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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Multitargeting Strategy Using Tetrathiomolybdate and Lenvatinib: Maximizing Antiangiogenesis Activity in a Preclinical Liver Cancer Model

Author(s): Li Nan*, Wan Yuan, Chen Guodong and Huang Yonghui*

Volume 23, Issue 7, 2023

Published on: 10 October, 2022

Page: [786 - 793] Pages: 8

DOI: 10.2174/1871520622666220907115027

Price: $65

Abstract

Purpose: The study aims to investigate the suppressing tumor-promoting effects via multi-anti-angiogenesis activity of the copper chelator (ammonium tetrathiomolybdate, TM) combined with lenvatinib for hepatocellular carcinoma.

Methods: A total of 55 C57 mice were injected subcutaneously with Hepa1-6 hepatoma cell suspensions into the right posterior thigh. After 7 days, the subcutaneous tumors were formed, and the mice were randomly divided into five groups: TM (G1), Lenvatinib (G2), TM+Lenvatinib (G3), Control (G4), and Copper (II) Gluconate (G5). The copper concentrations in serum and tumors were measured at the predetermined time points. After 14 days of treatments, tumor weight and volumes were analyzed, histology was observed, and the expressions of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor tissues were measured by immunohistochemistry.

Results: The median concentration of copper in serum was 401.70, 469.40, and 665.35 μg/L in normal mice, in mice 7 days after implantation, and in the control group, respectively. The intratumoral copper concentrations were higher in G4 mice than in mice 7 days after implantation (P < 0.05). The serum concentration of copper was higher in G5 than all the other groups (P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G2, P = 0.013; G2 vs. G3, P = 0.018; G1 vs. G3, P = 0.903. The intratumoral copper concentrations were 608.40, 980.00, 539.31, and 2938.90 μg/L in G1, G2, G3, and G5, respectively. The average tumor weight was 0.55, 0.44, 0.08, 1.37, and 3.11 in G1, G2, G3, G4, and G5, respectively. G5 vs. other groups, P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05; G1 vs. G2, P > 0.05. Furthermore, the expression levels of VEGF were significantly lower in G1, G2, and G3 than in G4 and G5 (P < 0.05). A similar trend was observed for MVD in the five groups, but no significant difference was detected in G1 and G2.

Conclusion: The study showed a significant positive correlation between tumor load and copper. Copper promotes tumor progression, but copper chelating suppresses tumor growth. The combination of TM with lenvatinib reduces tumor angiogenesis and improves the effect of antitumor treatment. These findings underlie the clinical application of combination therapy.

Keywords: liver tumor, copper, copper chelator, lenvatinib, combination therapy, angiogenesis

« Previous Next »
[1]
Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med., 2019, 380(15), 1450-1462.
[http://dx.doi.org/10.1056/NEJMra1713263] [PMID: 30970190]
[2]
Jemal, A.; Ward, E.M.; Johnson, C.J.; Cronin, K.A.; Ma, J.; Ryerson, A.B.; Mariotto, A.; Lake, A.J.; Wilson, R.; Sherman, R.L.; Anderson, R.N.; Henley, S.J.; Kohler, B.A.; Penberthy, L.; Feuer, E.J.; Weir, H.K. Annual Report to the Nation on the Status of Cancer, 1975–2014, Featuring Survival. J. Natl. Cancer Inst., 2017, 109(9)
[http://dx.doi.org/10.1093/jnci/djx030] [PMID: 28376154]
[3]
Reig, M.; Forner, A.; Rimola, J.; Ferrer-Fàbrega, J.; Burrel, M.; Garcia-Criado, Á.; Kelley, R.K.; Galle, P.R.; Mazzaferro, V.; Salem, R.; Sangro, B.; Singal, A.G.; Vogel, A.; Fuster, J.; Ayuso, C.; Bruix, J. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J. Hepatol., 2022, 76(3), 681-693.
[http://dx.doi.org/10.1016/j.jhep.2021.11.018] [PMID: 34801630]
[4]
Morse, M.A.; Sun, W.; Kim, R.; He, A.R.; Abada, P.B.; Mynderse, M.; Finn, R.S. The role of angiogenesis in hepatocellular carcinoma. Clin. Cancer Res., 2019, 25(3), 912-920.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1254] [PMID: 30274981]
[5]
Yang, Z.F.; Poon, R.T.P. Vascular changes in hepatocellular carcinoma. Anat. Rec. (Hoboken), 2008, 291(6), 721-734.
[http://dx.doi.org/10.1002/ar.20668] [PMID: 18484619]
[6]
Fu, Y.; Liu, S.; Zeng, S.; Shen, H. From bench to bed: The tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J. Exp. Clin. Cancer Res., 2019, 38(1), 396-396.
[http://dx.doi.org/10.1186/s13046-019-1396-4] [PMID: 31500650]
[7]
Liu, K.; Min, X.L.; Peng, J.; Yang, K.; Yang, L.; Zhang, X.M. The changes of HIF-1α and VEGF expression after TACE in patients with hepatocellular carcinoma. J. Clin. Med. Res., 2016, 8(4), 297-302.
[http://dx.doi.org/10.14740/jocmr2496w] [PMID: 26985249]
[8]
Kudo, M.; Finn, R.S.; Qin, S.; Han, K.H.; Ikeda, K.; Piscaglia, F.; Baron, A.; Park, J.W.; Han, G.; Jassem, J.; Blanc, J.F.; Vogel, A.; Komov, D.; Evans, T.R.J.; Lopez, C.; Dutcus, C.; Guo, M.; Saito, K.; Kraljevic, S.; Tamai, T.; Ren, M.; Cheng, A.L. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet, 2018, 391(10126), 1163-1173.
[http://dx.doi.org/10.1016/S0140-6736(18)30207-1] [PMID: 29433850]
[9]
Teleanu, R.I.; Chircov, C.; Grumezescu, A.M.; Teleanu, D.M. Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J. Clin. Med., 2019, 9(1), 84.
[http://dx.doi.org/10.3390/jcm9010084] [PMID: 31905724]
[10]
Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; de Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; Schwartz, M.; Porta, C.; Zeuzem, S.; Bolondi, L.; Greten, T.F.; Galle, P.R.; Seitz, J.F.; Borbath, I.; Häussinger, D.; Giannaris, T.; Shan, M.; Moscovici, M.; Voliotis, D.; Bruix, J. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359(4), 378-390.
[http://dx.doi.org/10.1056/NEJMoa0708857] [PMID: 18650514]
[11]
Wang, Z.; Dabrosin, C.; Yin, X. Broad targeting of angiogenesis for cancer prevention and therapy. Semin. Cancer Biol., 2015, 35(Suppl. 1), S224-S243.
[http://dx.doi.org/10.1016/j.semcancer.2015.01.001]
[12]
Llovet, J.M.; Montal, R.; Sia, D.; Finn, R.S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol., 2018, 15(10), 599-616.
[http://dx.doi.org/10.1038/s41571-018-0073-4] [PMID: 30061739]
[13]
Gupte, A.; Mumper, R.J. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat. Rev., 2009, 35(1), 32-46.
[http://dx.doi.org/10.1016/j.ctrv.2008.07.004] [PMID: 18774652]
[14]
Grubman, A.; White, A.R. Copper as a key regulator of cell signalling pathways. Expert Rev. Mol. Med., 2014, 16, e11.
[http://dx.doi.org/10.1017/erm.2014.11] [PMID: 24849048]
[15]
da Silva, D.A.; De Luca, A.; Squitti, R.; Rongioletti, M.; Rossi, L.; Machado, C.M.L.; Cerchiaro, G. Copper in tumors and the use of copper-based compounds in cancer treatment. J. Inorg. Biochem., 2022, 226, 111634.
[http://dx.doi.org/10.1016/j.jinorgbio.2021.111634] [PMID: 34740035]
[16]
Ge, E.J.; Bush, A.I.; Casini, A.; Cobine, P.A.; Cross, J.R.; DeNicola, G.M.; Dou, Q.P.; Franz, K.J.; Gohil, V.M.; Gupta, S.; Kaler, S.G.; Lutsenko, S.; Mittal, V.; Petris, M.J.; Polishchuk, R.; Ralle, M.; Schilsky, M.L.; Tonks, N.K.; Vahdat, L.T.; Van Aelst, L.; Xi, D.; Yuan, P.; Brady, D.C.; Chang, C.J. Connecting copper and cancer: From transition metal signalling to metalloplasia. Nat. Rev. Cancer, 2022, 22(2), 102-113.
[http://dx.doi.org/10.1038/s41568-021-00417-2] [PMID: 34764459]
[17]
Blockhuys, S.; Wittung-Stafshede, P. Copper chaperone Atox1 plays role in breast cancer cell migration. Biochem. Biophys. Res. Commun., 2017, 483(1), 301-304.
[http://dx.doi.org/10.1016/j.bbrc.2016.12.148] [PMID: 28027931]
[18]
Jana, A.; Das, A.; Krett, N.L.; Guzman, G.; Thomas, A.; Mancinelli, G.; Bauer, J.; Ushio-Fukai, M.; Fukai, T.; Jung, B. Nuclear translocation of Atox1 potentiates activin A-induced cell migration and colony formation in colon cancer. PLoS One, 2020, 15(1), e0227916-e0227916.
[http://dx.doi.org/10.1371/journal.pone.0227916] [PMID: 31961892]
[19]
Kim, Y-J.; Bond, G.J.; Tsang, T. Copper chaperone ATOX1 is required for MAPK signaling and growth in BRAF mutation-positive melanoma. Metallomics, 2019, 11(8), 1430-1440.
[http://dx.doi.org/10.1039/c9mt00042a]
[20]
Fang, A.P.; Chen, P.Y.; Wang, X.Y.; Liu, Z.Y.; Zhang, D.M.; Luo, Y.; Liao, G.C.; Long, J.A.; Zhong, R.H.; Zhou, Z.G.; Xu, Y.J.; Xu, X.J.; Ling, W.H.; Chen, M.S.; Zhang, Y.J.; Zhu, H.L. Serum copper and zinc levels at diagnosis and hepatocellular carcinoma survival in the Guangdong liver cancer cohort. Int. J. Cancer, 2019, 144(11), 2823-2832.
[http://dx.doi.org/10.1002/ijc.31991] [PMID: 30426509]
[21]
Denoyer, D.; Masaldan, S.; La Fontaine, S. Targeting copper in cancer therapy: ‘Copper that cancer’. Metallomics, 2015, 7(11), 1459-1476.
[22]
Rigiracciolo, D.C.; Scarpelli, A.; Lappano, R.; Pisano, A.; Santolla, M.F.; De Marco, P.; Cirillo, F.; Cappello, A.R.; Dolce, V.; Belfiore, A.; Maggiolini, M.; De Francesco, E.M. Copper activates HIF-1α/GPER/VEGF signalling in cancer cells. Oncotarget, 2015, 6(33), 34158-34177.
[http://dx.doi.org/10.18632/oncotarget.5779] [PMID: 26415222]
[23]
Finney, L.; Vogt, S.; Fukai, T.; Glesne, D. Copper and angiogenesis: Unravelling a relationship key to cancer progression. Clin. Exp. Pharmacol. Physiol., 2009, 36(1), 88-94.
[http://dx.doi.org/10.1111/j.1440-1681.2008.04969.x] [PMID: 18505439]
[24]
Carmeliet, P.; Jain, R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature, 2011, 473(7347), 298-307.
[http://dx.doi.org/10.1038/nature10144] [PMID: 21593862]
[25]
Khan, M.K.; Miller, M.W.; Taylor, J.; Gill, N.K.; Dick, R.D.; Van Goled, K.; Brewert, G.J.; Merajver, S.D. Radiotherapy and antiangiogenic TM in lung cancer. Neoplasia, 2002, 4(2), 164-170.
[http://dx.doi.org/10.1038/sj.neo.7900218] [PMID: 11896571]
[26]
Moriguchi, M.; Nakajima, T.; Kimura, H.; Watanabe, T.; Takashima, H.; Mitsumoto, Y.; Katagishi, T.; Okanoue, T.; Kagawa, K. The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin-8 production. Int. J. Cancer, 2002, 102(5), 445-452.
[http://dx.doi.org/10.1002/ijc.10740] [PMID: 12432545]
[27]
Yoshida, D.; Ikeda, Y.; Nakazawa, S. Suppression of tumor growth in experimental 9L gliosarcoma model by copper depletion. Neurol. Med. Chir. (Tokyo), 1995, 35(3), 133-135.
[http://dx.doi.org/10.2176/nmc.35.133] [PMID: 7770105]
[28]
Brem, S.S.; Zagzag, D.; Tsanaclis, A.M.; Gately, S.; Elkouby, M.P.; Brien, S.E. Inhibition of angiogenesis and tumor growth in the brain. Suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor. Am. J. Pathol., 1990, 137(5), 1121-1142.
[PMID: 1700617]
[29]
Pan, Q.; Kleer, C.G.; van Golen, K.L.; Irani, J.; Bottema, K.M.; Bias, C.; De Carvalho, M.; Mesri, E.A.; Robins, D.M.; Dick, R.D.; Brewer, G.J.; Merajver, S.D. Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res., 2002, 62(17), 4854-4859.
[PMID: 12208730]
[30]
Khan, G.; Merajver, S. Copper chelation in cancer therapy using tetrathiomolybdate: An evolving paradigm. Expert Opin. Investig. Drugs, 2009, 18(4), 541-548.
[http://dx.doi.org/10.1517/13543780902845622] [PMID: 19335282]
[31]
Jain, S.; Cohen, J.; Ward, M.M.; Kornhauser, N.; Chuang, E.; Cigler, T.; Moore, A.; Donovan, D.; Lam, C.; Cobham, M.V.; Schneider, S.; Hurtado Rúa, S.M.; Benkert, S.; Mathijsen Greenwood, C.; Zelkowitz, R.; Warren, J.D.; Lane, M.E.; Mittal, V.; Rafii, S.; Vahdat, L.T. Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Ann. Oncol., 2013, 24(6), 1491-1498.
[http://dx.doi.org/10.1093/annonc/mds654] [PMID: 23406736]
[32]
Chan, N.; Willis, A.; Kornhauser, N.; Ward, M.M.; Lee, S.B.; Nackos, E.; Seo, B.R.; Chuang, E.; Cigler, T.; Moore, A.; Donovan, D.; Vallee Cobham, M.; Fitzpatrick, V.; Schneider, S.; Wiener, A.; Guillaume-Abraham, J.; Aljom, E.; Zelkowitz, R.; Warren, J.D.; Lane, M.E.; Fischbach, C.; Mittal, V.; Vahdat, L. Influencing the tumor microenvironment: A phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clin. Cancer Res., 2017, 23(3), 666-676.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1326] [PMID: 27769988]
[33]
Brewer, G.J.; Dick, R.D.; Grover, D.K.; LeClaire, V.; Tseng, M.; Wicha, M.; Pienta, K.; Redman, B.G.; Jahan, T.; Sondak, V.K.; Strawderman, M.; LeCarpentier, G.; Merajver, S.D. Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study. Clin. Cancer Res., 2000, 6(1), 1-10.
[PMID: 10656425]
[34]
Denoyer, D.; Clatworthy, S.A.S.; Cater, M.A. Copper complexes in cancer therapy. Met. Ions Life Sci., 2018, 18, 18.
[PMID: 29394035]
[35]
Kim, K.K.; Abelman, S.; Yano, N.; Ribeiro, J.R.; Singh, R.K.; Tipping, M.; Moore, R.G. Tetrathiomolybdate inhibits mitochondrial complex IV and mediates degradation of hypoxia-inducible factor-1α in cancer cells. Sci. Rep., 2015, 5(1), 14296.
[http://dx.doi.org/10.1038/srep14296] [PMID: 26469226]
[36]
Lopez, J.; Ramchandani, D.; Vahdat, L. Copper depletion as a therapeutic strategy in cancer. Met. Ions Life Sci., 2019, 19, 303-330.
[http://dx.doi.org/10.1515/9783110527872-012] [PMID: 30855113]
[37]
Brewer, G.J. The promise of copper lowering therapy with tetrathiomolybdate in the cure of cancer and in the treatment of inflammatory disease. J. Trace Elem. Med. Biol., 2014, 28(4), 372-378.
[http://dx.doi.org/10.1016/j.jtemb.2014.07.015] [PMID: 25194954]
[38]
Brewer, G.J.; Merajver, S.D. Cancer therapy with tetrathiomolybdate: Antiangiogenesis by lowering body copper - A review. Integr. Cancer Ther., 2002, 1(4), 327-337.
[http://dx.doi.org/10.1177/1534735402238185] [PMID: 14664727]
[39]
Yamamoto, Y.; Matsui, J.; Matsushima, T.; Obaishi, H.; Miyazaki, K.; Nakamura, K.; Tohyama, O.; Semba, T.; Yamaguchi, A.; Hoshi, S.; Mimura, F.; Haneda, T.; Fukuda, Y.; Kamata, J.; Takahashi, K.; Matsukura, M.; Wakabayashi, T.; Asada, M.; Nomoto, K.; Watanabe, T.; Dezso, Z.; Yoshimatsu, K.; Funahashi, Y.; Tsuruoka, A. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc. Cell, 2014, 6(1), 18.
[http://dx.doi.org/10.1186/2045-824X-6-18] [PMID: 25197551]
[40]
Zhou, B.; Guo, L.; Zhang, B.; Liu, S.; Zhang, K.; Yan, J.; Zhang, W.; Yu, M.; Chen, Z.; Xu, Y.; Xiao, Y.; Zhou, J.; Fan, J.; Li, H.; Ye, Q. Disulfiram combined with copper induces immunosuppression via PD-L1 stabilization in hepatocellular carcinoma. Am. J. Cancer Res., 2019, 9(11), 2442-2455.
[PMID: 31815045]
[41]
Cedeño, Y.; López-Alonso, M.; Miranda, M. Hepatic concentrations of copper and other metals in dogs with and without chronic hepatitis. J. Small Anim. Pract., 2016, 57(12), 703-709.
[http://dx.doi.org/10.1111/jsap.12591] [PMID: 27747881]
[42]
Li, N.; Chen, B.; Lin, R.; Liu, N.; Dai, H.; Tang, K.; Yang, J.; Huang, Y. The earlier, the better: The effects of different administration timepoints of sorafenib in suppressing the carcinogenesis of VEGF in rats. Cancer Chemother. Pharmacol., 2018, 81(1), 207-216.
[http://dx.doi.org/10.1007/s00280-017-3493-4] [PMID: 29196964]
[43]
Weidner, N.; Semple, J.P.; Welch, W.R.; Folkman, J. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N. Engl. J. Med., 1991, 324(1), 1-8.
[http://dx.doi.org/10.1056/NEJM199101033240101] [PMID: 1701519]
[44]
Peng, Z.; Chen, S.; Xiao, H.; Wang, Y.; Li, J.; Mei, J.; Chen, Z.; Zhou, Q.; Feng, S.; Chen, M.; Qian, G.; Peng, S.; Kuang, M. Microvascular invasion as a predictor of response to treatment with sorafenib and transarterial chemoembolization for recurrent intermediate-stage hepatocellular carcinoma. Radiology, 2019, 292(1), 237-247.
[http://dx.doi.org/10.1148/radiol.2019181818] [PMID: 31135299]
[45]
Zhang, T.; Huang, W.; Dong, H.; Chen, Y. Trans-catheter arterial chemoembolization plus Sorafenib, an unsuccessful therapy in the treatment of hepatocellular carcinoma? Medicine (Baltimore), 2020, 99(29), e20962.
[http://dx.doi.org/10.1097/MD.0000000000020962] [PMID: 32702836]
[46]
Couri, T.; Pillai, A. Goals and targets for personalized therapy for HCC. Hepatol. Int., 2019, 13(2), 125-137.
[http://dx.doi.org/10.1007/s12072-018-9919-1] [PMID: 30600478]
[47]
Zhu, X.D.; Tang, Z.Y.; Sun, H.C. Targeting angiogenesis for liver cancer: Past, present, and future. Genes Dis., 2020, 7(3), 328-335.
[http://dx.doi.org/10.1016/j.gendis.2020.03.010] [PMID: 32884987]
[48]
Branda, M.; Wands, J.R. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology, 2006, 43(5), 891-902.
[http://dx.doi.org/10.1002/hep.21196] [PMID: 16628664]
[49]
Kudo, M. Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma. World J. Gastroenterol., 2012, 18(42), 6005-6017.
[http://dx.doi.org/10.3748/wjg.v18.i42.6005] [PMID: 23155330]
[50]
Llovet, J.M.; Villanueva, A.; Lachenmayer, A.; Finn, R.S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol., 2015, 12(7), 408-424.
[http://dx.doi.org/10.1038/nrclinonc.2015.103] [PMID: 26054909]
[51]
Kim, S.Y.; Kim, S.M.; Chang, H.J.; Kim, B.W.; Lee, Y.S.; Park, C.S.; Park, K.C.; Chang, H.S. SoLAT (Sorafenib Lenvatinib alternating treatment): A new treatment protocol with alternating Sorafenib and Lenvatinib for refractory thyroid Cancer. BMC Cancer, 2018, 18(1), 956.
[http://dx.doi.org/10.1186/s12885-018-4854-z] [PMID: 30286728]
[52]
Pan, Q.; Bao, L.W.; Merajver, S.D. Tetrathiomolybdate inhibits angiogenesis and metastasis through suppression of the NFkappaB signaling cascade. Mol. Cancer Res., 2003, 1(10), 701-706.
[PMID: 12939395]
[53]
Rust, R.; Gantner, C.; Schwab, M.E. Pro‐ and antiangiogenic therapies: Current status and clinical implications. FASEB J., 2019, 33(1), 34-48.
[http://dx.doi.org/10.1096/fj.201800640RR] [PMID: 30085886]
[54]
Barratt, S.; Flower, V.; Pauling, J.; Millar, A. VEGF (Vascular Endothelial Growth Factor) and fibrotic lung disease. Int. J. Mol. Sci., 2018, 19(5), 1269.
[http://dx.doi.org/10.3390/ijms19051269] [PMID: 29695053]
[55]
Kampoli, K.; Foukas, P.G.; Ntavatzikos, A.; Arkadopoulos, N.; Koumarianou, A. Interrogating the interplay of angiogenesis and immunity in metastatic colorectal cancer. World J. Methodol., 2022, 12(1), 43-53.
[http://dx.doi.org/10.5662/wjm.v12.i1.43] [PMID: 35117981]
[56]
Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 1996, 86(3), 353-364.
[http://dx.doi.org/10.1016/S0092-8674(00)80108-7] [PMID: 8756718]
[57]
Gasparini, G.; Longo, R.; Fanelli, M.; Teicher, B.A. Combination of antiangiogenic therapy with other anticancer therapies: Results, challenges, and open questions. J. Clin. Oncol., 2005, 23(6), 1295-1311.
[http://dx.doi.org/10.1200/JCO.2005.10.022] [PMID: 15718328]

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