Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma

Scala, Stefania; Ottaiano, Alessandro; Ascierto, Paolo A.; Cavalli, Manuela; Simeone, Ester; Giuliano, Paola; Napolitano, Maria; Franco, Renato; Botti, Gerardo; Castello, Giuseppe

doi:10.1158/1078-0432.ccr-04-1887

Cited by 264 publications

(203 citation statements)

References 32 publications

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“…Previous results showed that the expression of CXCR4 correlated with a worse prognosis in terms of disease-free survival and overall survival (28). Here, the analysis of the data through a KaplanMeier curve showed no statistically significant differences in terms of overall survival between patients with CXCR4À and CXCR4+ metastases (data not shown).…”

Section: Discussioncontrasting

confidence: 43%

“…Recently, CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma (28). To evaluate the role of CXCR4 in human melanoma metastases, CXCR4 expression was analyzed in a panel of 63 melanoma metastases from melanoma patients who had undergone curative intent surgery (29 s.c., 22 lymph node, and 12 visceral metastases).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, it was shown that CXCR4 expression predicted prognosis in human primary melanoma (28). The aim of the study was to evaluate the role of CXCR4 in human melanoma metastases.…”

mentioning

confidence: 99%

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Human Melanoma Metastases Express Functional CXCR4

Scala

Giuliano

Ascierto

et al. 2006

Clinical Cancer Research

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117

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Purpose: The chemokine receptor CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma. The aim of the study was to investigate the role of CXCR4 in human melanoma metastases. Experimental Design: CXCR4 expression was evaluated in melanoma metastases and in metastatic cell lines through immunohistochemistry, immunoblotting, immunofluorescence, and reverse transcription-PCR. The function of CXCR4 was tested in the presence of the ligand, CXCL12, through induction of extracellular signal-regulated kinase-1and -2 (Erk-1and -2) phosphorylation, proliferation, apoptosis, and migration capabilities. Results: CXCR4 expression was detected in 33 out of 63 (52.4%) metastases from cutaneous melanomas. Metastatic melanoma cell lines expressed cell surface CXCR4; PES 43, Alo 40, and COPA cell lines showed the highest levels of CXCR4 (>90% of positive cells); PES 41, Alo 39, PES 47, POAG, and CIMA cell lines showed low to moderate degrees of expression (5-65% of positive cells). Other chemokine receptors, CCR7 and CCR10, were detected on the melanoma cell lines; CXCL12 activated Erk-1 and Erk-2, the whose induction was specifically inhibited by AMD3100 treatment. CXCL12 increased the growth in PES 41, PES 43, and PES 47 cells under suboptimal (1% serum) and serum-free culture conditions; AMD3100 (1 Amol/L) inhibited the spontaneous and CXCL12-induced proliferation. No rescue from apoptosis was shown but PES 41, PES 43, and PES 47 cells migrate toward CXCL12. Conclusions: These findings indicate that CXCR4 is expressed and active in human melanoma metastases, suggesting that active inhibitors such as AMD3100 may be experienced in human melanoma.The incidence and mortality rate of melanoma have increased in the last 30 years. The National Cancer Institute Surveillance, Epidemiology, and End Results database documents increases of 619% in annual diagnoses of cutaneous melanoma and of 165% in annual mortality from 1950 to 2000 (1). Metastatic spread may arise from very small tumor masses and in about two-thirds of all cases of malignant melanoma, spreading develop primarily as locoregional metastases. In about onethird of the cases, primary development of distant metastases is observed (2). The metastatic potential of primary melanoma is considerably higher than that of other primary solid tumors when comparing the size of primary lesion. The usual outcome for patients with distant metastases remains bleak, with median survival of 6 to 10 months and <5% of patients surviving for >5 years (1). Except for high-dose IFN as adjuvant therapy in stage III disease, little success has emerged over the last 20 years for metastatic melanoma (3). The underlying molecular events that explain malignant melanoma genesis and progression have been only partially characterized, and only a small number of genes have been identified as playing key roles in melanoma. Among these, some cell cycle regulators, apoptotic, signal transduction, cell adhesion, and matrix digestion genes have been shown to be deregu...

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Section: Discussioncontrasting

confidence: 43%

Section: Resultsmentioning

confidence: 99%

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Human Melanoma Metastases Express Functional CXCR4

Scala

Giuliano

Ascierto

et al. 2006

Clinical Cancer Research

Self Cite

117

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“…In oesophageal cancer and melanoma, CXCR4 expression is associated with poor clinical outcome [147,148]. In breast cancer, CXCR4 expression predicted lymph node metastasis [138].…”

Section: Chemokines and Their Receptors In Tumor Growth And Metastasismentioning

confidence: 99%

Chemokines in tumor angiogenesis and metastasis

Singh

Sadanandam

Singh

2007

Cancer Metastasis Rev

158

132

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Chemokines are a large group of low molecular weight cytokines that are known to selectively attract and activate different cell types. Although the primary function of chemokines is well recognized as leukocyte attractants, recent evidences indicate that they also play a role in number of tumor-related processes, such as growth, angiogenesis and metastasis. Chemokines activate cells through cell surface seven trans-membranes, G-protein-coupled receptors (GPCR). The role played by chemokines and their receptors in tumor pathophysiology is complex as some chemokines favor tumor growth and metastasis, while others may enhance anti-tumor immunity. These diverse functions of chemokines establish them as key mediators between the tumor cells and their microenvironment and play critical role in tumor progression and metastasis. In this review, we present some of the recent advances in chemokine research with special emphasis on its role in tumor angiogenesis and metastasis.

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“…In particular, cases were considered positive when >10% of the tumor cells showed cytoplasmic and/or membrane expression. These staining and scoring methods have been widely used to evaluate the results of immunohistochemical staining for CXCR4 and CXCL12 (18,19).…”

Section: -Aza-2'-deoxycytidine (5-aza-cdr) Treatmentmentioning

confidence: 99%

Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis

et al. 2008

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Abstract.Chemokines play an important role in the pathogenesis of non-small cell lung cancer (NSCLC). However, aberrant methylation of CXCL12 has not been examined in NSCLC. CXCL12 mRNA expression and methylation were examined in 17 NSCLC cell lines by RT-PCR and methylationspecific PCR (MSP). MSP was performed on 236 tumor specimens from NSCLC patients who received curative intent surgery. CXCL12 and CXCR4 protein expression was examined in 90 of the 236 NSCLC specimens by immunohistochemistry. Down-regulation of CXCL12 expression was found in 10 of 17 (59%) NSCLC cell lines compared with normal bronchial cells. Treatment of 8 expression-negative cell lines with a demethylating agent restored expression in all cases. Twelve cell lines (71%) showed aberrant methylation, and good concordance between methylation and expression was present. Aberrant methylation occurred in 85 out of 236 (36%) primary NSCLCs in a tumor-specific manner. In multivariate analysis, CXCL12 methylation correlated strongly and independently with prognosis both in all patients with NSCLCs and in those with stage I NSCLCs (hazard ratio=1.68, P=0.015 and hazard ratio=3.58, P=0.017). Secreted protein CXCL12 and its receptor CXCR4 were abundant in NSCLC cells (72 out of 90, 80%; 57 out of 90, 63%) and correlated with the progression of NSCLCs. In conclusion, epigenetic silencing of CXCL12 is a frequent event in NSCLCs, and could be an independent and powerful prognostic marker in patients with NSCLCs and those with stage I disease. Analysis for CXCL12 may provide novel opportunities for prognosis and therapy of resected NSCLCs.

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Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma

Cited by 264 publications

References 32 publications

Human Melanoma Metastases Express Functional CXCR4

Human Melanoma Metastases Express Functional CXCR4

Chemokines in tumor angiogenesis and metastasis

Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis

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