{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:03:41Z","timestamp":1790737421527,"version":"4.1.0"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["Project-ID 360372040 - SFB 1335."],"award-info":[{"award-number":["Project-ID 360372040 - SFB 1335."]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Babe\u015f-Bolyai University","award":["Grants for Young Researchers (No. 35282\/18.11.2020)"],"award-info":[{"award-number":["Grants for Young Researchers (No. 35282\/18.11.2020)"]}]},{"name":"Babe\u015f-Bolyai University","award":["Grants for the support of strategic infrastructure for 2020 (33PFE\/2018 and CNFIS-FDI-2020-0387)"],"award-info":[{"award-number":["Grants for the support of strategic infrastructure for 2020 (33PFE\/2018 and CNFIS-FDI-2020-0387)"]}]},{"DOI":"10.13039\/501100006595","name":"UEFISCDI","doi-asserted-by":"crossref","award":["PN-II-RU-TE-2014\u20134\u20131191 (No. 235\/01.10.2015)"],"award-info":[{"award-number":["PN-II-RU-TE-2014\u20134\u20131191 (No. 235\/01.10.2015)"]}],"id":[{"id":"10.13039\/501100006595","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo\n                    <jats:italic>,<\/jats:italic>\n                    with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on\n                    <jats:italic>s.c.<\/jats:italic>\n                    B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy almost totally inhibited (&gt;\u200990%) the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and\u00a0simultaneous induction of a pro-apoptotic state\u00a0of tumor cells in the tumor microenvironment (TME). These effects were accompanied by the partial re-education of TAMs towards an M1 phenotype and augmented by combined therapy-induced suppression of major invasion and metastasis promoters (HIF-1\u03b1, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-01284-5","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T06:06:09Z","timestamp":1636610769000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression"],"prefix":"10.1038","volume":"11","author":[{"given":"Valentin-Florian","family":"Rauca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Patras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavinia","family":"Luput","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Licarete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad-Alexandru","family":"Toma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Porfire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augustin Catalin","family":"Mot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rakosy-Tican","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Sesarman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Banciu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"1284_CR1","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1053\/j.seminoncol.2007.09.009","volume":"34","author":"GH Mahabeleshwar","year":"2007","unstructured":"Mahabeleshwar, G. H. & Byzova, T. V. Angiogenesis in melanoma. Semin. Oncol. 34, 555\u2013565 (2007).","journal-title":"Semin. Oncol."},{"key":"1284_CR2","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nrc.2017.51","volume":"17","author":"M De Palma","year":"2017","unstructured":"De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457\u2013474 (2017).","journal-title":"Nat. Rev. Cancer"},{"key":"1284_CR3","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/nrc2403","volume":"8","author":"LM Ellis","year":"2008","unstructured":"Ellis, L. M. & Hicklin, D. J. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat. Rev. Cancer 8, 579\u2013591 (2008).","journal-title":"Nat. Rev. Cancer"},{"key":"1284_CR4","doi-asserted-by":"publisher","first-page":"15444","DOI":"10.18632\/oncotarget.6999","volume":"7","author":"W Liang","year":"2016","unstructured":"Liang, W., Ni, Y. & Chen, F. Tumor resistance to vascular disrupting agents: mechanisms, imaging, and solutions. Oncotarget 7, 15444\u201315459 (2016).","journal-title":"Oncotarget"},{"key":"1284_CR5","first-page":"185","volume":"2","author":"S Tazzyman","year":"2014","unstructured":"Tazzyman, S., Murdoch, C., Yeomans, J., Harrison, J. & Muthana, M. Macrophage-mediated response to hypoxia in disease. Hypoxia (Auckl) 2, 185\u2013196 (2014).","journal-title":"Hypoxia (Auckl)"},{"key":"1284_CR6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.3389\/fonc.2020.00221","volume":"10","author":"Y Haibe","year":"2020","unstructured":"Haibe, Y. et al. Resistance mechanisms to anti-angiogenic therapies in cancer. Front. Oncol. 10, 221 (2020).","journal-title":"Front. Oncol."},{"key":"1284_CR7","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1016\/j.canlet.2014.11.010","volume":"356","author":"MC Alupei","year":"2015","unstructured":"Alupei, M. C., Licarete, E., Patras, L. & Banciu, M. Liposomal simvastatin inhibits tumor growth via targeting tumor-associated macrophages-mediated oxidative stress. Cancer Lett. 356, 946\u2013952 (2015).","journal-title":"Cancer Lett."},{"key":"1284_CR8","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1038\/nrd.2018.169","volume":"17","author":"L Cassetta","year":"2018","unstructured":"Cassetta, L. & Pollard, J. W. Targeting macrophages: therapeutic approaches in cancer. Nat. Rev. Drug Discov. 17, 887\u2013904 (2018).","journal-title":"Nat. Rev. Drug Discov."},{"key":"1284_CR9","doi-asserted-by":"publisher","first-page":"e0202827","DOI":"10.1371\/journal.pone.0202827","volume":"13","author":"V-F Rauca","year":"2018","unstructured":"Rauca, V.-F. et al. Combination therapy of simvastatin and 5, 6-dimethylxanthenone-4-acetic acid synergistically suppresses the aggressiveness of B16.F10 melanoma cells. PLoS ONE 13, e0202827 (2018).","journal-title":"PLoS ONE"},{"key":"1284_CR10","doi-asserted-by":"publisher","first-page":"6970","DOI":"10.1038\/s41388-019-0932-1","volume":"38","author":"K Tang","year":"2019","unstructured":"Tang, K. et al. Hypoxia-reprogrammed tricarboxylic acid cycle promotes the growth of human breast tumorigenic cells. Oncogene 38, 6970\u20136984 (2019).","journal-title":"Oncogene"},{"key":"1284_CR11","doi-asserted-by":"publisher","first-page":"E1232","DOI":"10.3390\/cancers12051232","volume":"12","author":"A Dominiak","year":"2020","unstructured":"Dominiak, A., Che\u0142stowska, B., Olejarz, W. & Nowicka, G. Communication in the cancer microenvironment as a target for therapeutic interventions. Cancers (Basel) 12, E1232 (2020).","journal-title":"Cancers (Basel)"},{"key":"1284_CR12","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.jconrel.2008.01.008","volume":"127","author":"M Banciu","year":"2008","unstructured":"Banciu, M., Fens, M. H. A. M., Storm, G. & Schiffelers, R. M. Antitumor activity and tumor localization of liposomal glucocorticoids in B16 melanoma-bearing mice. J. Control Release 127, 131\u2013136 (2008).","journal-title":"J. Control Release"},{"key":"1284_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jconrel.2006.03.019","volume":"113","author":"M Banciu","year":"2006","unstructured":"Banciu, M., Schiffelers, R. M., Fens, M. H. A. M., Metselaar, J. M. & Storm, G. Anti-angiogenic effects of liposomal prednisolone phosphate on B16 melanoma in mice. J. Control Release 113, 1\u20138 (2006).","journal-title":"J. Control Release"},{"key":"1284_CR14","doi-asserted-by":"publisher","first-page":"2968","DOI":"10.3390\/ijms21082968","volume":"21","author":"E Licarete","year":"2020","unstructured":"Licarete, E. et al. Overcoming intrinsic doxorubicin resistance in melanoma by anti-angiogenic and anti-metastatic effects of liposomal prednisolone phosphate on tumor microenvironment. Int. J. Mol. Sci. 21, 2968 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"1284_CR15","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/S0021-9258(18)57021-6","volume":"177","author":"AG Gornall","year":"1949","unstructured":"Gornall, A. G., Bardawill, C. J. & David, M. M. Determination of serum proteins by means of the biuret reaction. J. Biol. Chem. 177, 751\u2013766 (1949).","journal-title":"J. Biol. Chem."},{"key":"1284_CR16","doi-asserted-by":"publisher","first-page":"440","DOI":"10.7150\/jca.21560","volume":"9","author":"L Luput","year":"2018","unstructured":"Luput, L. et al. In vivo double targeting of C26 colon carcinoma cells and microenvironmental protumor processes using liposomal simvastatin. J. Cancer 9, 440\u2013449 (2018).","journal-title":"J. Cancer"},{"key":"1284_CR17","doi-asserted-by":"publisher","first-page":"3942","DOI":"10.3892\/ol.2017.5928","volume":"13","author":"E Licarete","year":"2017","unstructured":"Licarete, E. et al. HIF-1\u03b1 acts as a molecular target for simvastatin cytotoxicity in B16.F10 melanoma cells cultured under chemically induced hypoxia. Oncol. Lett. 13, 3942\u20133950 (2017).","journal-title":"Oncol. Lett."},{"key":"1284_CR18","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S0076-6879(84)05016-3","volume":"105","author":"H Aebi","year":"1984","unstructured":"Aebi, H. Catalase in vitro. Methods Enzymol. 105, 121\u2013126 (1984).","journal-title":"Methods Enzymol."},{"key":"1284_CR19","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.clinbiochem.2003.11.015","volume":"37","author":"O Erel","year":"2004","unstructured":"Erel, O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin. Biochem. 37, 277\u2013285 (2004).","journal-title":"Clin. Biochem."},{"key":"1284_CR20","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1007\/s13346-018-00598-8","volume":"9","author":"A Sesarman","year":"2019","unstructured":"Sesarman, A. et al. Co-delivery of curcumin and doxorubicin in PEGylated liposomes favored the antineoplastic C26 murine colon carcinoma microenvironment. Drug Deliv. Transl. Res. 9, 260\u2013272 (2019).","journal-title":"Drug Deliv. Transl. Res."},{"key":"1284_CR21","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3109\/08982104.2014.987787","volume":"25","author":"A Porfire","year":"2015","unstructured":"Porfire, A. et al. Optimizing long-circulating liposomes for delivery of simvastatin to C26 colon carcinoma cells. J. Liposome Res. 25, 261\u2013269 (2015).","journal-title":"J. Liposome Res."},{"key":"1284_CR22","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1593\/neo.04340","volume":"7","author":"RM Schiffelers","year":"2005","unstructured":"Schiffelers, R. M. et al. Liposome-encapsulated prednisolone phosphate inhibits growth of established tumors in mice. Neoplasia 7, 118\u2013127 (2005).","journal-title":"Neoplasia"},{"key":"1284_CR23","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1172\/JCI59643","volume":"122","author":"A Sica","year":"2012","unstructured":"Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787\u2013795 (2012).","journal-title":"J. Clin. Invest."},{"key":"1284_CR24","first-page":"82","volume":"7","author":"M Miettinen","year":"1994","unstructured":"Miettinen, M., Lindenmayer, A. E. & Chaubal, A. Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigens\u2013evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod. Pathol. 7, 82\u201390 (1994).","journal-title":"Mod. Pathol."},{"key":"1284_CR25","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1593\/neo.07913","volume":"10","author":"M Banciu","year":"2008","unstructured":"Banciu, M., Metselaar, J. M., Schiffelers, R. M. & Storm, G. Antitumor activity of liposomal prednisolone phosphate depends on the presence of functional tumor-associated macrophages in tumor tissue. Neoplasia 10, 108\u2013117 (2008).","journal-title":"Neoplasia"},{"key":"1284_CR26","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s10456-018-9627-4","volume":"21","author":"MG Dallinga","year":"2018","unstructured":"Dallinga, M. G. et al. IGF2 and IGF1R identified as novel tip cell genes in primary microvascular endothelial cell monolayers. Angiogenesis 21, 823\u2013836 (2018).","journal-title":"Angiogenesis"},{"key":"1284_CR27","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1158\/0008-5472.CAN-15-1227","volume":"75","author":"G Gopinathan","year":"2015","unstructured":"Gopinathan, G. et al. Interleukin-6 stimulates defective angiogenesis. Cancer Res. 75, 3098\u20133107 (2015).","journal-title":"Cancer Res."},{"key":"1284_CR28","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.3892\/or.2014.3060","volume":"31","author":"F Zhu","year":"2014","unstructured":"Zhu, F., Liu, P., Li, J. & Zhang, Y. Eotaxin-1 promotes prostate cancer cell invasion via activation of the CCR3-ERK pathway and upregulation of MMP-3 expression. Oncol Rep. 31, 2049\u20132054 (2014).","journal-title":"Oncol Rep."},{"key":"1284_CR29","doi-asserted-by":"publisher","first-page":"e147","DOI":"10.1371\/journal.pbio.0060147","volume":"6","author":"LP Billen","year":"2008","unstructured":"Billen, L. P., Kokoski, C. L., Lovell, J. F., Leber, B. & Andrews, D. W. Bcl-XL inhibits membrane permeabilization by competing with Bax. PLoS Biol. 6, e147 (2008).","journal-title":"PLoS Biol."},{"key":"1284_CR30","doi-asserted-by":"publisher","first-page":"10384","DOI":"10.1038\/ncomms10384","volume":"7","author":"S Choi","year":"2016","unstructured":"Choi, S. et al. Bcl-xL promotes metastasis independent of its anti-apoptotic activity. Nat. Commun. 7, 10384 (2016).","journal-title":"Nat. Commun."},{"key":"1284_CR31","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1046\/j.0022-202x.2001.01409.x","volume":"117","author":"M Raisova","year":"2001","unstructured":"Raisova, M. et al. The Bax\/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95\/Fas-mediated apoptosis. J Invest. Dermatol. 117, 333\u2013340 (2001).","journal-title":"J Invest. Dermatol."},{"key":"1284_CR32","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1126\/science.aaf4405","volume":"352","author":"EB Rankin","year":"2016","unstructured":"Rankin, E. B. & Giaccia, A. J. Hypoxic control of metastasis. Science 352, 175\u2013180 (2016).","journal-title":"Science"},{"key":"1284_CR33","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1042\/bj20020707","volume":"369","author":"MR Bergman","year":"2003","unstructured":"Bergman, M. R. et al. A functional activating protein 1 (AP-1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and JunB-FosB heterodimers. Biochem. J. 369, 485\u2013496 (2003).","journal-title":"Biochem. J."},{"key":"1284_CR34","doi-asserted-by":"publisher","first-page":"862","DOI":"10.3390\/cells10040862","volume":"10","author":"E Dratkiewicz","year":"2021","unstructured":"Dratkiewicz, E. et al. Hypoxia and extracellular acidification as drivers of melanoma progression and drug resistance. Cells 10, 862 (2021).","journal-title":"Cells"},{"key":"1284_CR35","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ejcb.2013.10.003","volume":"93","author":"M Kappelmann","year":"2014","unstructured":"Kappelmann, M., Bosserhoff, A. & Kuphal, S. AP-1\/c-Jun transcription factors: regulation and function in malignant melanoma. Eur. J. Cell Biol. 93, 76\u201381 (2014).","journal-title":"Eur. J. Cell Biol."},{"key":"1284_CR36","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/1756-9966-30-95","volume":"30","author":"K Soda","year":"2011","unstructured":"Soda, K. The mechanisms by which polyamines accelerate tumor spread. J. Exp. Clin. Cancer Res. 30, 95 (2011).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"1284_CR37","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.4049\/jimmunol.1701135","volume":"199","author":"K Ley","year":"2017","unstructured":"Ley, K. M1 Means Kill; M2 means heal. J. Immunol. 199, 2191\u20132193 (2017).","journal-title":"J. Immunol."},{"key":"1284_CR38","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.lfs.2003.10.042","volume":"75","author":"F Aktan","year":"2004","unstructured":"Aktan, F. iNOS-mediated nitric oxide production and its regulation. Life Sci. 75, 639\u2013653 (2004).","journal-title":"Life Sci."},{"key":"1284_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.niox.2019.04.009","volume":"89","author":"HP Monteiro","year":"2019","unstructured":"Monteiro, H. P. et al. Nitric oxide and interactions with reactive oxygen species in the development of melanoma, breast, and colon cancer: A redox signaling perspective. Nitric Oxide 89, 1\u201313 (2019).","journal-title":"Nitric Oxide"},{"key":"1284_CR40","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1016\/j.cell.2018.04.012","volume":"173","author":"L Wang","year":"2018","unstructured":"Wang, L. et al. An acquired vulnerability of drug-resistant melanoma with therapeutic potential. Cell 173, 1413-1425.e14 (2018).","journal-title":"Cell"},{"key":"1284_CR41","doi-asserted-by":"publisher","first-page":"E1661","DOI":"10.3390\/cancers12061661","volume":"12","author":"L Yuan","year":"2020","unstructured":"Yuan, L. et al. BRAF mutant melanoma adjusts to BRAF\/MEK inhibitors via dependence on increased antioxidant SOD2 and increased reactive oxygen species levels. Cancers (Basel) 12, E1661 (2020).","journal-title":"Cancers (Basel)"},{"key":"1284_CR42","doi-asserted-by":"publisher","first-page":"110135","DOI":"10.1016\/j.biopha.2020.110135","volume":"127","author":"P Mabeta","year":"2020","unstructured":"Mabeta, P. Paradigms of vascularization in melanoma: clinical significance and potential for therapeutic targeting. Biomed. Pharmacother. 127, 110135 (2020).","journal-title":"Biomed. Pharmacother."},{"key":"1284_CR43","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1136\/jclinpath-2015-203482","volume":"69","author":"G Jour","year":"2016","unstructured":"Jour, G., Ivan, D. & Aung, P. P. Angiogenesis in melanoma: an update with a focus on current targeted therapies. J. Clin. Pathol. 69, 472\u2013483 (2016).","journal-title":"J. Clin. Pathol."},{"key":"1284_CR44","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.lfs.2008.09.029","volume":"83","author":"X-Y Zhu","year":"2008","unstructured":"Zhu, X.-Y. et al. Disparate effects of simvastatin on angiogenesis during hypoxia and inflammation. Life Sci. 83, 801\u2013809 (2008).","journal-title":"Life Sci."},{"key":"1284_CR45","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1016\/j.ijrobp.2005.02.048","volume":"62","author":"DW Siemann","year":"2005","unstructured":"Siemann, D. W. & Rojiani, A. M. The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors. Int. J. Radiat. Oncol. Biol. Phys. 62, 846\u2013853 (2005).","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"1284_CR46","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.apsb.2015.05.007","volume":"5","author":"GN Masoud","year":"2015","unstructured":"Masoud, G. N. & Li, W. HIF-1\u03b1 pathway: role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B 5, 378\u2013389 (2015).","journal-title":"Acta Pharm. Sin. B"},{"key":"1284_CR47","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.3390\/ijms19041232","volume":"19","author":"Y Itatani","year":"2018","unstructured":"Itatani, Y., Kawada, K., Yamamoto, T. & Sakai, Y. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway. Int. J. Mol. Sci. 19, 1232 (2018).","journal-title":"Int. J. Mol. Sci."},{"key":"1284_CR48","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.smim.2014.01.008","volume":"26","author":"DT Fisher","year":"2014","unstructured":"Fisher, D. T., Appenheimer, M. M. & Evans, S. S. The two faces of IL-6 in the tumor microenvironment. Semin. Immunol. 26, 38\u201347 (2014).","journal-title":"Semin. Immunol."},{"key":"1284_CR49","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1038\/s41419-019-1568-3","volume":"10","author":"EF Lee","year":"2019","unstructured":"Lee, E. F. et al. BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival. Cell Death Dis. 10, 342 (2019).","journal-title":"Cell Death Dis."},{"key":"1284_CR50","doi-asserted-by":"publisher","first-page":"107731","DOI":"10.1016\/j.celrep.2020.107731","volume":"31","author":"K Berthenet","year":"2020","unstructured":"Berthenet, K. et al. Failed apoptosis enhances melanoma cancer cell aggressiveness. Cell Rep. 31, 107731 (2020).","journal-title":"Cell Rep."},{"key":"1284_CR51","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/nrc2442","volume":"8","author":"G Bergers","year":"2008","unstructured":"Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592\u2013603 (2008).","journal-title":"Nat. Rev. Cancer"},{"key":"1284_CR52","first-page":"3186","volume":"5","author":"M Tsubaki","year":"2015","unstructured":"Tsubaki, M. et al. Statins improve survival by inhibiting spontaneous metastasis and tumor growth in a mouse melanoma model. Am. J. Cancer Res. 5, 3186\u20133197 (2015).","journal-title":"Am. J. Cancer Res."},{"key":"1284_CR53","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1172\/JCI66715","volume":"123","author":"SC Hanna","year":"2013","unstructured":"Hanna, S. C. et al. HIF1\u03b1 and HIF2\u03b1 independently activate SRC to promote melanoma metastases. J. Clin. Invest. 123, 2078\u20132093 (2013).","journal-title":"J. Clin. Invest."},{"key":"1284_CR54","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1007\/s00018-019-03351-7","volume":"77","author":"R Lugano","year":"2020","unstructured":"Lugano, R., Ramachandran, M. & Dimberg, A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol. Life Sci. 77, 1745\u20131770 (2020).","journal-title":"Cell Mol. Life Sci."},{"key":"1284_CR55","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.canlet.2006.08.016","volume":"249","author":"B Sun","year":"2007","unstructured":"Sun, B. et al. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett. 249, 188\u2013197 (2007).","journal-title":"Cancer Lett."},{"key":"1284_CR56","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.gendis.2016.11.003","volume":"4","author":"X Lv","year":"2017","unstructured":"Lv, X. et al. The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism. Genes Dis. 4, 19\u201324 (2017).","journal-title":"Genes Dis."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01284-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01284-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01284-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T12:06:42Z","timestamp":1670069202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01284-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,11]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["1284"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-01284-5","relation":{"has-review":[{"id-type":"doi","id":"10.32388\/H3MED1","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.26.441259","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,11]]},"assertion":[{"value":"21 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2022","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original online version of this Article was revised: In the original version of this Article the Supplementary Information file contained tracked changes. The original Article has been corrected.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22102"}}