Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development

Lichtenberger, Beate M.; Tan, Poi Kiang; Niederleithner, Heide; Ferrara, Napoleone; Petzelbauer, Peter; Sibilia, Maria

doi:10.1016/j.cell.2009.12.046

Cited by 313 publications

(291 citation statements)

References 44 publications

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“…This conclusion is particularly apt for prostate cancer because we reported that high-grade prostate cancer, which exhibits an EMT phenotype, is characterized by elevated HIF-1α expression and decreased expression of ERβ (9). Moreover, high-grade prostate cancers exhibit markedly elevated levels of the HIF-target gene VEGF in tumor cells (9), consistent with reports from our laboratory and others that autocrine VEGF signaling in tumor cells promotes a dedifferentiated, EMT phenotype (9,(33)(34)(35)(36). Clearly, other HIF-target genes may contribute to this dedifferentiated state characteristic of high-grade prostate tumors, but we suggest that ERβ regulation of PHD2 has a key role in their regulation.…”

Section: Discussionsupporting

confidence: 78%

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Mak

Chang

Pursell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Estrogen receptor β (ERβ) promotes the degradation of hypoxia inducible factor 1α (HIF-1α), which contributes to the ability of this hormone receptor to sustain the differentiation of epithelial and carcinoma cells. Although the loss of ERβ and consequent HIF-1 activation occur in prostate cancer with profound consequences, the mechanism by which ERβ promotes the degradation of HIF-1α is unknown. We report that ERβ regulates the ligand (3β-adiol)-dependent transcription of prolyl hydroxylase 2 (PHD2) also known as Egl nine homolog 1 (EGLN1), a 2-oxoglutarate-dependent dioxygenase that hydroxylates HIF-1α and targets it for recognition by the von Hippel-Lindau tumor suppressor and consequent degradation. ERβ promotes PHD2 transcription by interacting with a unique estrogen response element in the 5′ UTR of the PHD2 gene that functions as an enhancer. PHD2 itself is critical for maintaining epithelial differentiation. Loss of PHD2 expression or inhibition of its function results in dedifferentiation with characteristics of an epithelial-mesenchymal transition, and exogenous PHD2 expression in dedifferentiated cells can restore an epithelial phenotype. Moreover, expression of HIF-1α in cells that express PHD2 does not induce dedifferentiation but expression of HIF-1α containing mutations in the proline residues that are hydroxylated by PHD2 induces dedifferentiation. These data describe a unique mechanism for the regulation of HIF-1α stability that involves ERβ-mediated transcriptional regulation of PHD2 and they highlight an unexpected role for PHD2 in maintaining epithelial differentiation.T he role of estrogen receptors (ERs), which are transcription factors belonging to the steroid/thyroid nuclear receptor superfamily (1-3), in regulating epithelial differentiation is an emerging area of considerable biological interest and pathological relevance. In the prostate, the discovery of ERβ (4, 5) has generated intense interest in the roles played by this ER in several tissues including prostate and breast epithelia (6-11). Increasing evidence supports the hypothesis that ERβ functions to maintain epithelial differentiation in the prostate and breast (9,10,12,13). In the normal prostate, ERβ contributes to epithelial differentiation as evidenced by the observation that ERβ knockout mice exhibit altered differentiation in the ventral prostate, whereas the glands of ERα knockout mice lack these lesions and appear to be normal (12). ERβ in human prostate cancer is of substantial relevance because there is an inverse relationship between the expression of ERβ and highly invasive prostate cancer (9,14). In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9). This observation is in agreement with the recent findings that 3β-adiol is a natural ligand for ERβ in ...

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Section: Discussionsupporting

confidence: 78%

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Mak

Chang

Pursell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Both genes have previously been shown to be upregulated in cancer. 42,43 Furthermore, FLT1 has been shown play a role in the proliferation of tumor cells, 44 and suppression of MELK expression by siRNA has been shown to inhibit the growth of cancer cells. Therefore, the aberrant expression of these genes due to DNA methylation may provide a survival advantage to malignant cells and play a role in pediatric ALL.…”

Section: Discussionmentioning

confidence: 99%

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

et al. 2015

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Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 15. In addition to genetic aberrations, epigenetic modifications such as DNA methylation are altered in cancer and impact gene expression. To identify epigenetic alterations in ALL, genome-wide methylation profiles were generated using the methylated CpG island recovery assay followed by next-generation sequencing. More than 25,000 differentially methylated regions (DMR) were observed in ALL patients with »90% present within intronic or intergenic regions. To determine the regulatory potential of the DMR, whole-transcriptome analysis was performed and integrated with methylation data. Aberrant promoter methylation was associated with the altered expression of genes involved in transcriptional regulation, apoptosis, and proliferation. Novel enhancer-like sequences were identified within intronic and intergenic DMR. Aberrant methylation in these regions was associated with the altered expression of neighboring genes involved in cell cycle processes, lymphocyte activation and apoptosis. These genes include potential epi-driver genes, such as SYNE1, PTPRS, PAWR, HDAC9, RGCC, MCOLN2, LYN, TRAF3, FLT1, and MELK, which may provide a selective advantage to leukemic cells. In addition, the differential expression of epigenetic modifier genes, pseudogenes, and non-coding RNAs was also observed accentuating the role of erroneous epigenetic gene regulation in ALL.

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“…However, additional roles for VEGF-A in tumorigenesis are emerging. VEGF-A was shown to promote tumor cell growth in an autocrine manner, in skin and lung cancer cells expressing VEGFRs ( 22,23 ). Moreover, VEGF-A also has nonangiogenic functions in normal physiology.…”

Section: Introductionmentioning

confidence: 99%

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

et al. 2014

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Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplifi cation, displaying distinct biologic characteristics. Unlike common tumor amplifi cations, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifi cally in amplicon-positive mouse HCCs. Sorafenib-the fi rst-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild benefi cial effect. We found that VEGFA amplifi cation specifi es mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA -amplifi ed HCCs, suggesting that VEGFA amplifi cation is a potential biomarker for HCC response to VEGF-A-blocking drugs. SIGNIFICANCE:Using a mouse model of infl ammation-driven cancer, we identifi ed a subclass of HCC carrying VEGFA amplifi cation, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplifi cation in human HCC identifi es patients who favorably responded to sorafenib-the fi rst-line treatment of advanced HCC-which has an overall moderate therapeutic effi cacy. Cancer Discov; 4(6);

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Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development

Cited by 313 publications

References 44 publications

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

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