CLINICAL RESEARCH
 
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Tumor neovascularization, an essential requirement for malignant disease progression and metastasis, depends on the dysregulation of pro-angiogenic and anti-angiogenic activities. This study aimed to investigate the utilization of circulatory angiopoietins (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF-A and VEGF-C), and basic fibroblast growth factor (bFGF) as a prognostic tool for acute myeloid leukemia (AML).

Material and methods:
Twenty-four AML patients who were under chemotherapeutic intervention were included. Patients’ relapse status, responsiveness to chemotherapy, and remission status were obtained from their medical profiles. For comparative purposes, fifteen healthy subjects were included. Serum levels of growth factors were measured.

Results:
As compared to control subjects, AML patients had significantly lower average levels of Ang-1 (170.8 ±12.7 versus 59.2 ±12.5 ng/ml) and VEGF-A (56.0 ±13.1 versus 98.6 ±11.9 ng/dl) that coincide with a higher average level of Ang-2 (18.5 ±4.1 ng/ml versus 7.5 ±0.8 ng/ml). Spearman’s correlation analysis defined a significant association of sAng-1 and sAng-2 with patients’ response to chemotherapy ( = 0.488) and remission status ( = 0.476), respectively. According to the receiver operating characteristic (ROC) curve, downregulation of Ang-1 has good predictivity for poor responsiveness to chemotherapy (AUC = 0.781, p < 0.05) while upregulation of sAng-2 has good predictivity for failed remission status (AUC = 0.779, p < 0.05).

Conclusions:
In the context of AML, dysregulated circulatory levels of Ang-1 and Ang-2 are suggested prognostic markers to provide useful predictivity of patients’ adverse responsiveness to chemotherapy and remission status, respectively.

 
REFERENCES (37)
1.
van Dijk MR, Steyerberg EW, Habbema JD. A decision-analytic approach to define poor prognosis patients: a case study for non-seminomatous germ cell cancer patients. BMC Med Inform Decis Mak 2008; 8: 1.
 
2.
Kurosawa S, Yamaguchi T, Miyawaki S, et al. Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse. Haematologica 2010; 95: 1857-64.
 
3.
Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005; 23: 1969-78.
 
4.
Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 2020; 77: 1745-70.
 
5.
Ribatti D, Pezzella F. Overview on the different patterns of tumor vascularization. Cells 2021; 10: 639.
 
6.
Trujillo A, McGee C, Cogle CR. Angiogenesis in acute myeloid leukemia and opportunities for novel therapies J Oncol 2012; 2012: 128608.
 
7.
La Mendola D, Trincavelli ML, Martini C. Angiogenesis in disease. Int J Mol Sci 2022; 23: 10962.
 
8.
Tait CR, Jones PF. Angiopoietins in tumours: the angiogenic switch. J Pathol 2004; 204: 1-10.
 
9.
Atkin GK, Chopada A. Tumour angiogenesis: the relevance to surgeons. Ann R Coll Surg Engl 2006; 88: 525-9.
 
10.
Yang P, Chen N, Yang D, et al. The ratio of serum Angiopoietin-1 to Angiopoietin-2 in patients with cervical cancer is a valuable diagnostic and prognostic biomarker. PeerJ 2017; 5: e3387.
 
11.
Reiss Y. Angiopoietins. Recent Results Cancer Res 2010; 180: 3-13.
 
12.
Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res 2005; 65: 550-63.
 
13.
Stavri GT, Zachary IC, Baskerville PA, Martin JF, Erusalimsky JD. Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells. Synergistic interaction with hypoxia. Circulation 1995; 92: 11-4.
 
14.
Pang RW, Poon RT. Clinical implications of angiogenesis in cancers. Vasc Health Risk Manag 2006; 2: 97-108.
 
15.
Brouwers J, Noviyanti R, Fijnheer R, et al. Platelet activation determines angiopoietin-1 and VEGF levels in malaria: implications for their use as biomarkers. PLoS One 2014; 8: e64850.
 
16.
Zalewska-Ziob M, Adamek B, Kasperczyk J, Dobija-Kubica K. Prognostic value of tumour tissue ANG-1 expression and Ang-1 concentration in patients with non-small-cell lung cancer. Pol J Pathol 2022; 73: 6-13.
 
17.
Villegas G, Lange-Sperandio B, Tufro A. Autocrine and paracrine functions of vascular endothelial growth factor (VEGF) in renal tubular epithelial cells. Kidney Int 2005; 67: 449-57.
 
18.
Ferrara N, Carver-Moore K, Chen H, et al, Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439-42.
 
19.
Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol 2001; 193: 468-75.
 
20.
de Jonge HJ, Valk PJ, Veeger NJ, et al. High VEGFC expression is associated with unique gene expression profiles and predicts adverse prognosis in pediatric and adult acute myeloid leukemia. Blood 2010; 116: 1747-54.
 
21.
Skowerski T, Nabrdalik K, Kwiendacz H, et al, Angiopoietin-2 as a biomarker of non-ST-segment elevation myocardial infarction in patients with or without type 2 diabetes. Arch Med Sci 2022; 18: 624-31.
 
22.
Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 2007; 26: 489-502.
 
23.
Yoshiji H, Kuriyama S, Noguchi R, et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut 2005; 54: 1768-75.
 
24.
Asahara T, Chen D, Takahashi T, et al. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res 1998; 83: 233-40.
 
25.
Metheny-Barlow LJ, Li LY. The enigmatic role of angiopoietin-1 in tumor angiogenesis. Cell Res 2003; 13: 309-17.
 
26.
Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277: 55-60.
 
27.
Daly C, Eichten A, Castanaro C, et al. Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res 2013; 73: 108-18.
 
28.
Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999; 284: 1994-8.
 
29.
Cao Y, Sonveaux P, Liu S, et al. Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res 2007; 67: 3835-44.
 
30.
Fagiani E, Christofori G. Angiopoietins in angiogenesis. Cancer Lett 2013; 328: 18-26.
 
31.
Korn C, Augustin HG. Mechanisms of vessel pruning and regression. Dev Cell 2015; 34: 5-17.
 
32.
Irani K. Angiotensin II-stimulated vascular remodeling: the search for the culprit oxidase. Circ Res 2001; 88: 858-60.
 
33.
Mazzieri R, Pucci F, Moi D, 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: 512-26.
 
34.
Schliemann C, Bieker R, Thoennissen N, et al, Circulating angiopoietin-2 is a strong prognostic factor in acute myeloid leukemia. Leukemia 2007; 21: 1901-6.
 
35.
Quartarone E, Alonci A, Allegra A, et al. Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies. Eur J Haematol 2006; 77: 480-5.
 
36.
Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354-65.
 
37.
Tripon F, Banescu C, Trifa AP, et al. TERT rs2853669 as a predictor for overall survival in patients with acute myeloid leukaemia. Arch Med Sci 2022; 18: 103-11.
 
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ISSN:1734-1922
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