Endothelial Cells Enhance Tumor Cell Invasion through a Crosstalk Mediated by CXC Chemokine Signaling

Warner, Kristy A.; Miyazawa, Marta; Cordeiro, Mabel Mariela Rodríguez; Love, William J.; Pinsky, Matthew Stephen; Neiva, Kathleen G.; Spalding, Aaron C.; Nör, Jacques E.

doi:10.1593/neo.07815

Cited by 64 publications

(61 citation statements)

References 35 publications

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“…Little information is available describing CXCL1 expression and function in human endothelial cells associated with tumors. Warner et al 38 reported that CXC chemokines (specifically CXCL1) secreted by endothelial cells induce tumor cell invasion and then suggested that the process of lateral spread of tumor cells observed in tumorigenesis is guided by chemotactic signals that originated from endothelial cells, which is in line with our findings. Herein, we demonstrated that CXCL1 stimulates human endothelial cells and increases rates of angiogenesis.…”

Section: Discussionsupporting

confidence: 91%

“…46,47 We have demonstrated that CXCL1 is produced by endothelial cells and by various epithelial cells, including human bladder cancer cells and human prostate cancer cell line (data not shown). It is feasible that endothelial cells' CXCL1 also has a role as a paracrine 38,48 and autocrine growth factor, and like IL-8 may have wide-ranging influence on angiogenic and even metastatic propensity. Additional studies are underway to investigate the potential cross-talk between CXCL1 and IL-8, and a possible correlation between angiogenesis and CXCL1 expression within disease states.…”

Section: Discussionmentioning

confidence: 99%

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Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways

Miyake¹,

Goodison

Urquidi³

et al. 2013

Laboratory Investigation

113

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Endothelial cell growth and proliferation are critical for angiogenesis; thus, greater insight into the regulation of pathological angiogenesis is greatly needed. Previous studies have reported on chemokine (C-X-C motif) ligand 1 (CXCL1) expression in epithelial cells and that secretion of CXCL1 from these epithelial cells induces angiogenesis. However, limited reports have demonstrated CXCL1 expression in endothelial cells. In this report, we present data that expand on the role of CXCL1 in human endothelial cells inducing angiogenesis. Specifically, CXCL1 is expressed and secreted from human endothelial cells. Interference of CXCL1 function using neutralizing antibodies resulted in a reduction in endothelial cell migration and viability/proliferation, the latter associated with a decrease in levels of cyclin D and cdk4. In vitro studies revealed that CXCL1 influenced neoangiogenesis through the regulation of epidermal growth factor and ERK1/2. In a xenograft angiogenesis model, interference of CXCL1 function resulted in inhibition of angiogenesis. A better understanding of the role of CXCL1 in the interactions between the endothelial and epithelial components will provide insight into how human tissues use CXCL1 to survive and thrive in a hostile environment.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways

Miyake¹,

Goodison

Urquidi³

et al. 2013

Laboratory Investigation

113

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“…Previously we have shown that signaling through the Cxcr2 receptor, which is activated by both Cxcl1 and Cxcl5, was responsible for part of an enhanced inflammatory cell recruitment observed in association with the TβRII (WKO;PY) tumor microenvironment as compared with TβRII (fl/fl;PY) controls (20). However, the literature suggested that in addition to recruitment of inflammatory cell populations, Cxcr2 signaling may enhance the migration of carcinoma cells (35)(36)(37). To test this in mammary carcinoma cells, we stimulated the highly metastatic murine 4T1 and human MDA-MB-231 cell lines with Cxcl1 at increasing doses in wound closure assays ( Figure 2B).…”

Section: Pyvmt Mammary Carcinoma Cells Exhibit An Epithelial-mesenchymentioning

confidence: 99%

Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer

Bierie¹,

Chung²,

Parker³

et al. 2009

J. Clin. Invest.

126

113

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In human breast cancer, loss of carcinoma cell-specific response to TGF-β signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-β regulates these processes remain largely unknown. In an effort to address this issue, we have now identified gene expression signatures associated with the TGF-β signaling pathway in human mammary carcinoma cells. The results strongly suggest that TGF-β signaling mediates intrinsic, stromal-epithelial, and host-tumor interactions during breast cancer progression, at least in part, by regulating basal and oncostatin M-induced CXCL1, CXCL5, and CCL20 chemokine expression. To determine the clinical relevance of our results, we queried our TGF-β-associated gene expression signatures in 4 human breast cancer data sets containing a total of 1,319 gene expression profiles and associated clinical outcome data. The signature representing complete abrogation of TGF-β signaling correlated with reduced relapse-free survival in all patients; however, the strongest association was observed in patients with estrogen receptor-positive (ER-positive) tumors, specifically within the luminal A subtype. Together, the results suggest that assessment of TGF-β signaling pathway status may further stratify the prognosis of ER-positive patients and provide novel therapeutic approaches in the management of breast cancer.Introduction TGF-β ligands are key factors in the regulation of tumor initiation, progression, and metastasis. In human breast cancer, alterations in the carcinoma cell response to TGF-β signaling have been linked to tumor progression. It has been shown, using tissues from women with mammary epithelial hyperplasia lacking atypia, that decreased immunohistochemical staining for the type II TGF-β receptor (TβRII) correlated with an increased risk of developing invasive breast cancer (1). In this study, a 3-fold reduction in the number of TβRII-positive carcinoma cells correlated with an approximately 3-fold increase in the risk of developing subsequent invasive breast cancer (1). The loss of TβRII expression has also been correlated with high-grade human carcinoma in situ and invasive breast cancer (2). These observations are consistent with previously reported data demonstrating that human breast cancer cells with deficient TβRII expression were more tumorigenic than the same tumor cells in which the receptor was experimentally reintroduced (3). Notably, it has been shown that loss of TGFBR2 gene expression can occur through promoter hypermethylation in human breast carcinoma cells (4). In addition, the presence of an activating T29→C polymorphism in the TGFB1 gene increased the serum levels of TGF-β1 ligand and correlated with a reduced risk of developing breast cancer (5).

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“…7 In addition to protecting from apoptosis and increasing survival, bcl-2 and bcl-xL are involved in several other important functions, including angiogenesis. [8][9][10][11][12][13][14][15][16] In this context, we have previously reported that bcl-2 expression in tumor cells exposed to hypoxia increases the expression of vascular endothelial growth factor (VEGF) through the hypoxia-inducible factor-1 (HIF-1). 9,11 In vitro and in vivo inhibition of bcl-2 functions has a strong effect on HIF-1 target genes that, in some cases, is functionally unrelated to the prosurvival effect of bcl-2.…”

mentioning

confidence: 99%

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

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In addition to act as an antiapoptotic protein, B-cell lymphoma (bcl)-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogate the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes, such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1a protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF-1a protein half-life impairing HIF-1a protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally, we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2.

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Endothelial Cells Enhance Tumor Cell Invasion through a Crosstalk Mediated by CXC Chemokine Signaling

Cited by 64 publications

References 35 publications

Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways

Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways

Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

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