Nuclear expression of CXCR4 in tumor cells of non–small cell lung cancer is correlated with lymph node metastasis

Na, Il‐Kang; Scheibenbogen, Carmen; Adam, Christine; Stroux, Andrea; Ghadjar, Pirus; Thiel, Eckhard; Keilholz, Ulrich; Coupland, Sarah E.

doi:10.1016/j.humpath.2008.04.017

Cited by 67 publications

(52 citation statements)

References 23 publications

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“…In FOLFOX-treated patients, the CXCR4 signal in cancer cells was strong and mainly localized in the nucleus. It is noteworthy that CXCR4 nuclear localization is associated with metastasis (28,29). Consistently, a nuclear localization sequence mediates the transfer of CXCR4 to the nucleus after interaction with its ligand CXCL12/SDF-1 (30).…”

Section: Enhanced Expression Of Cxcr4 In Drug-resistant Human Colon Cmentioning

confidence: 85%

Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells

et al. 2010

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Metastasis and drug resistance are major problems in cancer chemotherapy. The purpose of this work was to analyze the molecular mechanisms underlying the invasive potential of drug-resistant colon carcinoma cells. Cellular models included the parental HT-29 cell line and its drug-resistant derivatives selected after chronic treatment with either 5-fluorouracil, methotrexate, doxorubicin, or oxaliplatin. Drug-resistant invasive cells were compared with noninvasive cells using cDNA microarray, quantitative reverse transcription-PCR, flow cytometry, immunoblots, and ELISA. Functional and cellular signaling analyses were undertaken using pharmacologic inhibitors, function-blocking antibodies, and silencing by retrovirus-mediated RNA interference. 5-Fluorouracil-and methotrexate-resistant HT-29 cells expressing an invasive phenotype in collagen type I and a metastatic behavior in immunodeficient mice exhibited high expression of the chemokine receptor CXCR4. Macrophage migration-inhibitory factor (MIF) was identified as the critical autocrine CXCR4 ligand promoting invasion in drug-resistant colon carcinoma HT-29 cells. Silencing of CXCR4 and impairing the MIF-CXCR4 signaling pathways by ISO-1, pAb FL-115, AMD-3100, monoclonal antibody 12G5, and BIM-46187 abolished this aggressive phenotype. Induction of CXCR4 was associated with the upregulation of two genes encoding transcription factors previously shown to control CXCR4 expression (HIF-2α and ASCL2) and maintenance of intestinal stem cells (ASCL2). Enhanced CXCR4 expression was detected in liver metastases resected from patients with colon cancer treated by the standard FOLFOX regimen. Combination therapies targeting the CXCR4-MIF axis could potentially counteract the emergence of the invasive metastatic behavior in clonal derivatives of drug-resistant colon cancer cells. Cancer Res; 70(11); 4644-54. ©2010 AACR.

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Section: Enhanced Expression Of Cxcr4 In Drug-resistant Human Colon Cmentioning

confidence: 85%

Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells

et al. 2010

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“…Tregs are physiologically engaged in the maintenance of immunological self-tolerance, but they also inhibit anti-tumor activity of T cells. A large amount of Tregs are present in tumors of patients with different entities and their draining lymph nodes [9,29,30]. Importantly the number of Tregs in tumors of patients with lung cancer, breast cancer, gastric cancer and ovarian cancer correlate with poor prognosis and relapse of the disease [31][32][33][34][35][36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Serum Level of CC-Chemokine Ligand 18 is Increased in Patients with Non-small-cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

et al. 2012

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CC-chemokine ligand18 (CCL18) ismainly expressed by alternativelyactivated macrophages and DCs and plays an important role in lung fibrosis, arthritis and other diseases. Here CCL18 was measured in sera of 31 healthy volunteers and 170 patients with lung cancer and correlatedthese data with histology, tumor stage and clinicalparameters. Mean CCL18 serum levelofthe patients with non-small-cell lung cancer was 150(857) ng/ml vs. 32(61) ng/ml in the healthy control group. Patient groups differ significantly according their histology (adenocarcinoma 143(528) ng/ml vssquamous cell carcinoma 187(857) ng/ml, p,0.02). In addition, we found a significant difference between patients with lower versus higher T-stage (p,0.003). Receiver operating characteristic (ROC) analyses revealed a cutoff point of 83 ng/ml (area under the curve (AUC): 0.968; p,0.0001) to discriminate between healthy controls and non-small-cell lung cancer patients. ROC analyses to discriminate between patients, who died because of cancer related death and those who died for other reasons did not lead to a valid AUC. To stratify the tumor patients, a criterion value plot was performed leading to a point of equal sensitivity and specificity (54%) of 162 ng/ml. Patients with a CCL18 serum level higher than 160 ng/ml had a mean survival time of 623 days. In contrast, those in patients with a baseline level between 83 ng/ml and 160 ng/ml the mean survival time was 984 days (p,0.005). Survival-analysis revealed in adenocarcinoma a mean survival of 1152 days in the group below 83 ng/ml. In the median group the mean survival time was 788 days and in the group with the highest levels the mean survival time was 388 days (p,0.001). In contrast, we found no correlation between the FEV1 and the CCL18 baseline level. In conclusion, in patients suffering from adenocarcinoma increased serum CCL18 levels predict a diminished survival time.

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“…In the final selection step, 12 of 14 studies were extracted; the remaining 2 were excluded for not supplying enough information. Twelve full-text studies conformed to our selection criteria, and provided information on the correlation between CXCR4 protein expression and prognosis of NSCLC (Takanami, 2003;Spano et al, 2004;Su et al, 2005;Na et al, 2008;Suzuki et al, 2008;Reckamp et al, 2009;Wagner et al, 2009;Otsuka et al, 2011;Franco et al, 2012;Al Zobair et al, 2013;Wang et al, 2011Wang et al, , 2014. Demographic information, baseline characteristics, and methodological quality of the extracted studies are summarized in Tables 1 and 2.…”

Section: Studies Includedmentioning

confidence: 99%

“…CXCR4, a seven-transmembrane trimeric G-protein-coupled receptor, is the most common chemokine receptor expressed by tumor cells (Na et al, 2008). Chemokines are critical contributors driving tumor cell invasion and metastasis, modulating the trafficking and extravasation of leukocytes, especially during the progression of inflammation, infection, and tissue damage (Choi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of CXCR4 and correlation with clinicopathological features and prognosis of non-small cell lung cancer patients: a meta-analysis

Wang

Xie

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The specific correlation between CXCR4 expression and survival in non-small cell lung cancer (NSCLC) has been investigated independently; however, these have yielded inconsistent results. Therefore, we examined the exact relationship between CXCR4 expression and NSCLC in this meta-analysis. The bibliographic databases in English and Chinese were carefully searched and data regarding the prognostic value of CXCR4 and its association with pathological parameters of NSCLC were collected. Pooled odds ratios (OR) with 95% confidence interval (CI) were applied. A total of twelve studies (CXCR4 positive cases = 565, CXCR4 negative = 755; 2003-2013) that matched our predefined criteria were finally incorporated into our study. The pooled OR revealed that expression of CXCR4 in NSCLC patients was apparently correlated with lymphatic (2015) metastasis, distant metastasis, and TNM stages (lymphatic metastasis: OR = 1.91, 95%CI = 1.21-3.27, P = 0.018; distant metastasis: OR = 4.81, 95%CI = 1.69-13.66, P = 0.003; TNM stages: OR = 3.91, 95%CI = 1.22-12.55, P = 0.022). Positive expression of CXCR4 was also strongly correlated with a shorter overall survival (OS) rate in NSCLC patients (hazard ratio = 2.10, 95%CI = 1.21-2.99, P < 0.05). Further stratification by ethnicity indicated a negative association between CXCR4 expression and NSCLC development and prognosis in Asians NSCLC patients in all four models (P < 0.05). This indicated that elevated CXCR4 expression may be correlated with aggressive metastasis, advanced TNM stages, and shorter OS rate in NSCLC patients, suggesting a poor prognostic outcome of this disease.

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Nuclear expression of CXCR4 in tumor cells of non–small cell lung cancer is correlated with lymph node metastasis

Cited by 67 publications

References 23 publications

Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells

Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells

Serum Level of CC-Chemokine Ligand 18 is Increased in Patients with Non-small-cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

Elevated expression of CXCR4 and correlation with clinicopathological features and prognosis of non-small cell lung cancer patients: a meta-analysis

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