The Expression and Prognostic Significance of VEGF and CXCR4 in Gastric Cancer: Correlation with Angiogenesis, Lymphangiogenesis and Progression

The cellular response to hypoxia includes the expression of hypoxia-inducible factor-1 (HIF-1) and its target genes: vascular endothelial growth factor (VEGF) and CXC chemokine receptor 4 (CXCR4). The aim of this study was to investigate the expression and prognostic significance of VEGF and CXCR4, which are responsible for angiogenesis and progression in gastric cancer. Twenty-eight gastric cancer patients were analyzed. The mRNA expression was examined in primary tumors and corresponding normal gastric mucosa by RT-PCR. The protein level was examined by immunohistochemistry staining. The high expression of VEGF and CXCR4 was found in 71.0 and 64.0% of tumors, respectively. The mean levels of VEGF and CXCR4 were upregulated in primary tumors compared to normal mucosa (p = 0.0007, p = 0.0052). A correlation between VEGF expression and tumor invasion (p = 0.0216) and stage (p = 0.0181) was found. CXCR4 expression correlated with lymph node metastases (p = 0.0237) and stage (p = 0.0054). The VEGF expression correlated with microvessel density (MVD) (p = 0.0491). The overall 3-year survival rate was 46.4% and correlated negatively with high CXCR4 mRNA expression (p = 0.0089). VEGF and CXCR4 play an important role in tumor progression. Their overexpression correlates with a bad prognosis and may improve high-risk patient selection, and these patients may obtain additional survival benefits if treated more aggressively.

[1]  M. Tarnowski,et al.  Impact of Selected Serum Factors on Metastatic Potential of Gastric Cancer Cells , 2022, Diagnostics.

[2]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[3]  Rui Xu,et al.  Correlations of TNM staging and lymph node metastasis of gastric cancer with MRI features and VEGF expression. , 2018, Cancer biomarkers : section A of Disease markers.

[4]  C. Justinger,et al.  CXCL12/CXCR4 display an inverse mRNA expression profile in gastric carcinoma which correlates with tumor progression , 2017, Zeitschrift für Gastroenterologie.

[5]  X. Chu,et al.  Inhibition of CXCL12/CXCR4 axis as a potential targeted therapy of advanced gastric carcinoma , 2017, Cancer medicine.

[6]  Jian Wang,et al.  Vascular endothelial growth factor gene polymorphisms and gastric cancer risk: a meta-analysis. , 2017, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[7]  Jie Zhang,et al.  SDF-1/CXCR7 axis regulates the proliferation, invasion, adhesion, and angiogenesis of gastric cancer cells , 2016, World Journal of Surgical Oncology.

[8]  Bao-Ling Zhu,et al.  Vascular Endothelial Growth Factor and Cluster of Differentiation 34 for Assessment of Perioperative Bleeding Risk in Gastric Cancer Patients , 2016, Chinese medical journal.

[9]  D. Coit,et al.  Serum VEGF-A and Tumor Vessel VEGFR-2 Levels Predict Survival in Caucasian but Not Asian Patients Undergoing Resection for Gastric Adenocarcinoma , 2015, Annals of Surgical Oncology.

[10]  F. Roviello,et al.  Angiogenesis inhibitors in gastric and gastroesophageal junction cancer , 2015, Gastric Cancer.

[11]  H. Kato,et al.  Can expression of CXCL12 and CXCR4 be used to predict survival of gastric cancer patients? , 2014, Anticancer research.

[12]  Fátima Carneiro,et al.  Unmet needs and challenges in gastric cancer: the way forward. , 2014, Cancer treatment reviews.

[13]  D. Roshani,et al.  The chemokine receptor CXCR4 is associated with the staging of gastric cancer , 2014, Advanced biomedical research.

[14]  Zhi Wang,et al.  Prognostic value of vascular endothelial growth factor A expression in gastric cancer: a meta-analysis , 2014, Tumor Biology.

[15]  E. Maiello,et al.  Chemokine receptor CXCR4: role in gastrointestinal cancer. , 2013, Critical reviews in oncology/hematology.

[16]  X. Qin,et al.  Upregulated Expression of C-X-C Chemokine Receptor 4 Is an Independent Prognostic Predictor for Patients with Gastric Cancer , 2013, PloS one.

[17]  Q. Chu,et al.  The chemokine receptor CXCR4 as a novel independent prognostic marker for node‐positive breast cancer patients , 2012, Journal of surgical oncology.

[18]  Yuquan Wei,et al.  Prognostic value of vascular endothelial growth factor expression in resected gastric cancer. , 2012, Asian Pacific Journal of Cancer Prevention.

[19]  J. Ying,et al.  The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis , 2012, Medical Oncology.

[20]  Tieliu Shi,et al.  Prognostic significance of vascular endothelial growth factor expression in gastric carcinoma: a meta-analysis , 2011, Journal of Cancer Research and Clinical Oncology.

[21]  Hua-chong Ma,et al.  CXCR4/SDF-1 axis is involved in lymph node metastasis of gastric carcinoma. , 2011, World journal of gastroenterology.

[22]  J. Sul,et al.  Evaluation of the combined expression of chemokine SDF-1α and its receptor CXCR4 as a prognostic marker for gastric cancer. , 2011, Experimental and therapeutic medicine.

[23]  A. Saftoiu,et al.  Vascular endothelial growth factor expression and microvessel density--two useful tools for the assessment of prognosis and survival in gastric cancer patients. , 2010, Journal of gastrointestinal and liver diseases : JGLD.

[24]  S. Natsugoe,et al.  CCR7 and CXCR4 expression predicts lymph node status including micrometastasis in gastric cancer. , 2009, International journal of oncology.

[25]  K. Nakashiro,et al.  Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. , 2009, Oncology reports.

[26]  J. Imura,et al.  Expression of SDF-1α and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer , 2008, British Journal of Cancer.

[27]  C. Niu,et al.  Correlation of integrin beta3 mRNA and vascular endothelial growth factor protein expression profiles with the clinicopathological features and prognosis of gastric carcinoma. , 2008, World journal of gastroenterology.

[28]  Y. Kodera,et al.  Expression of CXCL12 and CXCR4 in pT3-stage gastric cancer does not correlate with peritoneal metastasis. , 2008, Oncology reports.

[29]  Pei Wu,et al.  Relationship between vascular invasion and microvessel density and micrometastasis. , 2007, World journal of gastroenterology.

[30]  Takafumi Ando,et al.  Prevalence and prognosis of gastric cancer detected by screening in a large Japanese population: Data from a single institute over 30 years , 2007, Journal of gastroenterology and hepatology.

[31]  T. Kawano,et al.  Prognostic Significance of VEGF Expression in Correlation With COX-2, Microvessel Density, and Clinicopathological Characteristics in Human Gastric Carcinoma , 2007, Annals of Surgical Oncology.

[32]  M. Gazouli,et al.  Vascular endothelial growth factor polymorphisms in gastric cancer development, prognosis, and survival , 2006, Journal of surgical oncology.

[33]  Y. Kakeji,et al.  Clinicopathologic significance of hypoxia‐inducible factor 1α overexpression in gastric carcinomas , 2006, Journal of surgical oncology.

[34]  T. Kipps,et al.  CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. , 2006, Blood.

[35]  Ming-Tsang Wu,et al.  Hypoxia-inducible Factor-1α is Associated with Risk of Aggressive Behavior and Tumor Angiogenesis in Gastrointestinal Stromal Tumor , 2005 .

[36]  K. Choe,et al.  Expression of Chemokine Receptors in Human Gastric Cancer , 2005, Tumor Biology.

[37]  L. Ellis,et al.  Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  Ming-Tsang Wu,et al.  Hypoxia-inducible factor-1alpha is associated with risk of aggressive behavior and tumor angiogenesis in gastrointestinal stromal tumor. , 2005, Japanese journal of clinical oncology.

[39]  K. Shirouzu,et al.  VEGF significance in peritoneal recurrence from gastric cancer , 2005, Gastric Cancer.

[40]  F. Greene.  AJCC cancer staging handbook , 2002 .

[41]  C. Caux,et al.  Selective Recruitment of Immature and Mature Dendritic Cells by Distinct Chemokines Expressed in Different Anatomic Sites , 1998, The Journal of experimental medicine.

[42]  N. Weidner,et al.  Tumoural vascularity as a prognostic factor in cancer patients: the evidence continues to grow , 1998, The Journal of pathology.

[43]  A. Logan,et al.  Angiogenesis , 1993, The Lancet.

[44]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.