Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Patients
2.2. Sample Preparation and Ang-2 Level Measurement
2.3. Statistical Analysis
3. Results
3.1. Association of Ang-2 Serum Levels with the Development of Lung Cancer
3.2. Association of Baseline Ang-2 Serum Level with the 5-Year Overall Survival of NSCLC and SCLC
3.3. Ang-2 Serum Concentration before Treatment and after the Third Cycle of Chemotherapy
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Global Burden of Disease Cancer Collaboration; Fitzmaurice, C.; Dicker, D.; Pain, A.; Hamavid, H.; Moradi-Lakeh, M.; MacIntyre, M.F.; Allen, C.; Hansen, G.; Woodbrook, R.; et al. The Global Burden of Cancer 2013. JAMA Oncol. 2015, 1, 505–527. [Google Scholar] [CrossRef]
- Torre, L.A.; Siegel, R.L.; Jemal, A. Lung Cancer Statistics. Adv. Exp. Med. Biol. 2016, 893, 1–19. [Google Scholar] [CrossRef] [PubMed]
- Govindan, R.; Page, N.; Morgensztern, D.; Read, W.; Tierney, R.; Vlahiotis, A.; Spitznagel, E.L.; Piccirillo, J. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database. J. Clin. Oncol. 2006, 24, 4539–4544. [Google Scholar] [CrossRef]
- Molina, J.R.; Yang, P.; Cassivi, S.D.; Schild, S.E.; Adjei, A.A. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc. 2008, 83, 584–594. [Google Scholar] [CrossRef]
- Rajabi, M.; Mousa, S.A. The Role of Angiogenesis in Cancer Treatment. Biomedicines 2017, 5, 34. [Google Scholar] [CrossRef] [Green Version]
- Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Angiogenesis in cancer. Vasc. Health Risk Manag. 2006, 2, 213–219. [Google Scholar] [CrossRef]
- Bacic, I.; Karlo, R.; Zadro, A.S.; Zadro, Z.; Skitarelic, N.; Antabak, A. Tumor angiogenesis as an important prognostic factor in advanced non-small cell lung cancer (Stage IIIA). Oncol. Lett. 2018, 15, 2335–2339. [Google Scholar] [CrossRef]
- Farzaneh Behelgardi, M.; Zahri, S.; Mashayekhi, F.; Mansouri, K.; Asghari, S.M. A peptide mimicking the binding sites of VEGF-A and VEGF-B inhibits VEGFR-1/-2 driven angiogenesis, tumor growth and metastasis. Sci. Rep. 2018, 8, 17924. [Google Scholar] [CrossRef] [Green Version]
- Shim, W.S.; Ho, I.A.; Wong, P.E. Angiopoietin: A TIE(d) balance in tumor angiogenesis. Mol. Cancer Res. 2007, 5, 655–665. [Google Scholar] [CrossRef]
- Tsakogiannis, D.; Nikolakopoulou, A.; Zagouri, F.; Stratakos, G.; Syrigos, K.; Zografos, E.; Koulouris, N.; Bletsa, G. Update Overview of the Role of Angiopoietins in Lung Cancer. Medicina 2021, 57, 1191. [Google Scholar] [CrossRef] [PubMed]
- Xuan, Z.X.; Zhang, S.; Yuan, S.J.; Wang, W.; Yu, J. Prognostic value of angiopoietin-2 in non-small cell lung cancer patients: A meta-analysis. World J. Surg. Oncol. 2016, 14, 237. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, Y.; Zhang, Y.; Wang, Z.; Chen, N.; Zhou, J.; Liu, L. The role of serum angiopoietin-2 levels in progression and prognosis of lung cancer: A meta-analysis. Medicine 2017, 96, e8063. [Google Scholar] [CrossRef] [PubMed]
- Fawzy, A.; Gaafar, R.; Kasem, F.; Ali, S.S.; Elshafei, M.; Eldeib, M. Importance of serum levels of angiopoietin-2 and survivin biomarkers in non-small cell lung cancer. J. Egypt. Natl. Cancer Inst. 2012, 24, 41–45. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, J.H.; Choi, H.; Kim, Y.B.; Kim, Y.S.; Sheen, S.S.; Choi, J.H.; Lee, H.L.; Lee, K.S.; Chung, W.Y.; Lee, S.; et al. Serum angiopoietin-1 as a prognostic marker in resected early stage lung cancer. Lung Cancer 2009, 66, 359–364. [Google Scholar] [CrossRef] [PubMed]
- Park, J.H.; Park, K.J.; Kim, Y.S.; Sheen, S.S.; Lee, K.S.; Lee, H.N.; Oh, Y.J.; Hwang, S.C. Serum angiopoietin-2 as a clinical marker for lung cancer. Chest 2007, 132, 200–206. [Google Scholar] [CrossRef] [PubMed]
- Canadas, I.; Taus, A.; Villanueva, X.; Arpi, O.; Pijuan, L.; Rodriguez, Y.; Menendez, S.; Mojal, S.; Rojo, F.; Albanell, J.; et al. Angiopoietin-2 is a negative prognostic marker in small cell lung cancer. Lung Cancer 2015, 90, 302–306. [Google Scholar] [CrossRef]
- Zhang, C.L.; Ge, S.L.; Yang, N.; Zhang, J.R.; Tian, D.D. Elevated Serum Level of Angiopoietin-2 as a Potential Marker for Poor Prognosis in Small Cell Lung Cancer. Tohoku J. Exp. Med. 2015, 236, 305–309. [Google Scholar] [CrossRef] [Green Version]
- Xu, C.; Wang, W.; Wang, Y.; Zhang, X.; Yan, J.; Yu, L. Serum Angiopoietin-2 as a Clinical Marker for Lung Cancer in Patients with Solitary Pulmonary Nodules. Ann. Clin. Lab. Sci. 2016, 46, 60–64. [Google Scholar]
- Naumnik, W.; Naumnik, B.; Niewiarowska, K.; Ossolinska, M.; Chyczewska, E. Angiogenic axis angiopoietin-1 and angiopoietin-2/Tie-2 in non-small cell lung cancer: A bronchoalveolar lavage and serum study. Adv. Exp. Med. Biol. 2013, 788, 341–348. [Google Scholar] [CrossRef]
- Dong, Z.; Chen, J.; Yang, X.; Zheng, W.; Wang, L.; Fang, M.; Wu, M.; Yao, M.; Yao, D. Ang-2 promotes lung cancer metastasis by increasing epithelial-mesenchymal transition. Oncotarget 2018, 9, 12705–12717. [Google Scholar] [CrossRef] [PubMed]
- Zhou, L.; Lan, H.; Zhou, Q.; Yue, J.; Liu, B. Plasma angiopoietin-2 is persistently elevated after non-small cell lung cancer surgery and stimulates angiogenesis in vitro. Medicine 2016, 95, e4493. [Google Scholar] [CrossRef] [PubMed]
- Kopczynska, E.; Dancewicz, M.; Kowalewski, J.; Makarewicz, R.; Kardymowicz, H.; Kaczmarczyk, A.; Tyrakowski, T. Time-dependent changes of plasma concentrations of angiopoietins, vascular endothelial growth factor, and soluble forms of their receptors in nonsmall cell lung cancer patients following surgical resection. ISRN Oncol. 2012, 2012, 638352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ng, C.S.; Wan, S.; Wong, R.H.; Ho, A.M.; Yim, A.P. Angiogenic response to major lung resection for non-small cell lung cancer with video-assisted thoracic surgical and open access. Sci. World J. 2012, 2012, 636754. [Google Scholar] [CrossRef] [Green Version]
- Daly, S.; Kubasiak, J.C.; Rinewalt, D.; Pithadia, R.; Basu, S.; Fhied, C.; Lobato, G.C.; Seder, C.W.; Hong, E.; Warren, W.H.; et al. Circulating angiogenesis biomarkers are associated with disease progression in lung adenocarcinoma. Ann. Thorac. Surg. 2014, 98, 1968–1975; discussion 1975. [Google Scholar] [CrossRef]
- Coelho, A.L.; Araujo, A.M.; Gomes, M.P.; Catarino, R.J.; Andrade, E.B.; Lopes, A.M.; Medeiros, R.M. Combined Ang-2 and VEGF serum levels: Holding hands as a new integral biomarker in non-small-cell lung cancers. Future Oncol. 2015, 11, 3233–3242. [Google Scholar] [CrossRef]
- Coelho, A.L.; Gomes, M.P.; Catarino, R.J.; Rolfo, C.; Medeiros, R.M.; Araujo, A.M. CSF-1 and Ang-2 serum levels—Prognostic and diagnostic partners in non-small cell lung cancer. ESMO Open 2018, 3, e000349. [Google Scholar] [CrossRef] [Green Version]
- Hu, W.; Tang, C.H.; Chen, H.T.; Zhao, J.; Jin, L.; Kang, L.; Wu, Y.; Ying, P.; Wang, C.Q.; Su, C.M. Correlations between angiopoietin-2 gene polymorphisms and lung cancer progression in a Chinese Han population. J. Cancer 2019, 10, 2935–2941. [Google Scholar] [CrossRef] [Green Version]
- Fagiani, E.; Christofori, G. Angiopoietins in angiogenesis. Cancer Lett. 2013, 328, 18–26. [Google Scholar] [CrossRef]
- Naumnik, W.; Chyczewska, E.; Ossolinska, M. Serum levels of angiopoietin-1, angiopoietin-2, and their receptor tie-2 in patients with nonsmall cell lung cancer during chemotherapy. Cancer Investig. 2009, 27, 741–746. [Google Scholar] [CrossRef]
- Angermann, R.; Rauchegger, T.; Nowosielski, Y.; Seifarth, C.; Egger, S.; Kralinger, M.T.; Kieselbach, G.F.; Zehetner, C. Systemic counterregulatory response of angiopoietin-2 after aflibercept therapy for nAMD: A potential escape mechanism. Acta Ophthalmol. 2021, 99, e869–e875. [Google Scholar] [CrossRef] [PubMed]
- Peterson, T.E.; Kirkpatrick, N.D.; Huang, Y.; Farrar, C.T.; Marijt, K.A.; Kloepper, J.; Datta, M.; Amoozgar, Z.; Seano, G.; Jung, K.; et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl. Acad. Sci. USA 2016, 113, 4470–4475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Winkler, F.; Kozin, S.V.; Tong, R.T.; Chae, S.S.; Booth, M.F.; Garkavtsev, I.; Xu, L.; Hicklin, D.J.; Fukumura, D.; di Tomaso, E.; et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004, 6, 553–563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Batchelor, T.T.; Mulholland, P.; Neyns, B.; Nabors, L.B.; Campone, M.; Wick, A.; Mason, W.; Mikkelsen, T.; Phuphanich, S.; Ashby, L.S.; et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J. Clin. Oncol. 2013, 31, 3212–3218. [Google Scholar] [CrossRef] [Green Version]
- Rigamonti, N.; Kadioglu, E.; Keklikoglou, I.; Wyser Rmili, C.; Leow, C.C.; De Palma, M. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 2014, 8, 696–706. [Google Scholar] [CrossRef] [Green Version]
- Moon, W.S.; Rhyu, K.H.; Kang, M.J.; Lee, D.G.; Yu, H.C.; Yeum, J.H.; Koh, G.Y.; Tarnawski, A.S. Overexpression of VEGF and angiopoietin 2: A key to high vascularity of hepatocellular carcinoma? Mod. Pathol. 2003, 16, 552–557. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.L.; Deng, C.S.; Lin, J.; Pan, D.Y.; Zou, Z.Y.; Zhou, X.Y. Expression of angiopoietin-2 is correlated with vascularization and tumor size in human colorectal adenocarcinoma. Tohoku J. Exp. Med. 2007, 213, 33–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Labussiere, M.; Cheneau, C.; Prahst, C.; Gallego Perez-Larraya, J.; Farina, P.; Lombardi, G.; Mokhtari, K.; Rahimian, A.; Delattre, J.Y.; Eichmann, A.; et al. Angiopoietin-2 May Be Involved in the Resistance to Bevacizumab in Recurrent Glioblastoma. Cancer Investig. 2016, 34, 39–44. [Google Scholar] [CrossRef]
- Socinski, M.A.; Nishio, M.; Jotte, R.M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodriguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C.A.; et al. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J. Thorac. Oncol. 2021, 16, 1909–1924. [Google Scholar] [CrossRef]
- Scholz, A.; Harter, P.N.; Cremer, S.; Yalcin, B.H.; Gurnik, S.; Yamaji, M.; Di Tacchio, M.; Sommer, K.; Baumgarten, P.; Bahr, O.; et al. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol. Med. 2016, 8, 39–57. [Google Scholar] [CrossRef]
- Daly, C.; Eichten, A.; Castanaro, C.; Pasnikowski, E.; Adler, A.; Lalani, A.S.; Papadopoulos, N.; Kyle, A.H.; Minchinton, A.I.; Yancopoulos, G.D.; et al. Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res. 2013, 73, 108–118. [Google Scholar] [CrossRef] [PubMed]
- Mazzieri, R.; Pucci, F.; Moi, D.; Zonari, E.; Ranghetti, A.; Berti, A.; Politi, L.S.; Gentner, B.; Brown, J.L.; Naldini, L.; et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 2011, 19, 512–526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Holopainen, T.; Saharinen, P.; D’Amico, G.; Lampinen, A.; Eklund, L.; Sormunen, R.; Anisimov, A.; Zarkada, G.; Lohela, M.; Helotera, H.; et al. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis. J. Natl. Cancer Inst. 2012, 104, 461–475. [Google Scholar] [CrossRef] [PubMed]
- Srivastava, K.; Hu, J.; Korn, C.; Savant, S.; Teichert, M.; Kapel, S.S.; Jugold, M.; Besemfelder, E.; Thomas, M.; Pasparakis, M.; et al. Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 2014, 26, 880–895. [Google Scholar] [CrossRef] [Green Version]
- Schmittnaegel, M.; Rigamonti, N.; Kadioglu, E.; Cassara, A.; Wyser Rmili, C.; Kiialainen, A.; Kienast, Y.; Mueller, H.J.; Ooi, C.H.; Laoui, D.; et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl. Med. 2017, 9, eaak9670. [Google Scholar] [CrossRef]
Ang-2 Median (pg/mL) | p-Values | |
---|---|---|
Patients (n = 99) | 3459 | |
Control (n = 55) | 2148 | <0.0001 |
Patients | ||
Age | ||
≥65 (n = 50) | 3520 | |
<65 (n = 49) | 3479 | 0.91 |
Smoke | ||
Yes (n = 62) | 3643 | |
No (n = 37) | 3338 | 0.16 |
Gender | ||
Males (n = 74) | 3493 | |
Females (n = 25) | 3526 | 0.61 |
Metastasis | ||
Metastasis (n = 64) | 3538 | |
No Metastasis (n = 35) | 3318 | 0.23 |
Lung cancer type | ||
NSCLC (n = 73) | 3508 | |
SCLC (n = 26) | 3479 | 0.91 |
SCLC | Ang-2 Median (pg/mL) | p-Values | NSCLC | Ang-2 Median (pg/mL) | p-Values |
---|---|---|---|---|---|
Patients (n = 26) | 3479 | Patients (n = 73) | 3508 | ||
Control (n = 55) | 2148 | <0.0001 | Control (n = 55) | 2148 | <0.0001 |
Patients | Patients | ||||
Age | Age | ||||
≥65 (n = 13) | 3552 | ≥65 (n = 44) | 3573 | ||
<65 (n = 13) | 2683 | 0.64 | <65 (n = 29) | 3350 | 0.96 |
Smoke | Smoke | ||||
Yes (n = 20) | 3434 | Yes (n = 43) | 3628 | ||
No (n = 6) | 3678 | 0.8 | No (n = 30) | 3161 | 0.24 |
Gender | Gender | ||||
Males (n = 19) | 3493 | Males (n = 55) | 3458 | ||
Females (n = 7) | 2683 | 0.4 | Females (n = 18) | 3538 | 0.9 |
Metastasis | Metastasis | ||||
Metastasis (n = 19) | 3891 | Metastasis (n = 45) | 3526 | ||
No Metastasis (n = 7) | 2683 | 0.11 | No Metastasis (n = 28) | 3350 | 0.61 |
Parameters | Hazard Ratio | Low Limit | Upper Limit | p-Value |
---|---|---|---|---|
Ang-2 | 2.97 | 1.05 | 8.40 | 0.04 |
Age | 0.67 | 0.21 | 2.14 | 0.50 |
Smoke | 0.96 | 0.34 | 2.71 | 0.94 |
Gender | 0.76 | 0.22 | 2.69 | 0.68 |
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Nikolakopoulou, A.; Tsakogiannis, D.; Zagouri, F.; Zografos, E.; Tzioga, L.; Stratakos, G.; Koulouris, N.; Syrigos, K.; Bletsa, G. Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC. Life 2022, 12, 2092. https://doi.org/10.3390/life12122092
Nikolakopoulou A, Tsakogiannis D, Zagouri F, Zografos E, Tzioga L, Stratakos G, Koulouris N, Syrigos K, Bletsa G. Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC. Life. 2022; 12(12):2092. https://doi.org/10.3390/life12122092
Chicago/Turabian StyleNikolakopoulou, Asimina, Dimitris Tsakogiannis, Flora Zagouri, Eleni Zografos, Lamprini Tzioga, Grigorios Stratakos, Nikolaos Koulouris, Konstantinos Syrigos, and Garyfalia Bletsa. 2022. "Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC" Life 12, no. 12: 2092. https://doi.org/10.3390/life12122092