Interaction of ligand–receptor system between stromal-cell-derived factor-1 and CXC chemokine receptor 4 in human prostate cancer: a possible predictor of metastasis

Mochizuki, Hidetaka; Matsubara, Akio; Teishima, Jun; Mutaguchi, Kazuaki; Yanagimoto, Hiroaki; Dahiya, Rajvir; Usui, Tsuguru; Kamiya, Kenji

doi:10.1016/j.bbrc.2004.06.013

Cited by 92 publications

(70 citation statements)

References 15 publications

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“…However, we will not approach any conclusions since the number of examined events is too small. The cytoplasmatic detection of the CXCR4 receptor was previously described in cancers of the breast (29), lung (30), colon (31 -33), prostate (34), pancreas (9), and in CD34 + hematopoietic cells (35). It might represent a functional status of the receptor because the binding to the specific ligand induce receptor internalization (36) and specific signals are required in order to express CXCR4 on cell surface (22).…”

Section: Discussionmentioning

confidence: 94%

Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma

Scala

Ottaiano

Ascierto

et al. 2005

Clinical Cancer Research

261

187

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Purpose: CXCR4 receptor and its unique ligand, the CXCL12 chemokine, have been recently implicated in cancer metastasis. Evidence about the role of CXCR4/CXCL12 axis has been reported in several cancers including melanoma. Our goal was to investigate if CXCR4 expression has a prognostic value in malignant melanoma.Experimental Design: Immunohistochemical expression of CXCR4 was evaluated on 71 specimens of primary cutaneous melanoma with a Breslow tumor thickness of >1 mm after radical resection. Associations between baseline patient features and tumors were analyzed by C 2 test. The prognostic value of CXCR4 expression was evaluated by univariate and multivariate analyses adjusted by age, sex, Breslow tumor thickness, presence of ulceration, and sentinel lymph node metastases.Results: CXCR4 expression was detected in 31 of 71 (43.6%) primary cutaneous melanomas. Membrane or cytoplasmic staining for CXCR4 protein was absent in 56% of the tumors. The positive cases were divided into three score classes according to their staining: low in 15 cases (21%), moderate in 10 (14%), and high in 6 (8%). After a median follow-up of 38 months, 26 patients progressed (16 of 26 expressed CXCR4) and 19 died (12 of 19 expressed CXCR4). The CXCR4 expression on tumor cells was correlated with an unfavorable prognosis with a median disease-free and overall survival of 22 and 35 months, respectively. The hazard ratios of relapse and death, compared with patients with CXCR4-negative tumors, were 2.5 (95% confidence interval, 1.2-6.1) and 3.1 (95% confidence interval, 1.1-7.2), respectively. Median time-to-event (progression and survival) was not reached in patients with CXCR4-negative tumors. In the multivariate analysis, CXCR4 expression, presence of ulceration, and sentinel lymph node status emerged as independent prognostic factors.Conclusions: This article provides the first evidence that CXCR4 expression could be an independent and powerful prognostic marker in primary cutaneous malignant melanomas.

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Section: Discussionmentioning

confidence: 94%

Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma

Scala

Ottaiano

Ascierto

et al. 2005

Clinical Cancer Research

261

187

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“…To test cellular motility, wound healing and Transwell migration assays were used. For wound healing, a section of a confluent cell monolayer was wounded with a pipette tip, and the ability of cells to migrate into the cleared section was observed at different time points as specified in Results (29). A Boyden chamber system was used for Transwell migration assay.…”

Section: +mentioning

confidence: 99%

Transforming Growth Factor-β Promotes Invasion in Tumorigenic but not in Nontumorigenic Human Prostatic Epithelial Cells

Ao¹,

Williams²,

et al. 2006

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Transforming growth factor-B (TGF-B) is a pleiotropic growth factor with actions that are dependent on circumstances, including dose, target cell type, and context. TGF-B can elicit both growth-promoting and growth-suppressive activities. In normal tissues, TGF-B generally acts to restrict growth and maintain differentiation. However, during tumorigenesis, changes in TGF-B expression and cellular responses can promote tumorigenesis. The present study examines the effects of TGF-B on the nontumorigenic human prostatic epithelial cell line BPH1 and on three derivative tumorigenic sublines BPH1 CAFTD 1, BPH1 CAFTD 3, and BPH1 CAFTD 5. The data show that TGF-B has different effects on the nontumorigenic and tumorigenic cells. The nontumorigenic cells are growth inhibited by TGF-B. In contrast, the tumorigenic sublines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-B. The tumorigenic lines show constitutively elevated levels of phosphorylated Akt, which modulates their response to TGF-B by blocking Smad3 and p21 nuclear translocation. On TGF-B stimulation of the tumorigenic sublines, the activated Akt allows the cell to escape cell cycle arrest. The phosphatidylinositol 3-kinase/Akt pathway is also involved in TGF-B-induced EMT, defined here by induction of vimentin expression and enhanced cellular motility. In vivo, tumorigenic cells with constitutively active TGF-B signaling show increased invasion with EMT, which express vimentin, located specifically at the invasive front of the tumor. These data indicate that following malignant transformation TGF-B can play a direct role in promoting prostatic cancer and further that these responses are context specific in vivo. (Cancer Res 2006; 66(16): 8007-16)

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“…The mechanism of bone metastasis is not well understood. As one possible metastatic mechanism, it has been shown that the SDF-1 (CXCL12)/CXCR4 chemokine axis is involved in PC metastasis (7). Chemokines play important roles in both normal embryonic development and migration and metastasis of cancer cells (8).…”

mentioning

confidence: 99%

CXCL12 G801A Polymorphism Is a Risk Factor for Sporadic Prostate Cancer Susceptibility

Hirata

Hinoda

Kikuno

et al. 2007

Clinical Cancer Research

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Purpose: The chemokine CXCL12 and its receptor CXCR4 have been found to be associated with cancer metastasis. A single nucleotide polymorphism of CXCL12 G801A has been described and is regarded as a target for cis-acting factor that has the ability to up-regulate CXCL12 expression. Currently, there are no reports investigating the role of CXCL12 G801A polymorphism in prostate cancer (PC). Experimental Design: We genotyped CXCL12 G801A and p53Arg72Pro in 167 PC patients and 167 age-matched healthy subjects. Genotyping was done with PCR-RFLP and confirmed by direct DNA sequencing. To investigate the effect of the CXCL12 G801A polymorphism on CXCL12 and CXCR4 expression, immunohistochemistry was done in genotyped PC tissues. Results: A significant increase in the GA + AA genotype of the CXCL12 G801A polymorphism was observed in PC patients compared with healthy controls. The frequency of CXCL12 AA genotype was significantly higher in a group of patients with lymph node metastasis (23%) compared with those without metastasis (7 %). The frequency of CXCL12 expression in AA + GA genotype carriers was significantly higher than that in GG genotype carriers. Among the carriers with CXCL12 GA + AA genotypes, CXCR4 expression was also significantly higher compared with those with the GG genotype. Moreover, among the groups with both CXCL12-and CXCR4-positive staining, the frequency of the CXCL12 GA + AA genotype was high. Although we did not find a significant relationship between the frequency of the Arg/Pro + Pro/Pro genotype of p53 Arg72Pro and susceptibility in PC, there was a combined effect of CXCL12 GA + AA genotype and the p53 72Arg/Pro + Pro/Pro genotype on the frequency of PC. These results indicate that the p53 codon 72 polymorphism may interact with CXCL12 G801A. Conclusions: This is the first report showing that CXCL12 G801A polymorphism may be a risk factor for PC. Moreover, this study suggests that this polymorphism can be an important marker for detecting microinvasion and PC metastasis.

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Interaction of ligand–receptor system between stromal-cell-derived factor-1 and CXC chemokine receptor 4 in human prostate cancer: a possible predictor of metastasis

Cited by 92 publications

References 15 publications

Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma

Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma

Transforming Growth Factor-β Promotes Invasion in Tumorigenic but not in Nontumorigenic Human Prostatic Epithelial Cells

CXCL12 G801A Polymorphism Is a Risk Factor for Sporadic Prostate Cancer Susceptibility

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