Abstract
Micro-RNAs (miRNAs) have a complex role in carcinogenesis and tumour progression. Several miRNAs, such as miR-221, miR-27b and miR-132, have been implicated in the regulation of VEGF tumour angiogenic activity. In this pilot study, we assessed angiogenesis and DLL4+ vascular maturation index (VMI) in breast cancer tissues, in parallel with the plasma levels of the above-mentioned miRNAs. Significantly higher than control samples pre-operative levels were recorded in 10/11, 7/11 and 9/11 cases for the miR-221, miR-27b and miR-132, respectively. Seven days after surgery, a significant reduction of these miRNAs was noted in 6/11, 3/11 and 2/11 cases, respectively. High pre-operative levels of miR-27b were linked with node metastasis (p = 0.04). High pre-operative levels of miR-132 were linked with small tumours (p = 0.03) and her2 overexpression (p = 0.003). The DLL4+ VMI ranged from 26 to 69% (median 45%). Patients with poor DLL4+ VMI had significantly high pre-operative and post-operative levels of miR-221 (p = 0.01 and 0.02, respectively) and high post-operative levels of miR-132 (p = 0.02). It is concluded that angiogenesis-related miRs as detected in the plasma of patients may prove of a useful tool in the identification of patients with poor vascular maturation and high risk to develop metastasis. Whether such miRs may identify patients who would benefit from vascular normalization policies is a hypothesis that emerges from the current study.
References
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
Network CGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.
Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, Viale G, Sotiriou C, Piccart M. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32:2794–803.
Győrffy B, Hatzis C, Sanft T, Hofstatter E, Aktas B, Pusztai L. Multigene prognostic tests in breast cancer: past, present, future. Breast Cancer Res. 2015;17:11.
Amorim M, Salta S, Henrique R, Jerónimo C. Decoding the usefulness of non-coding RNAs as breast cancer markers. J Transl Med. 2016;14:265.
Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet. 2006;15:17–29.
Zoni E, van der Pluijm G. The role of microRNAs in bone metastasis. J Bone Oncol. 2016;5:104–8.
Muluhngwi P, Klinge CM. Roles for miRNAs in endocrine resistance in breast cancer. Endocr Relat Cancer. 2015;22:R279–300.
Wang J, Yang M, Li Y, Han B. The role of microRNAs in the chemoresistance of breast cancer. Drug Dev Res. 2015;76:368–74.
Chakraborty C, Chin KY, Das S. miRNA-regulated cancer stem cells: understanding the property and the role of miRNA in carcinogenesis. Tumour Biol. 2016;37:13039–48.
Uzzan B, Nicolas P, Cucherat M, Perret GY. Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res. 2004;64:2941–55.
Kristensen TB, Knutsson ML, Wehland M, Laursen BE, Grimm D, Warnke E, Magnusson NE. Anti-vascular endothelial growth factor therapy in breast cancer. Int J Mol Sci. 2014;15:23024–41.
Brizzi MF, Defilippi P. Dll4/Notch1 signaling from tip/stalk endothelial cell specification to stroma-dependent lung tumor inhibition: a flavor of Dll4/Notch1 pleiotropy in tumor cell biology. Transl Lung Cancer Res. 2013;2:466–9.
Li JL, Sainson RC, Oon CE, Turley H, Leek R, Sheldon H, Bridges E, Shi W, Snell C, Bowden ET, Wu H, Chowdhury PS, Russell AJ, Montgomery CP, Poulsom R, Harris AL. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 2011;71:6073–83.
Nicoli S, Knyphausen CP, Zhu LJ, Lakshmanan A, Lawson ND. miR-221 is required for endothelial tip cell behaviors during vascular development. Dev Cell. 2012;22:418–29.
Biyashev D, Veliceasa D, Topczewski J, Topczewska JM, Mizgirev I, Vinokour E, Reddi AL, Licht JD, Revskoy SY, Volpert OV. miR-27b controls venous specification and tip cell fate. Blood. 2012;119:2679–87.
Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105:10513–8.
Westenskow PD, Kurihara T, Aguilar E, Scheppke EL, Moreno SK, Wittgrove C, Marchetti V, Michael IP, Anand S, Nagy A, Cheresh D, Friedlander M. Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. J Clin Investig. 2013;123:4900–8.
Kontomanolis E, Panteliadou M, Giatromanolaki A, Pouliliou S, Efremidou E, Limberis V, Galazios G, Sivridis E, Koukourakis MI. Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis. Med Oncol. 2014;31:945.
Giatromanolaki A, Koukourakis MI, Simopoulos C, Polychronidis A, Gatter KC, Harris AL, Sivridis E. c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent. Clin Cancer Res. 2004;10:7972–7.
Fox SB, Gasparini G, Harris AL. Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs. Lancet Oncol. 2001;2:278–89.
Koukourakis MI, Giatromanolaki A, Sivridis E, Fezoulidis I. Cancer vascularization: implications in radiotherapy? Int J Radiat Oncol Biol Phys. 2000;48:545–53.
Giatromanolaki A, Sivridis E, Koukourakis MI. Tumour angiogenesis: vascular growth and survival. APMIS. 2004;112:431–40.
Tolaney SM, Boucher Y, Duda DG, Martin JD, Seano G, Ancukiewicz M, Barry WT, Goel S, Lahdenrata J, Isakoff SJ, Yeh ED, Jain SR, Golshan M, Brock J, Snuderl M, Winer EP, Krop IE, Jain RK. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. Proc Natl Acad Sci USA. 2015;112:14325–30.
Jubb AM, Soilleux EJ, Turley H, Steers G, Parker A, Low I, Blades J, Li JL, Allen P, Leek R, Noguera-Troise I, Gatter KC, Thurston G, Harris AL. Expression of vascular notch ligand delta-like 4 and inflammatory markers in breast cancer. Am J Pathol. 2010;176:2019–28.
Patel NS, Dobbie MS, Rochester M, Steers G, Poulsom R, Le Monnier K, Cranston DW, Li JL, Harris AL. Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer. Clin Cancer Res. 2006;12:4836–44.
Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL. High DLL4 expression in tumour-associated vessels predicts for favorable radiotherapy outcome in locally advanced squamous cell head-neck cancer (HNSCC). Angiogenesis. 2013;16:343–51.
He S, Lai R, Chen D, Yan W, Zhang Z, Liu Z, Ding X, Chen Y. Downregulation of miR-221 inhibits cell migration and invasion through targeting methyl-CpG binding domain protein 2 in human oral squamous cell carcinoma cells. Biomed Res Int. 2015;2015:751672.
Cai Guilan, Qiao Shanshan, Chen Kui. Suppression of miR-221 inhibits glioma cells proliferation and invasion via targeting SEMA3B. Biol Res. 2015;48:37.
Ye Jun, Xianguo Wu, Dang Wu, Pin Wu, Ni Chao, Zhang Zhigang, Chen Zhigang, Qiu Fuming, Jinghong Xu, Huang Jian. miRNA-27b targets vascular endothelial growth factor C to inhibit tumor progression and angiogenesis in colorectal cancer. PLoS ONE. 2013;8:e60687.
Yilmaz SS, Guzel E, Karatas OF, Yilmaz M, Creighton CJ, Ozen M. MiR-221 as a pre- and postoperative plasma biomarker for larynx cancer patients. Laryngoscope. 2015;125:E377–81.
Stückrath I, Rack B, Janni W, Jäger B, Pantel K, Schwarzenbach H. Aberrant plasma levels of circulating miR-16, miR-107, miR-130a and miR-146a are associated with lymph node metastasis and receptor status of breast cancer patients. Oncotarget. 2015;6:13387–401.
Mao L, Sun AJ, Wu JZ, Tang JH. Involvement of microRNAs in HER2 signaling and trastuzumab treatment. Tumour Biol. 2016. doi:10.1007/s13277-016-5405-3.
Wong PP, Bodrug N, Hodivala-Dilke KM. Exploring novel methods for modulating tumor blood vessels in cancer treatment. Curr Biol. 2016;26:R1161–6.
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The study has been financially supported by the Tumour and Angiogenesis Research Group.
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All patients provided a written informed consent for sample collection, and further analysis was approved by the local Ethics and Research Committee. The study has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
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Kontomanolis, E., Mitrakas, A., Giatromanolaki, A. et al. A pilot study on plasma levels of micro-RNAs involved in angiogenesis and vascular maturation in patients with breast cancer. Med Oncol 34, 20 (2017). https://doi.org/10.1007/s12032-016-0881-2
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DOI: https://doi.org/10.1007/s12032-016-0881-2