA expression compared with EGFR/ErbB-3, EGFR/ErbB-4, ErbB-2/ErbB-4, and ErbB-3/ErbB-4. Immunohistochemistry of tumor xenografts overexpressing these heterodimers shows increased VEGF expression and remarkably enhanced vascularity. Enhanced VEGF expression is associated with increased VEGF transcription. Deletional analysis reveals that ErbB-mediated transcriptional up-regulation of VEGF involves a hypoxia-inducible factor 1-independent responsive region located between nucleotides −88 to −66 of the VEGF promoter. Mutational analysis reveals that the Sp-1 and AP-2 transcription factor binding elements within this region are required for up-regulation of VEGF by heregulin β1 and that this up-regulation is dependent on the activity of extracellular signal-related protein kinases. These results emphasize the biological implications of cell signaling diversity among members of the ErbB receptor family in regulation of the tumor microenvironment.

scholarly journals Sp1 Is Involved in Akt-mediated Induction of VEGF Expression through an HIF-1–independent Mechanism

2004 ◽  
Vol 15 (11) ◽  
pp. 4841-4853 ◽  
Author(s):  
Nabendu Pore ◽  
Shuang Liu ◽  
Hui-Kuo Shu ◽  
Bin Li ◽  
Daphne Haas-Kogan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Proximal Promoter ◽  
Alternative Mechanism ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Activity Increase ◽  
Potent Inducer

Increased expression of vascular endothelial growth factor (VEGF) contributes to the growth of many tumors by increasing angiogenesis. Although hypoxia is a potent inducer of VEGF, we previously showed that epidermal growth factor receptor amplification and loss of PTEN, both of which can increase phosphatidylinositol-3-kinase (PI3K) activity, increase VEGF expression. Using both adenoviral vectors and a cell line permanently expressing constitutively active myristoylated Akt (myrAkt), we show that activation of Akt, which is downstream of PI3K, increases VEGF expression in vitro and increases angiogenesis in a Matrigel plug assay. Transient transfection experiments using reporter constructs containing the VEGF promoter showed that up-regulation of VEGF by Akt is mediated through Sp1 binding sites located in the proximal promoter. Small interfering RNA directed against Sp1 prevented the induction of VEGF mRNA in response to myrAkt but not to hypoxia. Expression of myrAkt is associated with increased phosphorylation of Sp1 and its increased binding to a probe corresponding to the -88/-66 promoter region. In conclusion, our results indicate that Sp1 is required for transactivation of the VEGF by Akt. Others have proposed that the PI3K/Akt pathway can increase VEGF expression via the hypoxia-inducible factor 1 (HIF-1); however, our results suggest an alternative mechanism can also operate.

scholarly journals Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer

2019 ◽  
Vol 112 (3) ◽  
pp. 266-277 ◽  
Author(s):  
Nikhil S Chari ◽  
Cristina Ivan ◽  
Xiandong Le ◽  
Jinzhong Li ◽  
Ainiwaer Mijiti ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Oral Cavity ◽  
Head And Neck ◽  
Feedback Loop ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Abstract Background Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor–targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified. Methods We quantified miR-27a* in 47 oral cavity squamous cell carcinoma patient samples along with analysis of miR-27a* in 73 oropharyngeal and 66 human papillomavirus–positive (HPV+) samples from The Cancer Genome Atlas. In vivo and in vitro TP53 models engineered to express mutant TP53, along with promoter analysis using chromatin immunoprecipitation and luciferase assays, were used to identify the role of TP53 and TP63 in miR-27a* transcription. An HNSCC cell line engineered to conditionally express miR-27a* was used in vitro to determine effects of miR-27a* on target genes and tumor cells. Results miR-27a* expression was repressed in 47 oral cavity tumor samples vs matched normal tissue (mean log2 difference = −0.023, 95% confidence interval = −0.044 to −0.002; two-sided paired t test, P = .03), and low miR-27a* levels were associated with poor survival in HPV+ and oropharyngeal HNSCC samples. Binding of ΔNp63α to the promoter led to an upregulation of miR-27a*. In vitro and in vivo findings showed that mutant TP53 represses the miR-27a* promoter, downregulating miR-27a* levels. ΔNp63α and nucleoporin 62, a protein involved in ΔNP63α transport, were validated as novel targets of miR-27a*. Conclusion Our results characterize a negative feedback loop between TP63 and miR-27a*. Genetic alterations in TP53, a frequent event in HNSCC, disrupt this regulatory loop by repressing miR-27a* expression, promoting tumor survival.

scholarly journals An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor

2008 ◽  
Vol 180 (6) ◽  
pp. 1205-1218 ◽  
Author(s):  
Ingrid Roxrud ◽  
Camilla Raiborg ◽  
Nina Marie Pedersen ◽  
Espen Stang ◽  
Harald Stenmark
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Coated Pits ◽  
Kinase Substrate ◽  
Epidermal Growth

Down-regulation of activated and ubiquitinated growth factor (GF) receptors by endocytosis and subsequent lysosomal degradation ensures attenuation of GF signaling. The ubiquitin-binding adaptor protein Eps15 (epidermal growth factor receptor [EGFR] pathway substrate 15) functions in endocytosis of such receptors. Here, we identify an Eps15 isoform, Eps15b, and demonstrate its expression in human cells and conservation across vertebrate species. Although both Eps15 and Eps15b interact with the endosomal sorting protein Hrs (hepatocyte growth factor–regulated tyrosine kinase substrate) in vitro, we find that Hrs specifically binds Eps15b in vivo (whereas adaptor protein 2 preferentially interacts with Eps15). Although Eps15 mainly localizes to clathrin-coated pits at the plasma membrane, Eps15b localizes to Hrs-positive microdomains on endosomes. Eps15b overexpression, similarly to Hrs overexpression, inhibits ligand-mediated degradation of EGFR, whereas Eps15 is without effect. Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR. These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex.

scholarly journals Immunity against cancer cells may promote their proliferation and metastasis

2019 ◽  
Vol 117 (1) ◽  
pp. 426-431
Author(s):  
Chih-Wei Lin ◽  
Jia Xie ◽  
Ding Zhang ◽  
Kyung Ho Han ◽  
Geramie Grande ◽  
...  
Keyword(s):  
Immune Response ◽  
Growth Factor ◽  
Cell Growth ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Point Of View ◽  
Breast Cancer Cell Growth ◽  
Agonist Antibody

Herein we present a concept in cancer where an immune response is detrimental rather than helpful. In the cancer setting, the immune system is generally considered to be helpful in curtailing the initiation and progression of tumors. In this work we show that a patient’s immune response to their tumor can, in fact, either enhance or inhibit tumor cell growth. Two closely related autoantibodies to the growth factor receptor TrkB were isolated from cancer patients’ B cells. Although highly similar in sequence, one antibody was an agonist while the other was an antagonist. The agonist antibody was shown to increase breast cancer cell growth both in vitro and in vivo, whereas the antagonist antibody inhibited growth. From a mechanistic point of view, we showed that binding of the agonist antibody to the TrkB receptor was functional in that it initiated downstream signaling identical to its natural growth factor ligand, brain-derived neurotrophic factor (BDNF). Our study shows that individual autoantibodies may play a role in cancer patients.

scholarly journals Platelet-Derived Growth Factor-Receptor α Strongly Inhibits Melanoma Growth In Vitro and In Vivo

Neoplasia ◽  
2009 ◽  
Vol 11 (8) ◽  
pp. 732-W7 ◽  
Author(s):  
Debora Faraone ◽  
Maria Simona Aguzzi ◽  
Gabriele Toietta ◽  
Angelo M. Facchiano ◽  
Francesco Facchiano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Melanoma Growth

scholarly journals FGFRL1 Promotes Ovarian Cancer Progression by Crosstalk with Hedgehog Signaling

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Haiyan Tai ◽  
Zhiyong Wu ◽  
Su’an Sun ◽  
Zhigang Zhang ◽  
Congjian Xu
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Hh Signaling ◽  
And Migration

Fibroblast growth factor receptor-like-1 (FGFRL1) has been identified as the fifth fibroblast growth factor receptor. So far, little is known about its biological functions, particularly in cancer development. Here, for the first time, we demonstrated the roles of FGFRL1 in ovarian carcinoma (OC). An array and existing databases were used to investigate the expression profile of FGFRL1 and the relationship between FGFRL1 expression and clinicopathological parameters. FGFRL1 was significantly upregulated in OC patients, and high FGFRL1 expression was correlated with poor prognosis. In vitro cell proliferation, apoptosis and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the role of FGFRL1. Loss of function of FGFRL1 significantly influenced cell proliferation, apoptosis, and migration of OC cells in vitro and tumor growth in vivo. Chromatin immunoprecipitation PCR analysis and microarray hybridization were performed to uncover the mechanism. FGFRL1 expression could be induced by hypoxia through hypoxia-inducible factor 1α, which directly binds to the promoter elements of FGFRL1. FGFRL1 promoted tumor progression by crosstalk with Hedgehog (Hh) signaling. Taken together, FGFRL1 is a potential predictor and plays an important role in tumor growth and Hh signaling which could serve as potential therapeutic targets for the treatment of OC.

The role of fibroblast growth factor receptor 4 (FGFR4) signaling in anti-EGFR resistance in colon cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4060-4060
Author(s):  
Sang Hee Cho ◽  
Jo-Heon Kim ◽  
Chang-Soo Hong ◽  
Eun-Gene Sun ◽  
Kyung-Hyun Ryu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Colon Cancer ◽  
Rna Seq ◽  
Colon Cancer Cells ◽  
Egfr Signaling

4060 Background: Anti-EGFR therapy has been used as a standard treatment for metastatic colon cancer, but the innate resistance is still issues of increasing significance. Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cell proliferation, invasion and anti-apoptosis, through the pathway of MAPK-ERK and PI3K-AKT. We investigated potential crosstalk between FGFR4 and EGFR signaling to identify new resistant mechanism of anti-EGFR therapy and how to overcome it in colon cancer. Methods: RNA-Seq was used to identify the associated signal pathway and down targets induced by FGFR4. Molecular studies including RTK array, RT-qPCR, western blotting were performed to validate the interaction between FGFR4 and EGFR signaling in vitro and in vivo. Next, the effect of FGFR4 in cetuximab resistance was investigated in vitro and in colon cancer patients. Results: FGFR4 overexpression in colon cancer cells activates downstream signaling, such as, PI3K/Akt and RAS/RAF/Erk pathway. Gene Ontology (GO) analysis from RNA-seq revealed that differentially expressed genes (DEGs) altered by expression of FGFR4 were related to biological functions, including cell proliferation, epidermal growth factor receptor signaling, NIK/NF-kB signaling, interferon-gamma signaling, wound healing. RT–qRCR showed that FGFR4 promotes the EGFR and ErbB3 by inducing the expression of EGFR ligands such as AREG, BTC, EREG, HBEGF. In vivo tumorigenesis, we found that FGFR4 promotes tumor growth and high expression of AREG in xenograft tumors. FGFR4 expression reduced the sensitivity to cetuximab in colon cancer cells and synergistic effect was shown when treated with FGFR4 inhibitor with cetuximab. A positive correlation between FGFR4 and AREG expression was observed in cancer, but not in normal tissues and high FGFR4 or AREG expression showed significantly inferior overall survival than low expression in patients treated with cetuximab for metastatic colon cancer. Conclusions: We demonstrated a pivotal mechanism of FGFR4 in colon cancer progression and cetuximab resistance through inducing AREG. Our data point to FGFR4 as a new biomarker to predict cetuximab response and dual targeting of FGFR4 and EGFR may be a promising treatment modality for colon cancer.

Sign in / Sign up

Export Citation Format

Share Document