Stromal cell-derived factor-1α (SDF-1α/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation

Porcile, Carola; Bajetto, Adriana; Barbieri, Federica; Barbero, Simone; Bonavia, Rudy; Biglieri, Marianna; Pirani, Paolo; Florio, Tullio; Schettini, Gennaro

doi:10.1016/j.yexcr.2005.04.024

Cited by 154 publications

(132 citation statements)

References 32 publications

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“…Our data further suggest that the CXCL12/ CXCR4 axis, which is highly localized in lipid rafts, is an upstream activator of HER2. In accordance with our findings, Cabliogu et al (7) showed that CXCL12 induced HER2 phosphorylation in breast cancer cells; similarly, Porcile et al (8) found that CXCL12 induced EGFR phosphorylation in ovarian cancer cells. However, to our knowledge, our findings are the first to identify lipid raft microdomains as the site for this transactivation.…”

Section: Discussionsupporting

confidence: 93%

“…In breast cancer cells, CXCL12/CXCR4 interaction activates HER2 in a Src kinasedependent mechanism (7). In ovarian cancer cells, CXCL12/ CXCR4 interaction also activates epidermal growth factor receptor (EGFR), which leads to both mitogen-activated protein kinase and Akt activation (8). Whether CXCL12/CXCR4 activates HER2 in prostate cancer is unknown.…”

Section: Introductionmentioning

confidence: 99%

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CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

120

102

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Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient -human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft -disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4 -induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

120

102

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Section: Discussionmentioning

confidence: 96%

“…CXCL12 induced a dose dependent proliferation of human ovarian cancer cells through its specific interaction with CXCR4 (Porcile et al, 2005). This CXCR4 activation by CXCL12 further stimulated EGF receptor phosphorylation and its downstream kinases, ERK1/2, Akt and c-Src that might link several signallings of cell proliferation in ovarian cancer cells (Porcile et al, 2005). On the other hand, VEGF, a potent angiogenic factor, induced upregulation of CXCR4 gene expression in vascular endothelial cells, and expression of both VEGF and CXCL12 was very high in ascites of patients with advanced ovarian cancers (Kryczek et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

et al. 2006

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Y-box-binding protein 1 (YB-1), which is a member of the DNA-binding protein family containing a cold-shock domain, has pleiotropic functions in response to various environmental stimuli. As we previously showed that YB-1 is a global marker of multidrug resistance in ovarian cancer and other tumor types. To identify YB-1-regulated genes in ovarian cancers, we investigated the expression profile of YB-1 small-interfering RNA (siRNA)-transfected ovarian cancer cells using a high-density oligonucleotide array. YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. Exogenous serum addition stimulated YB-1 translocation from the cytoplasm to the nucleus, and treatment with Akt inhibitors as well as Akt siRNA and integrin-linked kinase (ILK) siRNA specifically blocked YB-1 nuclear localization. Inhibition of Akt activation downregulated CXCR4 and upregulated MDR1 (ABCB1) gene expression. Administration of Akt inhibitor resulted in decrease in nuclear YB-1-positive cancer cells in a xenograft animal model. Akt activation thus regulates the nuclear translocation of YB-1, affecting the expression of drug-resistance genes and other genes associated with the malignant characteristics in ovarian cancer cells. Therefore, the Akt pathway could be a novel target of disrupting the nuclear translocation of YB-1 that has important implications for further development of therapeutic strategy against ovarian cancers.

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“…45 Further analysis of the mechanism of induction of proliferation indicates that CXCL12 induces ERK activation through transactivation of the EGFR and can occur through release of EGFR ligands. 41,46,47 ADAM17/TACE has been associated with tumor progression in oral squamous cell carcinoma 48 and other cancers, 49,50 and can cleave multiple EGFR ligands, including TGF-␣, HB-EGF, and AREG. 51 It has been shown that GPCR activation by ligands such as LPA can lead to transactivation of EGFR in HNSCC cells 37,52,53 and in normal prostate cells, CXCL12 induced EGFR transactivation as the result of shedding an EGFR ligand AREG in vitro.…”

Section: In Vivo Invasion Of Hnscc 2863mentioning

confidence: 99%

In Vivo Invasion of Head and Neck Squamous Cell Carcinoma Cells Does Not Require Macrophages

Смирнова

Adomako

Locker

et al. 2011

The American Journal of Pathology

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Invasion of tumor cells into the local stroma is an important component in cancer progression.Here we report studies of the in vivo invasion of head and neck squamous cell carcinoma (HNSCC) cells in response to applied gradients of a growth factor [epidermal growth factor (EGF)] and a chemokine (CXCL12), using orthotopic floor-of-mouth models. Analysis of the invading cells indicated that >75% of them were tumor cells, about 15% macrophages, and <10% were unidentified. Surprisingly, although macrophages invaded together with tumor cells, macrophage contributions were not required for HNSCC invasion. CXCL12-induced in vivo invasion of HNSCC cells was also observed and found to occur via a unidirectional transactivation of epidermal growth factor receptor (EGFR) through CXCR4. Inhibition of tumor necrosis factor-␣-converting enzyme using TNF-␣ protease inhibitor-2 selectively inhibited CXCL12-induced invasion but not EGF-induced invasion, consistent with CXCL12 activation of EGFR via release of EGFR ligands. Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common types of cancer in the world, with over 500,000 new cases per year and 250,000 deaths worldwide as estimated by the World Health Organization. This includes 48,000 new cases and 11,260 deaths in 2009 from HNSCC in the United States. 1 HNSCC originates from mucosal tissues of the upper aerodigestive tract and spans the oral cavity to the larynx. Despite some improvements in treatment methods, the 5-year survival rate remains just above 50%. 1 Current treatments for HNSCC include single and multimodality therapies using surgical and nonsurgical approaches (chemotherapy and/or radiotherapy). 2 A key constraint that limits the ability of surgical treatment to cure HNSCC is the location-adequate margins to guarantee removal of all tumor cells are difficult to achieve in many cases without severely compromising quality of life or survival. Thus, the degree to which tumor cells have locally spread from the primary tumor can impact the likelihood of recurrence. Indeed, morphological examination of HNSCC has revealed that the pattern of tumor invasion, presence of perineural invasion, and presence of inflammatory cells correlate with clinical outcome. [3][4][5][6] Understanding the mechanisms underlying HNSCC invasion could provide an opportunity to reduce local invasion and improve patient outcome. The epidermal growth factor receptor (EGFR) is often overexpressed in HNSCC 7,8 and correlated with poor prognosis. 9 In addition to driving proliferation, the EGFR has the potential to drive invasion. EGFR ligands are chemoattractants, stimulating directly cell motility and HNSCC invasion in vitro. 10 -12 Studies of EGFR function in HNSCC in vivo have focused on tumor growth, 13,14 and direct evaluation of EGFR-mediated invasion in vivo has been poorly explored.

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Stromal cell-derived factor-1α (SDF-1α/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation

Cited by 154 publications

References 32 publications

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

In Vivo Invasion of Head and Neck Squamous Cell Carcinoma Cells Does Not Require Macrophages

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