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Angiopoietin-2 is a negative prognostic marker in small cell lung cancer
Lung Cancer 90 (2015) 302–306
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Angiopoietin-2 is a negative prognostic marker in small cell lung cancer a,∗ ˜ Israel Canadas , Álvaro Taus b , Xavier Villanueva b , Oriol Arpí a , Lara Pijuan c , a Yara Rodríguez , Silvia Menéndez a , Sergi Mojal d , Federico Rojo e , Joan Albanell a,b,f , Ana Rovira a,b , Edurne Arriola a,b a
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain Oncology Department, Hospital del Mar, Barcelona, Spain c Pathology Department, Hospital del Mar, Barcelona, Spain d Consulting Service on Methodology for Biomedical Research, IMIM, Barcelona, Spain e Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain f Universitat Pompeu Fabra, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 28 July 2015 Received in revised form 14 September 2015 Accepted 22 September 2015 Keywords: Small cell lung cancer (SCLC) Chemoresistance Angiogenesis Angiopoietin-2
a b s t r a c t Background: Small cell lung cancer (SCLC) is a highly lethal disease due to its chemorefractory nature after initial treatment. Angiogenesis plays an important role in tumor growth, metastasis and chemoresistance. We hypothesized that angiogenesis could predict chemoresistance in SCLC patients and be potentially a therapeutic target in this disease. Methods: Serum samples from forty-three SCLC patients were prospectively obtained at diagnosis, response evaluation and progression. Angiogenesis-related cytokines (Angiopoietin-2, VEGF-A, C and D) were simultaneously quantified by Luminex Technology. Clinical data were prospectively recorder. Results: Significantly higher concentration of angiogenesis-related cytokines were found in SCLC patients at diagnosis compared to healthy volunteers. High baseline serum concentration of Angiopoietin-2 (sAngiopoietin-2) were associated with a worse overall survival (p = 0.006) and remained independently associated with survival in the multivariate analysis (p = 0.008). In addition, sAngiopoietin-2 significantly increased at progression when compared to baseline. Conclusion: These data provide novel evidence on a role of sAngiopoietin-2 in the adverse clinical behavior of SCLC and could be a potential therapeutic target in this disease. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Small Cell Lung Carcinoma (SCLC) is a lethal disease that represents 15% of all lung cancers [1]. Many genetic alterations have been described, but targeted therapies are ineffective to date in SCLC [2]. The median overall survival does not exceed one year with available treatments [3]. One feature associated with the poor outcome of SCLC is the chemoresistant nature of progressive disease. We have demonstrated in SCLC cell lines and tumor samples from SCLC patients that chemoresistance is associated with epithelial to mesenchymal transition (EMT). In preclinical models, we observed that hep-
∗ Corresponding author at: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Doctor Aiguader, 88, 08003, Barcelona. Fax: +34 933160410. ˜ E-mail address: [email protected] (I. Canadas). http://dx.doi.org/10.1016/j.lungcan.2015.09.023 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
atocyte growth factor (HGF)-induced EMT was associated with increased chemoresistance, which could be reversed by treating cells with a Met inhibitor and chemotherapy [4]. Met activation is present in approximately 30% of patients with SCLC [4,5]. For the remaining patients, targetable mechanisms to revert chemoresistance remain elusive. Solid tumors require angiogenesis for survival, growth, and metastasis. Angiogenesis may also contribute to chemoresistance due to the abnormal characteristics of the neovessels and the resulting poor chemotherapy penetration into the tumors [6]. Antiangiogenic strategies directed towards tumor stroma have become standard therapies in solid tumors treatment. Unfortunately, clinical trials investigating the role of bevacizumab, a humanized mouse anti-human VEGF antibody, have not shown benefit in the outcome of SCLC patients [7,8]. However, angiogenesis is a complex process and different cytokines and receptors are involved [9]. Therefore, an agent targeting a single element of the
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Fig. 1. Serum concentration of the tested protein markers change in SCLC patients after treatment and at progression. Whole-blood samples were obtained from each SCLC patient during different disease stages (baseline, chemotherapy response assessment and progression). sAngiopoietin-2 and sVEGF-A, C and D were simultaneously measured by Luminex technology. Box plot is displayed indicating the serum concentration of the different proteins at different time points. Serum concentration medians of each protein are indicated below the graphs. Wilcoxon test was used for comparisons.
process might be not effective due to other compensatory escape mechanisms. More studies are needed to explore all possibilities that could contribute to the exit of anti-angiogenic targetedtherapy in SCLC patients. In the current study, we sought to investigate whether angiogenesis markers may predict chemoresistance in SCLC patients and be potentially a therapeutic target. For this purpose, we evaluated the protein expression profile of a number of angiogenesis-related cytokines in SCLC patients’ serum at baseline, after first line treatment and at progression.
2. Patients and methods
sex-matched healthy donors (N: 30) to the study population. This set of samples has been previously included in our previous studies [10]. 2.2. Luminex technology Using a commercially MILLIPLEX MAP Human Angiogenesis magnetic bead panel 1 kit (Millipore, Billerica, MA, USA) coupled with the Luminex® xMAP® platform we simultaneously measured circulating serum concentration of the angiogenesis-associated cytokines Angiopoietin-2, VEGF-A, C and D in accordance with the manufacturer’s procedure. These experiments were supervised by technical personal of the Luminex Core Facility at IMIM.
2.1. Patients and sample collection 2.3. Statistical analysis This study was an observational study with no intervention. Patients diagnosed with SCLC in our institution were prospectively included. The inclusion criteria were to have a cytohistological diagnosis of SCLC and to sign the informed consent. The first patient was included in January 2010 and the last in July 2013. This project was approved by the Ethics committee in our institution. As a control population, we have used serum samples from age- and
Statistical analysis was carried out with the R 3.1 program together with the Statistical Assessment Service from IMIM. To analyze associations between categorical variables we used the Chi-square test or the Fisher’s exact test as appropriate. Continuous variables were compared with Mann–Whitney U-test. Wilcoxontests were done to compare serum markers concentration from
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patients at different time points. Overall survival was analyzed by Kaplan–Meier method. Curves were compared by the log-rank test. Cox proportional hazards model was used for multivariate analysis. All tests were conducted at the two-sided 0.05 level of significance. This work was performed in accordance with REMARK guidelines [11]. 3. Results 3.1. SCLC patients have higher serum concentration of angiogenesis markers in comparison with healthy subjects Serum samples from 43 SCLC patients were included in this study. Patients’ characteristics are shown in Supplementary Table 1. The majority of patients were male and current smokers with good performance status (PS). The metastatic locations were expected, the majority of patients presenting liver and bone lesions. This cohort of SCLC patients has been included in our previous studies [10]. We first compared concentration of a panel of 4 serum markers in patients to the samples from 30 healthy volunteers. Significantly higher serum concentration of Angiopoietin-2 (sAngiopoietin-2) and VEGF-A (sVEGF-A) were found in SCLC patients at diagnosis compared to healthy volunteers, with an sAngiopoietin-2 median concentration of 3435 pg/ml versus 2185 pg/ml and 933 pg/ml sVEGF-A versus 409 pg/ml in patients vs healthy volunteers, respectively (p < 0.001) (Supplementary Fig. 1). Supplementary Table 2 illustrates the correlation of different markers evaluated by Luminex. A significant correlation of sAngiopoietin-2 with sVEGF-A and sVEGF-C was found. sVEGFC was significantly directly correlated with all of the cytokines assayed. 3.2. Serum concentration of angiogenesis markers change at the different moments of the disease in SCLC patients undergoing chemotherapy We next sought to investigate if there were changes of these markers at the different disease scenarios that could be related to chemoresistance. Fig. 1 shows serum concentration of the angiogenesis cytokines at diagnosis, response evaluation and first progression (n = 43). The cytokines evaluated showed significant changes in the different moments of the disease. Of note, sAngiopoietin-2 significantly increased at progression when compared to baseline with a median of 3649 pg/ml (p < 0.05). In 62% of patients sAngiopoietin-2 increased at progression. However, sVEGF-A and sVEGF-C decreased at progression and sVEGF-D increased during response evaluation. 3.3. Angiopoietin-2 serum concentration at diagnosis have an impact in prognosis Finally we analyzed the association of the serum biomarkers with prognosis (Supplementary Table 3). The median follow up of the series was 9.5 months (7.3–15.4) and the median overall survival was 14.8 months (10.9–18.8). PS and stage were the clinical variables associated with decreased survival in our series. Higher sAngiopoietin-2 concentration were associated with a worse outcome in SCLC patients (HR: 5.14 (1.69–15.66), p = 0.006). Fig. 2 shows the Kaplan–Meier curve for survival depending on sAngiopoietin-2 concentration in which we observed a correlation between the highest sAngiopoietin-2 concentration and a worse overall survival (p = 0.006). We performed a multivariate analysis including the significant variables of the univariate analysis. Supplementary Table 4 shows
Fig. 2. sAngiopoietin-2 concentration at diagnosis are predictive of outcome in SCLC patients. Kaplan-Meier curve for overall survival according to baseline sAngiopoietin-2 concentration in SCLC patients. Tertiles of sAngiopoietin-2 at diagnosis (2925, 2926–4114, 4115 pg/ml) were used as the cut-off. P-values were calculated using the log-rank test. Significance is displayed.
the Cox-regression model with the variables that remained independently associated with overall survival. We observe that higher sAngiopoietin-2 and extensive stage were independently associated with worse overall survival in SCLC patients (p < 0.05). 4. Discussion SCLC is one of the most aggressive types of lung cancer with absence of an effective targeted therapy. SCLC treatment has not changed in decades, always being the combination of etoposide and platinum compounds the treatment of choice. In recent years various targeted therapies have been tested in SCLC without success [12,13]. However, a patient selection based on specific biomarkers is lacking in most clinical trials. Our preclinical work has showed that Met inhibitors could be a promising therapy option for SCLC patients. We showed that circulating HGF concentration at diagnosis correlated with a shortened survival and mesenchymal phenotype in SCLC patients and could be a biomarker of patient selection for this treatment [4,10]. Recently, promising results about the efficacy of immunotherapy in a subset of patients with SCLC have been reported [14]. Angiogenesis is an important mediator of tumor progression. In the current work we show that high sAngiopoietin-2 concentration is significantly associated with poor outcome in SCLC patients. Moreover, sAngiopoietin-2 concentration increases at progression, suggesting a potential role in the chemoresistant phenotype. Angiopoietin-2 is a vascular endothelial growth factor that regulates angiogenesis during tumor progression. Its expression has been found increased in highly vascularized tumors and has been associated with poor prognosis [15]. There have emerged several modulators of Tie-2-Angiopoietin-2 axis for treating solid tumors, presenting promising results in clinical trials, such as Angiopoietin-2 selective fully human antibody (LC06) or Superavastin (Angiopoietin-2-VEGF-A crossmab) [16,17].
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Studies have addressed the correlation between Angiopoietin2 expression in tumor tissue and circulating concentration and cancer development and metastasis. However, few clinical studies have documented a correlation between Angiopoietin-2 and prognosis in lung cancer [18,19]. NSCLC patients with high circulating Angiopoietin-2 mRNA concentration have diminished overall survival when compared to those with low mRNA concentration [20]. To the best of our knowledge, the present study is the first to establish a correlation between sAngiopoietin-2 concentration and SCLC prognosis. Angiopoietin-2 expression has been associated to a mesenchymal phenotype in several tumors. [21,22]. In our previous data we showed that a mesenchymal phenotype in SCLC was associated with a worse outcome. However, in this study, we did not find an association between a mesenchymal phenotype and sAngiopoietin-2 concentration, maybe due to the limited number of samples. Several studies support angiogenesis as an attractive target in this disease. VEGF is expressed in about 80% of SCLC [23]. Several VEGFR inhibitors have been studied in SCLC, which have shown evidence of disease control [24,25]. Recently, it has been published the CALGB-30504 trial, in which Sunitinib (VEGFR specific inhibitor) improves PFS after standard chemotherapy in untreated, extensivestage SCLC [26]. We believe it would be of interest to evaluate the predictive role of sAngiopoietin-2 concentration in these trials with angiogenesis targeting agents. HGF/Met pathway has been described as a potential mechanism of resistance to anti-angiogenic therapy in some tumors. There are drugs that block simultaneously HGF/Met and angiogenesis, such as Cabozantinib, a specific inhibitor of Met and VEGFR2, capable of blocking survival, angiogenesis and metastasis in several tumor models [27]. In the current study, we analyzed serum HGF concentration and observed a correlation with sAngiopoietin-2 (data not shown). Therefore, in some patients a blockade of these two pathways may be able to revert chemoresistance and be of therapeutic benefit. In conclusion, Angiopoietin-2 serum concentration can serve as a useful prognostic marker in SCLC and may be a potential therapeutic target in this disease.
[3]
[4]
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12] [13]
Conflict of interest None declared. Acknowledgments
[14]
This work was supported by RD12/0036/0051 (J.A.), PI12/00680 (J.A.), PI13/00140 (E.A.), PI12/01552 (F.R.), 2014 SGR 740 grants and Fundació la Marató de TV3 (20130530). JA is recipient of intensification program ISCIII/FEDER. We thank Fundacion Cellex for a generous donation to the Oncology Service of Hospital del Mar.
[15] [16]
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.lungcan.2015.09. 023.
[17]
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Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Angiopoietin-2 is a negative prognostic marker in small cell lung cancer a,∗ ˜ Israel Canadas , Álvaro Taus b , Xavier Villanueva b , Oriol Arpí a , Lara Pijuan c , a Yara Rodríguez , Silvia Menéndez a , Sergi Mojal d , Federico Rojo e , Joan Albanell a,b,f , Ana Rovira a,b , Edurne Arriola a,b a
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain Oncology Department, Hospital del Mar, Barcelona, Spain c Pathology Department, Hospital del Mar, Barcelona, Spain d Consulting Service on Methodology for Biomedical Research, IMIM, Barcelona, Spain e Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain f Universitat Pompeu Fabra, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 28 July 2015 Received in revised form 14 September 2015 Accepted 22 September 2015 Keywords: Small cell lung cancer (SCLC) Chemoresistance Angiogenesis Angiopoietin-2
a b s t r a c t Background: Small cell lung cancer (SCLC) is a highly lethal disease due to its chemorefractory nature after initial treatment. Angiogenesis plays an important role in tumor growth, metastasis and chemoresistance. We hypothesized that angiogenesis could predict chemoresistance in SCLC patients and be potentially a therapeutic target in this disease. Methods: Serum samples from forty-three SCLC patients were prospectively obtained at diagnosis, response evaluation and progression. Angiogenesis-related cytokines (Angiopoietin-2, VEGF-A, C and D) were simultaneously quantified by Luminex Technology. Clinical data were prospectively recorder. Results: Significantly higher concentration of angiogenesis-related cytokines were found in SCLC patients at diagnosis compared to healthy volunteers. High baseline serum concentration of Angiopoietin-2 (sAngiopoietin-2) were associated with a worse overall survival (p = 0.006) and remained independently associated with survival in the multivariate analysis (p = 0.008). In addition, sAngiopoietin-2 significantly increased at progression when compared to baseline. Conclusion: These data provide novel evidence on a role of sAngiopoietin-2 in the adverse clinical behavior of SCLC and could be a potential therapeutic target in this disease. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Small Cell Lung Carcinoma (SCLC) is a lethal disease that represents 15% of all lung cancers [1]. Many genetic alterations have been described, but targeted therapies are ineffective to date in SCLC [2]. The median overall survival does not exceed one year with available treatments [3]. One feature associated with the poor outcome of SCLC is the chemoresistant nature of progressive disease. We have demonstrated in SCLC cell lines and tumor samples from SCLC patients that chemoresistance is associated with epithelial to mesenchymal transition (EMT). In preclinical models, we observed that hep-
∗ Corresponding author at: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Doctor Aiguader, 88, 08003, Barcelona. Fax: +34 933160410. ˜ E-mail address: [email protected] (I. Canadas). http://dx.doi.org/10.1016/j.lungcan.2015.09.023 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
atocyte growth factor (HGF)-induced EMT was associated with increased chemoresistance, which could be reversed by treating cells with a Met inhibitor and chemotherapy [4]. Met activation is present in approximately 30% of patients with SCLC [4,5]. For the remaining patients, targetable mechanisms to revert chemoresistance remain elusive. Solid tumors require angiogenesis for survival, growth, and metastasis. Angiogenesis may also contribute to chemoresistance due to the abnormal characteristics of the neovessels and the resulting poor chemotherapy penetration into the tumors [6]. Antiangiogenic strategies directed towards tumor stroma have become standard therapies in solid tumors treatment. Unfortunately, clinical trials investigating the role of bevacizumab, a humanized mouse anti-human VEGF antibody, have not shown benefit in the outcome of SCLC patients [7,8]. However, angiogenesis is a complex process and different cytokines and receptors are involved [9]. Therefore, an agent targeting a single element of the
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Fig. 1. Serum concentration of the tested protein markers change in SCLC patients after treatment and at progression. Whole-blood samples were obtained from each SCLC patient during different disease stages (baseline, chemotherapy response assessment and progression). sAngiopoietin-2 and sVEGF-A, C and D were simultaneously measured by Luminex technology. Box plot is displayed indicating the serum concentration of the different proteins at different time points. Serum concentration medians of each protein are indicated below the graphs. Wilcoxon test was used for comparisons.
process might be not effective due to other compensatory escape mechanisms. More studies are needed to explore all possibilities that could contribute to the exit of anti-angiogenic targetedtherapy in SCLC patients. In the current study, we sought to investigate whether angiogenesis markers may predict chemoresistance in SCLC patients and be potentially a therapeutic target. For this purpose, we evaluated the protein expression profile of a number of angiogenesis-related cytokines in SCLC patients’ serum at baseline, after first line treatment and at progression.
2. Patients and methods
sex-matched healthy donors (N: 30) to the study population. This set of samples has been previously included in our previous studies [10]. 2.2. Luminex technology Using a commercially MILLIPLEX MAP Human Angiogenesis magnetic bead panel 1 kit (Millipore, Billerica, MA, USA) coupled with the Luminex® xMAP® platform we simultaneously measured circulating serum concentration of the angiogenesis-associated cytokines Angiopoietin-2, VEGF-A, C and D in accordance with the manufacturer’s procedure. These experiments were supervised by technical personal of the Luminex Core Facility at IMIM.
2.1. Patients and sample collection 2.3. Statistical analysis This study was an observational study with no intervention. Patients diagnosed with SCLC in our institution were prospectively included. The inclusion criteria were to have a cytohistological diagnosis of SCLC and to sign the informed consent. The first patient was included in January 2010 and the last in July 2013. This project was approved by the Ethics committee in our institution. As a control population, we have used serum samples from age- and
Statistical analysis was carried out with the R 3.1 program together with the Statistical Assessment Service from IMIM. To analyze associations between categorical variables we used the Chi-square test or the Fisher’s exact test as appropriate. Continuous variables were compared with Mann–Whitney U-test. Wilcoxontests were done to compare serum markers concentration from
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patients at different time points. Overall survival was analyzed by Kaplan–Meier method. Curves were compared by the log-rank test. Cox proportional hazards model was used for multivariate analysis. All tests were conducted at the two-sided 0.05 level of significance. This work was performed in accordance with REMARK guidelines [11]. 3. Results 3.1. SCLC patients have higher serum concentration of angiogenesis markers in comparison with healthy subjects Serum samples from 43 SCLC patients were included in this study. Patients’ characteristics are shown in Supplementary Table 1. The majority of patients were male and current smokers with good performance status (PS). The metastatic locations were expected, the majority of patients presenting liver and bone lesions. This cohort of SCLC patients has been included in our previous studies [10]. We first compared concentration of a panel of 4 serum markers in patients to the samples from 30 healthy volunteers. Significantly higher serum concentration of Angiopoietin-2 (sAngiopoietin-2) and VEGF-A (sVEGF-A) were found in SCLC patients at diagnosis compared to healthy volunteers, with an sAngiopoietin-2 median concentration of 3435 pg/ml versus 2185 pg/ml and 933 pg/ml sVEGF-A versus 409 pg/ml in patients vs healthy volunteers, respectively (p < 0.001) (Supplementary Fig. 1). Supplementary Table 2 illustrates the correlation of different markers evaluated by Luminex. A significant correlation of sAngiopoietin-2 with sVEGF-A and sVEGF-C was found. sVEGFC was significantly directly correlated with all of the cytokines assayed. 3.2. Serum concentration of angiogenesis markers change at the different moments of the disease in SCLC patients undergoing chemotherapy We next sought to investigate if there were changes of these markers at the different disease scenarios that could be related to chemoresistance. Fig. 1 shows serum concentration of the angiogenesis cytokines at diagnosis, response evaluation and first progression (n = 43). The cytokines evaluated showed significant changes in the different moments of the disease. Of note, sAngiopoietin-2 significantly increased at progression when compared to baseline with a median of 3649 pg/ml (p < 0.05). In 62% of patients sAngiopoietin-2 increased at progression. However, sVEGF-A and sVEGF-C decreased at progression and sVEGF-D increased during response evaluation. 3.3. Angiopoietin-2 serum concentration at diagnosis have an impact in prognosis Finally we analyzed the association of the serum biomarkers with prognosis (Supplementary Table 3). The median follow up of the series was 9.5 months (7.3–15.4) and the median overall survival was 14.8 months (10.9–18.8). PS and stage were the clinical variables associated with decreased survival in our series. Higher sAngiopoietin-2 concentration were associated with a worse outcome in SCLC patients (HR: 5.14 (1.69–15.66), p = 0.006). Fig. 2 shows the Kaplan–Meier curve for survival depending on sAngiopoietin-2 concentration in which we observed a correlation between the highest sAngiopoietin-2 concentration and a worse overall survival (p = 0.006). We performed a multivariate analysis including the significant variables of the univariate analysis. Supplementary Table 4 shows
Fig. 2. sAngiopoietin-2 concentration at diagnosis are predictive of outcome in SCLC patients. Kaplan-Meier curve for overall survival according to baseline sAngiopoietin-2 concentration in SCLC patients. Tertiles of sAngiopoietin-2 at diagnosis (2925, 2926–4114, 4115 pg/ml) were used as the cut-off. P-values were calculated using the log-rank test. Significance is displayed.
the Cox-regression model with the variables that remained independently associated with overall survival. We observe that higher sAngiopoietin-2 and extensive stage were independently associated with worse overall survival in SCLC patients (p < 0.05). 4. Discussion SCLC is one of the most aggressive types of lung cancer with absence of an effective targeted therapy. SCLC treatment has not changed in decades, always being the combination of etoposide and platinum compounds the treatment of choice. In recent years various targeted therapies have been tested in SCLC without success [12,13]. However, a patient selection based on specific biomarkers is lacking in most clinical trials. Our preclinical work has showed that Met inhibitors could be a promising therapy option for SCLC patients. We showed that circulating HGF concentration at diagnosis correlated with a shortened survival and mesenchymal phenotype in SCLC patients and could be a biomarker of patient selection for this treatment [4,10]. Recently, promising results about the efficacy of immunotherapy in a subset of patients with SCLC have been reported [14]. Angiogenesis is an important mediator of tumor progression. In the current work we show that high sAngiopoietin-2 concentration is significantly associated with poor outcome in SCLC patients. Moreover, sAngiopoietin-2 concentration increases at progression, suggesting a potential role in the chemoresistant phenotype. Angiopoietin-2 is a vascular endothelial growth factor that regulates angiogenesis during tumor progression. Its expression has been found increased in highly vascularized tumors and has been associated with poor prognosis [15]. There have emerged several modulators of Tie-2-Angiopoietin-2 axis for treating solid tumors, presenting promising results in clinical trials, such as Angiopoietin-2 selective fully human antibody (LC06) or Superavastin (Angiopoietin-2-VEGF-A crossmab) [16,17].
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Studies have addressed the correlation between Angiopoietin2 expression in tumor tissue and circulating concentration and cancer development and metastasis. However, few clinical studies have documented a correlation between Angiopoietin-2 and prognosis in lung cancer [18,19]. NSCLC patients with high circulating Angiopoietin-2 mRNA concentration have diminished overall survival when compared to those with low mRNA concentration [20]. To the best of our knowledge, the present study is the first to establish a correlation between sAngiopoietin-2 concentration and SCLC prognosis. Angiopoietin-2 expression has been associated to a mesenchymal phenotype in several tumors. [21,22]. In our previous data we showed that a mesenchymal phenotype in SCLC was associated with a worse outcome. However, in this study, we did not find an association between a mesenchymal phenotype and sAngiopoietin-2 concentration, maybe due to the limited number of samples. Several studies support angiogenesis as an attractive target in this disease. VEGF is expressed in about 80% of SCLC [23]. Several VEGFR inhibitors have been studied in SCLC, which have shown evidence of disease control [24,25]. Recently, it has been published the CALGB-30504 trial, in which Sunitinib (VEGFR specific inhibitor) improves PFS after standard chemotherapy in untreated, extensivestage SCLC [26]. We believe it would be of interest to evaluate the predictive role of sAngiopoietin-2 concentration in these trials with angiogenesis targeting agents. HGF/Met pathway has been described as a potential mechanism of resistance to anti-angiogenic therapy in some tumors. There are drugs that block simultaneously HGF/Met and angiogenesis, such as Cabozantinib, a specific inhibitor of Met and VEGFR2, capable of blocking survival, angiogenesis and metastasis in several tumor models [27]. In the current study, we analyzed serum HGF concentration and observed a correlation with sAngiopoietin-2 (data not shown). Therefore, in some patients a blockade of these two pathways may be able to revert chemoresistance and be of therapeutic benefit. In conclusion, Angiopoietin-2 serum concentration can serve as a useful prognostic marker in SCLC and may be a potential therapeutic target in this disease.
[3]
[4]
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12] [13]
Conflict of interest None declared. Acknowledgments
[14]
This work was supported by RD12/0036/0051 (J.A.), PI12/00680 (J.A.), PI13/00140 (E.A.), PI12/01552 (F.R.), 2014 SGR 740 grants and Fundació la Marató de TV3 (20130530). JA is recipient of intensification program ISCIII/FEDER. We thank Fundacion Cellex for a generous donation to the Oncology Service of Hospital del Mar.
[15] [16]
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.lungcan.2015.09. 023.
[17]
[18]
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