Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients

Alessandro Ottaiano, Renato Franco, Annarita Aiello Talamanca, Giuseppina Liguori, Fabiana Tatangelo, Paolo Delrio, Guglielmo Nasti, Emiddio Barletta, Gaetano Facchini, Bruno Daniele, Arturo Di Blasi, Maria Napolitano, Caterina Ieranò, Rosa Calemma, Enrico Leonardi, Vittorio Albino, Valentina De Angelis, Marzia Falanga, Vincenzo Boccia, Maurizio CapuozzoValerio Parisi, Gerardo Botti, Giuseppe Castello, Rosario Vincenzo Iaffaioli, Stefania Scala

Research output: Contribution to journalArticle

Abstract

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 and VEGF 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 χ2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression 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 in 16 tumors (22.2%); it was expressed in ≤50% 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 ≤50% of cells in 16 (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 μmol/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.

Original languageEnglish
Pages (from-to)2795-2803
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number9
DOIs
Publication statusPublished - May 1 2006

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CXCR4 Receptors
Vascular Endothelial Growth Factor A
Colorectal Neoplasms
Recurrence
Proteins
Neoplasms
Intercellular Adhesion Molecule-1
HT29 Cells
Lymph
Disease-Free Survival
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients. / Ottaiano, Alessandro; Franco, Renato; Talamanca, Annarita Aiello; Liguori, Giuseppina; Tatangelo, Fabiana; Delrio, Paolo; Nasti, Guglielmo; Barletta, Emiddio; Facchini, Gaetano; Daniele, Bruno; Di Blasi, Arturo; Napolitano, Maria; Ieranò, Caterina; Calemma, Rosa; Leonardi, Enrico; Albino, Vittorio; De Angelis, Valentina; Falanga, Marzia; Boccia, Vincenzo; Capuozzo, Maurizio; Parisi, Valerio; Botti, Gerardo; Castello, Giuseppe; Iaffaioli, Rosario Vincenzo; Scala, Stefania.

In: Clinical Cancer Research, Vol. 12, No. 9, 01.05.2006, p. 2795-2803.

Research output: Contribution to journalArticle

Ottaiano, Alessandro ; Franco, Renato ; Talamanca, Annarita Aiello ; Liguori, Giuseppina ; Tatangelo, Fabiana ; Delrio, Paolo ; Nasti, Guglielmo ; Barletta, Emiddio ; Facchini, Gaetano ; Daniele, Bruno ; Di Blasi, Arturo ; Napolitano, Maria ; Ieranò, Caterina ; Calemma, Rosa ; Leonardi, Enrico ; Albino, Vittorio ; De Angelis, Valentina ; Falanga, Marzia ; Boccia, Vincenzo ; Capuozzo, Maurizio ; Parisi, Valerio ; Botti, Gerardo ; Castello, Giuseppe ; Iaffaioli, Rosario Vincenzo ; Scala, Stefania. / Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 9. pp. 2795-2803.
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title = "Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients",
abstract = "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 and VEGF 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 χ2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression 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 in 16 tumors (22.2{\%}); it was expressed in ≤50{\%} 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 ≤50{\%} of cells in 16 (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 μmol/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.",
author = "Alessandro Ottaiano and Renato Franco and Talamanca, {Annarita Aiello} and Giuseppina Liguori and Fabiana Tatangelo and Paolo Delrio and Guglielmo Nasti and Emiddio Barletta and Gaetano Facchini and Bruno Daniele and {Di Blasi}, Arturo and Maria Napolitano and Caterina Ieran{\`o} and Rosa Calemma and Enrico Leonardi and Vittorio Albino and {De Angelis}, Valentina and Marzia Falanga and Vincenzo Boccia and Maurizio Capuozzo and Valerio Parisi and Gerardo Botti and Giuseppe Castello and Iaffaioli, {Rosario Vincenzo} and Stefania Scala",
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TY - JOUR

T1 - Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients

AU - Ottaiano, Alessandro

AU - Franco, Renato

AU - Talamanca, Annarita Aiello

AU - Liguori, Giuseppina

AU - Tatangelo, Fabiana

AU - Delrio, Paolo

AU - Nasti, Guglielmo

AU - Barletta, Emiddio

AU - Facchini, Gaetano

AU - Daniele, Bruno

AU - Di Blasi, Arturo

AU - Napolitano, Maria

AU - Ieranò, Caterina

AU - Calemma, Rosa

AU - Leonardi, Enrico

AU - Albino, Vittorio

AU - De Angelis, Valentina

AU - Falanga, Marzia

AU - Boccia, Vincenzo

AU - Capuozzo, Maurizio

AU - Parisi, Valerio

AU - Botti, Gerardo

AU - Castello, Giuseppe

AU - Iaffaioli, Rosario Vincenzo

AU - Scala, Stefania

PY - 2006/5/1

Y1 - 2006/5/1

N2 - 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 and VEGF 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 χ2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression 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 in 16 tumors (22.2%); it was expressed in ≤50% 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 ≤50% of cells in 16 (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 μmol/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.

AB - 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 and VEGF 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 χ2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression 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 in 16 tumors (22.2%); it was expressed in ≤50% 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 ≤50% of cells in 16 (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 μmol/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.

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