Stromal Cell–Derived Factor-1α and CXCR4 Expression in Hemangioblastoma and Clear Cell-Renal Cell Carcinoma: von Hippel-Lindau Loss-of-Function Induces Expression of a Ligand and Its Receptor

Zagzag, David; Krishnamachary, Balaji; Yee, Herman; Okuyama, Hiroaki; Chiriboga, Luis; Ali, M. Aktar; Melamed, Jonathan; Semenza, Gregg L.

doi:10.1158/0008-5472.can-04-4406

Cited by 242 publications

(199 citation statements)

References 45 publications

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“…39,40 Currently, there are research efforts to utilize this mechanism by local intramyocardial delivery of a protease-resistant CXCL12 to attract progenitor cells to sites of hypoxic damage after myocardial infarction. 41 Moreover, in hypoxic tumors or in tumors that display mutations in the von Hippel-Lindau tumor suppressor protein pVHL (a negative regulator of HIF-1), HIF-1 upregulates CXCR4 expression, 42,43 providing a survival benefit for tumor cells with high CXCR4 expression.…”

Section: Cxcr4: a Unique Chemokine Receptormentioning

confidence: 99%

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Burger

Peled²

2008

Leukemia

414

316

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Section: Cxcr4: a Unique Chemokine Receptormentioning

confidence: 99%

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Burger

Peled²

2008

Leukemia

414

316

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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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“…[27][28][29] Prognostic impact of CXCR4 expression levels on the neoplastic cells has been demonstrated in breast cancer 30 and renal cell cancer. 31,32 Recently, Rombouts and colleagues reported that expression of CXCR4 by CD34 ϩ AML cells is related to Flt3 mutations and unfavorable prognosis. 33 In this study, we examined the prognostic impact of CXCR4 surface expression by the CD34 ϩ and/or CD117 ϩ fraction of AML cells at the time of initial diagnosis in a series of 90 consecutive AML patients.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 is a prognostic marker in acute myelogenous leukemia

Spoo

Lübbert

Wierda

et al. 2006

Blood

295

213

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CXCR4 chemokine receptors retain hematopoietic progenitors and leukemia cells within the marrow microenvironment. We prospectively evaluated the prognostic implication of CXCR4 in 90 consecutive patients with acute myelogenous leukemia (AML) by flow cytometry. Patients were divided into groups with low (n ‫؍‬ 32), intermediate (n ‫؍‬ 26), or high (n ‫؍‬ 32) CXCR4 expression, as defined by CXCR4 mean fluorescence intensity ratio thresholds of less than 5, 5 to 10, or more than 10, respectively. We found that low CXCR4 expression on AML cells correlated with a better prognosis, resulting in a longer relapse-free and overall survival of 24.3 ؎ 2.9 months for low CXCR4-expressing patients, compared with 17.4 ؎ 3.4 months for intermediate and 12.8 ؎ 2 months (mean ؎ SEM) for patients with high expression. In univariate analyses, CXCR4 expression, cytogenetics, white blood cell count, and serum lactate dehydrogenase (LDH) predicted for shorter survival. Multivariate analysis revealed CXCR4 expression and unfavorable cytogenetics as independent prognostic factors. We conclude that CXCR4 expression in AML is an independent prognostic predictor for disease relapse and survival that can rapidly and easily be determined at disease presentation. These findings warrant further investigation into the role of CXCR4 in AML and suggest that CXCR4 should be incorporated into the risk assessment of AML patients. IntroductionDespite major improvements in the understanding and treatment of certain leukemias during the past years, the overall survival (OS) of patients with acute myelogenous leukemia (AML) remains poor, and new prognostic markers and therapeutic strategies are urgently needed. Several prognostic markers have been described in AML, including age, performance status, karyotype, white blood cell (WBC) count, serum lactate dehydrogenase (LDH), presence or absence of an antecedent hematologic disorder (eg, myelodysplasia), and the presence of distinct cytogenetic abnormalities. [1][2][3] Cytogenetic abnormalities can be detected in approximately 60% of AML patients and represent the most important predictor for responses to therapy and relapse probability. Depending upon cytogenetic characteristics, patients can be classified into low-risk, intermediate-risk, or high-risk groups. 4,5 However, there is substantial heterogeneity within these groups. About 35% to 50% of AML patients display a normal karyotype, which can further be subdivided using predictive molecular markers, such as mutations in the fetal liver tyrosine kinase-3 (FLT3) gene and the mixed-lineage leukemia (MLL) gene. 6,7 Several studies indicated that adhesion to marrow stromal cells affects the survival and proliferation of AML cells 8,9 and protects AML cells from chemotherapy in vitro 10 and in vivo. 11 Adhesion molecules, particularly the very late antigen-4 (VLA-4) and VLA-5 integrins, are considered essential for AML cell adhesion to respective stromal ligands (fibronectin) 12 and for protection of AML cells from spontaneous or drug-induced apoptosis....

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Stromal Cell–Derived Factor-1α and CXCR4 Expression in Hemangioblastoma and Clear Cell-Renal Cell Carcinoma: von Hippel-Lindau Loss-of-Function Induces Expression of a Ligand and Its Receptor

Abstract: The genetic hallmark of hemangioblastomas and clear cellrenal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxiainducible factor-1A

Cited by 242 publications

References 45 publications

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

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

CXCR4 is a prognostic marker in acute myelogenous leukemia

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