Prognostic Significance of CXCR4 in Colorectal Cancer: An Updated Meta-Analysis and Critical Appraisal (original) (raw)
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Journal of Clinical Oncology, 2005
PurposeLiver metastasis is the predominant cause of colorectal cancer (CRC) related mortality. Chemokines, soluble factors that orchestrate hematopoetic cell movement, have been implicated in directing cancer metastasis, although their clinical relevance in CRC has not been defined. Our hypothesis was that the chemokine receptor CXCR4 expressed by CRC is a prognostic factor for poor disease outcome.MethodsCRC cell lines (n = 6) and tumor specimens (n = 139) from patients with different American Joint Committee on Cancer (AJCC) stages of CRC were assessed. Microarray screening of select specimens and cell lines identified CXCR4 as a prominent chemokine receptor. CXCR4 expression in tumor and benign specimens was assessed by quantitative real-time reverse transcription polymerase chain reaction and correlated with disease recurrence and overall survival.ResultsHigh CXCR4 expression in tumor specimens (n = 57) from AJCC stage I/II patients was associated with increased risk for local r...
The Chinese-German Journal of Clinical Oncology, 2007
Objective: Colorectal cancer is one of the leading causes of cancer related deaths, with recurrence and metastasis as the primary reasons for mortality. New evidence has implicated chemokines as the likely cause. We studied the positive expression of CXCR4 chemokine receptors in colorectal carcinoma and investigated its correlations to clinicpathological characteristics and prognosis. Methods: Tumor tissue specimens of patients with colorectal carcinoma (n = 67) who underwent surgery from January 2003 to December 2004 at the Department of Surgery, Tongji Hospital were collected. CXCR4 expression levels and tumor microvessel density were evaluated by immunohistochemistry. Specimens were immunostained using formalin-fixed, paraffin-embedded tissues. The correlation between the CXCR4 expression and clinicopathological factors was evaluated. Results: In 67 cancer tissue specimens, CXCR4 was positively expressed in 38 cases, positive rate being 56.7%. Positive expression of CXCR4 is associated with an increasing incidence of nodal involvement, higher clinic stage, higher tumor microvessel density and a lower 3-year disease free survival rate as compared to those with negative CXCR4 expression (P < 0.05). Conclusion: Positive CXCR4 expression and high tumor microvessel density are associated with poor prognosis and could be a potential predictive factor for recurrence or metastasis of colorectal cancer patients. So CXCR4 may be a potential target for specific therapeutic interventions in the future.
Clinical Cancer Research, 2006
Purpose: CXC chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) are implicated in the metastatic process of malignant tumors. However, no data are currently available on the biological relationship between these molecules in colorectal cancer.We studied whether CXCR4 andVEGF expression could predict relapse and evaluated in vitro the contribution of CXCR4 in promoting clonogenic growth,VEGF secretion, and intercellular adhesion molecule-1 (ICAM-1) expression of colorectal cancer cells. Experimental Design: CXCR4 and VEGF were studied in colorectal cancer tissues and in Lovo, HT29, and SW620 colorectal cancer cell lines by immunohistochemistry. Correlations with baseline characteristics of patients and tumors were analyzed by m 2 test.VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1expression was evaluated by flow cytometry. Clonogenic growth induced by CXCL12 was determined by clonogenic assays. Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4. Results: Seventy-two patients, seen between January 2003 and January 2004, were studied. CXCR4 was absent in16 tumors (22.2%); it was expressed in V50% of cells in 25 (34.7%) tumors and in >50% of cells in 31 (43.0%) tumors. VEGF was absent in 17 (23.6%) tumors; it was expressed in V50% of cells in16 (22.2%) tumors and in >50% of cells in 39 (54.2%) tumors. There was a significant association between CXCR4 expression and lymph nodal status (P = 0.0393). There were significant associations between VEGF and tumor invasion (P = 0.0386) and lymph nodal involvement (P = 0.0044). American Joint Committee on Cancer stage (P = 0.0016),VEGF expression (P = 0.0450), CXCR4 expression (P = 0.0428), and VEGF/CXCR4 expression (P = 0.0004) had a significant prognostic value for disease-free survival with univariate analysis. The predictive ability of the American Joint Committee on Cancer stage and of the concomitant and high expression of VEGF and CXCR4 was confirmed by multivariate analysis. Prognosis is particularly unfavorable for patients whose primary tumors express CXCR4 and VEGF in >50% of cells (median disease-free survival in relapsed patients, 5.8 months; hazard ratio of relapse, 8.23; 95% confidence interval, 7.24-14.29). In clonogenic assays, CXCL12 (20 ng/mL/d) significantly increased the number of clones in SW620, HT29, and Lovo cells at 7 and 14 days. Again, CXCL12 was able to stimulate VEGF secretion in SW620, HT29, and Lovo cells as well as up-regulated ICAM-1. These effects were prevented by the administration of AMD3100 (1 Amol/L). Conclusions: We have shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in colorectal cancer. CXCR4 triggers a plethora of phenomena, including stimulation of clonogenic growth, induction of VEGF release, and ICAM-1 up-regulation. These data support the inhibition of CXCR4 to prevent the development of colorectal cancer metastasis.
Effect of Chemokine Receptors CXCR4 and CCR7 on the Metastatic Behavior of Human Colorectal Cancer
Clinical Cancer Research, 2005
Purpose: The expression of chemokine receptors CXCR4 and CCR7 has been associated with tumor dissemination and poor prognosis in a limited number of tumor entities. However, no data are currently available on the impact of chemokine receptor expression on disease progression and prognosis in human colorectal cancer. Experimental Design: The expression of CXCR4 and CCR7 was evaluated in 96 patients with histologically confirmed colorectal cancers and in four colorectal cancer cell lines by immunohistochemical staining. Furthermore, cell migration assays were done with SW480, SW620, and LS174T cancer cells to confirm the effect of the CXCR4 ligand stromal cell–derived factor 1α on migration. Results: Human colorectal cancer specimens and cell lines displayed a CXCR4 and CCR7 expression with variable intensities. Interestingly, strong expression of CXCR4, but not of CCR7, was significantly associated with higher Union International Contre Cancer stages 3/4 (P = 0.0017), lymph node meta...
Chemokine receptor CXCR4-prognostic factor for gastrointestinal tumors
World Journal of Gastroenterology, 2008
To review the implication of CXCR4 for gastrointestinal cancer, a "Pubmed" analysis was performed in order to evaluate the relevance of CXCR4 and its ligands for gastrointestinal cancers. Search terms applied were "cancer, malignoma, esophageal, gastric, colon, colorectal, hepatic, pancreatic, CXCR4, SDF-1α, and SDF-1b". CXCR4 expression correlated with dissemination of diverse gastrointestinal malignomas. The CXCR4 ligand SDF-1α might act as "chemorepellent" while SDF-1b might act as "chemorepellent" for CTLs, inducing tumor rejection. The paracrine expression of SDF-1α was furthermore closely associated with neoangiogenesis. CXCR4 and its ligands influence the dissemination, immune rejection, and neoangiogenesis of human gastrointestinal cancers. Inhibition of CXCR4 might be an interesting therapeutic option.
Journal of Translational Medicine, 2013
Background The chemokine CXCL14 has been reported to play an important role in the progression of many malignancies such as breast cancer and papillary thyroid carcinoma, but the role of CXCL14 in colorectal carcinoma (CRC) remains to be established. The purpose of this study was to investigate the expression pattern and significance of CXCL14 in CRC progression. Method 265 colorectal carcinoma specimens and 129 matched adjacent normal colorectal mucosa specimens were collected. Expression of CXCL14 in clinical samples was examined by immunostaining. The effect of CXCL14 on colorectal carcinoma cell proliferation was measured by MTT assay, BrdU incorporation assay and colony formation assay. The impact of CXCL14 on migration and invasion of colorectal carcinoma cells was determined by transwell assay and Matrigel invasion assay, respectively. Results CXCL14 expression was significantly up-regulated in tumor tissues compared with adjacent nontumorous mucosa tissues (P
Annals of Surgery, 2006
To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. Summary Background Data: Murine and in vitro models have identified CR as potential factors in organ-specific metastasis of multiple cancers. Chemokines via their respective receptors have been shown to promote cell migration to distant organs. Methods: Patients who underwent hepatic surgery for melanoma or CRC liver metastases were assessed. Screening cDNA microarrays of melanoma/CRC cell lines and tumor specimens were analyzed to identify CR. Microarray data were validated by quantitative realtime RT-PCR (qRT) in paraffin-embedded liver metastases. Migration assays and immunohistochemistry were performed to verify CR function and confirm CR expression, respectively. Results: Microarray analysis identified CXCR4 as the most common CR expressed by both cancers. qRT demonstrated CXCR4 expression in 24 of 27 (89%) melanoma and 28 of 29 (97%) CRC liver metastases. In vitro treatment of melanoma or CRC cells with CXCL12, the ligand for CXCR4, significantly increased cell migration (P Ͻ 0.001). Low versus high CXCR4 expression in CRC liver metastases correlated with a significant difference in overall survival (median 27 months vs. 10 months, respectively; P ϭ 0.036). In melanoma, low versus high CXCR4 expression in liver metastases demonstrated no difference in overall survival (median 11 months vs. 8 months, respectively; P ϭ not significant). Conclusions: CXCR4 is expressed and functional on melanoma and CRC cells. The ligand for CXCR4 is highly expressed in liver and may specifically attract melanoma and CRC CXCR4 (ϩ) cells. Quantitative analysis of CXCR4 gene expression in patients with liver metastases has prognostic significance for disease outcome.
Chemokine receptor CXCR4 expression, function, and clinical implications in gastric cancer
2009
The chemokine receptor CXCR4 is associated with the biological behavior of cancer, but few studies have addressed the expression and function of CXCR4 in human gastric cancer and its impact on disease prognosis. We studied the expression of CXCR4 using RT-PCR, Western blotting, flow cytometry, and confocal microscopy in five gastric cancer cell lines. We also examined cell proliferation, migration, and anti-apoptotic activity in response to stromal cell-derived factor (SDF)-1· and evaluated SDF-1·/CXCR4 signaling pathways. Furthermore, we investigated the correlation between CXCR4 expression and the clinical features of 221 gastric cancer tissue samples. CXCR4 transcripts and proteins were detectable in all five gastric cancer cell lines. However, MKN-28, MKN-45, MKN-74, and SNU16 cells did not express membrane CXCR4. In contrast, KATO III cells expressed membrane CXCR4. In these cells, SDF-1·-induced migration was observed and was blocked by AMD3100, a specific inhibitor of CXCR4. SDF-1· induced rapid phosphorylation of Erk1/2 MAPK but did not promote phosphorylation of Stat3 or Akt. Gastric cancer tissue samples expressed CXCR4 with variable intensities. Strong CXCR4 expression was significantly associated with lymph node metastases (P=0.028) and higher stages III/IV (P=0.047), and further tended to be correlated with a reduced 5-year survival rate (42.6% vs. 53.9%; P=0.1). In conclusion, CXCR4 expression is associated with gastric cancer cell migration in vitro, and strong expression of CXCR4 by gastric cancer cells is significantly associated with lymphatic metastasis in patients with gastric cancer, suggesting that CXCR4 plays an important role during gastric cancer progression.
Clinicopathologic Significance of CXCL12 and CXCR4 Expressions in Patients with Colorectal Cancer
Gastroenterology research and practice, 2018
Colorectal cancer (CRC) is both a global and national burden, being the third most common malignancy in men and the second in women, worldwide. The prognosis of CRC is affected by various factors like the histological grade, angiolymphatic invasion, and distant metastases. Metastasis is an intricate process; one of the possible mechanisms is through the interaction of the chemokines CXCL12 and CXCR4. This study aims to reveal the expression patterns of CXCL12 and CXCR4 in CRC. The quantitative expressions of CXCL12 and CXCR4 messenger RNA (mRNA) were evaluated in 32 patients with adenocarcinoma-type CRC. Real-time polymerase chain reaction (qRT-PCR) was performed on formalin-fixed tissues. CXCL12 and CXCR4's expressions, clinicopathologic features, and the treatment response to the CRC were analysed. All tumour tissues showed higher levels of both chemokines compared to normal colonic tissue. The expression of CXCL12 mRNA was higher in rectal location ( = 0.04) with a tendency t...