New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells
Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Bogdan Alexandru Danalache, Amira Ouanouki, Richard Béliveau, Christian Marsolais, Borhane Annabi, Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Bogdan Alexandru Danalache, Amira Ouanouki, Richard Béliveau, Christian Marsolais, Borhane Annabi
Abstract
Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by genetically deregulated cancer cells and is often associated with high tumor grade and cancer therapy resistance. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumors, and contributes also in part to metastasis. VM has been observed in ovarian cancer and in triple negative breast cancer (TNBC) and shown to correlate with decreased overall cancer patient survival. Thus, strategies designed to inhibit VM may improve cancer patient treatments. In this study, sortilin (SORT1) receptor was detected in in vitro 3D capillary-like structures formed by ES-2 ovarian cancer and MDA-MB-231 TNBC-derived cells when grown on Matrigel. SORT1 gene silencing or antibodies directed against its extracellular domain inhibited capillary-like structure formation. In vitro, VM also correlated with increased gene expression of matrix metalloproteinase-9 (MMP-9) and of the cancer stem cell marker CD133. In vivo ES-2 xenograft model showed PAS+/CD31- VM structures (staining positive for both SORT1 and CD133). TH1904, a Doxorubicin-peptide conjugate that is internalized by SORT1, significantly decreased in vitro VM at low nM concentrations. In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. TH1902, a Docetaxel-peptide conjugate, altered even more efficiently in vitro VM at pM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.
Keywords: Docetaxel; Doxorubicin; breast cancer; ovarian cancer; peptide-drug conjugates; sortilin; vasculogenic mimicry.
Conflict of interest statement
MD, AL, RB, and BA were scientific founders of Katana Biopharma. CM is senior vice president and chief medical officer at Theratechnologies. Authors CC, MD, JCC and AL was employed by Theratechnologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Copyright © 2021 Charfi, Demeule, Currie, Larocque, Zgheib, Danalache, Ouanouki, Béliveau, Marsolais and Annabi.
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References
- Sobierajska K, Ciszewski WM, Sacewicz-Hofman I, Niewiarowska J. Endothelial Cells in the Tumor Microenvironment. Adv Exp Med Biol (2020) 1234:71–86. doi: 10.1007/978-3-030-37184-5_6
- Donnem T, Reynolds AR, Kuczynski EA, Gatter K, Vermeulen PB, Kerbel RS, et al. . Non-Angiogenic Tumours and Their Influence on Cancer Biology. Nat Rev Cancer (2018) 18(5):323–36. doi: 10.1038/nrc.2018.14
- Kirschmann DA, Seftor EA, Hardy KM, Seftor RE, Hendrix MJ. Molecular Pathways: Vasculogenic Mimicry in Tumor Cells: Diagnostic and Therapeutic Implications. Clin Cancer Res (2012) 18(10):2726–32. doi: 10.1158/1078-0432.CCR-11-3237
- Qiao L, Liang N, Zhang J, Xie J, Liu F, Xu D, et al. . Advanced Research on Vasculogenic Mimicry in Cancer. J Cell Mol Med (2015) 19(2):315–26. doi: 10.1111/jcmm.12496
- Ge H, Luo H. Overview of Advances in Vasculogenic Mimicry - A Potential Target for Tumor Therapy. Cancer Manag Res (2018) 10:2429–37. doi: 10.2147/CMAR.S164675
- Maniotis AJ, Chen X, Garcia C, DeChristopher PJ, Wu D, Pe'er J, et al. . Control of Melanoma Morphogenesis, Endothelial Survival, and Perfusion by Extracellular Matrix. Lab Invest (2002) 82(8):1031–43. doi: 10.1097/01.lab.0000024362.12721.67
- Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, et al. . Vessel Co-Option Is Common in Human Lung Metastases and Mediates Resistance to Anti-Angiogenic Therapy in Preclinical Lung Metastasis Models. J Pathol (2017) 241(3):362–74. doi: 10.1002/path.4845
- Cao Z, Bao M, Miele L, Sarkar FH, Wang Z, Zhou Q. Tumour Vasculogenic Mimicry Is Associated With Poor Prognosis of Human Cancer Patients: A Systemic Review and Meta-Analysis. Eur J Cancer (2013) 49(18):3914–23. doi: 10.1016/j.ejca.2013.07.148
- Yang JP, Liao YD, Mai DM, Xie P, Qiang YY, Zheng LS, et al. . Tumor Vasculogenic Mimicry Predicts Poor Prognosis in Cancer Patients: A Meta-Analysis. Angiogenesis (2016) 19(2):191–200. doi: 10.1007/s10456-016-9500-2
- Sun B, Zhang D, Zhao N, Zhao X. Epithelial-To-Endothelial Transition and Cancer Stem Cells: Two Cornerstones of Vasculogenic Mimicry in Malignant Tumors. Oncotarget (2017) 8(18):30502–10. doi: 10.18632/oncotarget.8461
- Kipps E, Tan DS, Kaye SB. Meeting the Challenge of Ascites in Ovarian Cancer: New Avenues for Therapy and Research. Nat Rev Cancer (2013) 13(4):273–82. doi: 10.1038/nrc3432
- Liang J, Yang B, Cao Q, Wu X. Association of Vasculogenic Mimicry Formation and CD133 Expression With Poor Prognosis in Ovarian Cancer. Gynecol Obstet Invest (2016) 81(6):529–36. doi: 10.1159/000445747
- Zhang J, Guo X, Chang DY, Rosen DG, Mercado-Uribe I, Liu J. CD133 Expression Associated With Poor Prognosis in Ovarian Cancer. Mod Pathol (2012) 25(3):456–64. doi: 10.1038/modpathol.2011.170
- Liu TJ, Sun BC, Zhao XL, Zhao XM, Sun T, Gu Q, et al. . CD133+ Cells With Cancer Stem Cell Characteristics Associates With Vasculogenic Mimicry in Triple-Negative Breast Cancer. Oncogene (2013) 32(5):544–53. doi: 10.1038/onc.2012.85
- Sun H, Yao N, Cheng S, Li L, Liu S, Yang Z, et al. . Cancer Stem-Like Cells Directly Participate in Vasculogenic Mimicry Channels in Triple-Negative Breast Cancer. Cancer Biol Med (2019) 16(2):299–311. doi: 10.20892/j.issn.2095-3941.2018.0209
- Demeule M, Currie JC, Charfi C, Larocque A, Zgheib A, Kozelko S, et al. . Increasing Potency of Anticancer Drugs Through Sortilin Receptor-Mediated Cancer Therapy: A New-Targeted Approach for the Treatment of Ovarian Cancer. Cancer Res (2020) 80(16):1061.
- Demeule M, Charfi C, Currie JC, Larocque A, Zgheib A, Kozelko S, et al. . TH1902, a New Docetaxel-Peptide Conjugate for the Treatment of Sortilin-Positive Triple-Negative Breast Cancer. Cancer Sci (2021) 112(10):4317–44. doi: 10.1111/cas.15086
- Wilson CM, Naves T, Saada S, Pinet S, Vincent F, Lalloué F, et al. . The Implications of Sortilin/Vps10p Domain Receptors in Neurological and Human Diseases. CNS Neurol Disord Drug Targets (2014) 13(8):1354–65. doi: 10.2174/1871527313666141023151642
- Wilson CM, Naves T, Al Akhrass H, Vincent F, Melloni B, Bonnaud F, et al. . A New Role Under Sortilin's Belt in Cancer. Commun Integr Biol (2016) 9(1):e1130192. doi: 10.1080/19420889.2015.1130192
- Akil H, Perraud A, Mélin C, Jauberteau MO, Mathonnet M. Fine-Tuning Roles of Endogenous Brain-Derived Neurotrophic Factor, TrkB and Sortilin in Colorectal Cancer Cell Survival. PloS One (2011) 6(9):e25097. doi: 10.1371/journal.pone.0025097
- Lewin GR, Nykjaer A. Pro-Neurotrophins, Sortilin, and Nociception. Eur J Neurosci (2014) 39(3):363–74. doi: 10.1111/ejn.12466
- Mazella J, Vincent JP. Internalization and Recycling Properties of Neurotensin Receptors. Peptides (2006) 27(10):2488–92. doi: 10.1016/j.peptides.2006.02.012
- Al-Shawi R, Hafner A, Chun S, Raza S, Crutcher K, Thrasivoulou C, et al. . ProNGF, Sortilin, and Age-Related Neurodegeneration. Ann N Y Acad Sci (2007) 1119:208–15. doi: 10.1196/annals.1404.024
- Vincent JP, Mazella J, Kitabgi P. Neurotensin and Neurotensin Receptors. Trends Pharmacol Sci (1999) 20(7):302–9. doi: 10.1016/s0165-6147(99)01357-7
- Vaegter CB, Jansen P, Fjorback AW, Glerup S, Skeldal S, Kjolby M, et al. . Sortilin Associates With Trk Receptors to Enhance Anterograde Transport and Neurotrophin Signaling. Nat Neurosci (2011) 14(1):54–61. doi: 10.1038/nn.2689
- Rhost S, Hughes É, Harrison H, Rafnsdottir S, Jacobsson H, Gregersson P, et al. . Sortilin Inhibition Limits Secretion-Induced Progranulin-Dependent Breast Cancer Progression and Cancer Stem Cell Expansion. Breast Cancer Res (2018) 20(1):137. doi: 10.1186/s13058-018-1060-5
- Hemmati S, Zarnani AH, Mahmoudi AR, Sadeghi MR, Soltanghoraee H, Akhondi MM, et al. . Ectopic Expression of Sortilin 1 (NTR-3) in Patients With Ovarian Carcinoma. Avicenna J Med Biotechnol (2009) 1(2):125–31.
- Ghaemimanesh F, Ahmadian G, Talebi S, Zarnani AH, Behmanesh M, Hemmati S, et al. . The Effect of Sortilin Silencing on Ovarian Carcinoma Cells. Avicenna J Med Biotechnol (2014) 6(3):169–77.
- Roselli S, Pundavela J, Demont Y, Faulkner S, Keene S, Attia J, et al. . Sortilin is Associated With Breast Cancer Aggressiveness and Contributes to Tumor Cell Adhesion and Invasion. Oncotarget (2015) 6(12):10473–86. doi: 10.18632/oncotarget.3401
- Dal Farra C, Sarret P, Navarro V, Botto JM, Mazella J, Vincent JP. Involvement of the Neurotensin Receptor Subtype NTR3 in the Growth Effect of Neurotensin on Cancer Cell Lines. Int J Cancer (2001) 92(4):503–9. doi: 10.1002/ijc.1225
- Giorgi RR, Chile T, Bello AR, Reyes R, Fortes MA, Machado MC, et al. . Expression of Neurotensin and Its Receptors in Pituitary Adenomas. J Neuroendocrinol (2008) 20(9):1052–7. doi: 10.1111/j.1365-2826.2008.01761.x
- Truzzi F, Marconi A, Lotti R, Dallaglio K, French LE, Hempstead BL, et al. . Neurotrophins and Their Receptors Stimulate Melanoma Cell Proliferation and Migration. J Invest Dermatol (2008) 128(8):2031–40. doi: 10.1038/jid.2008.21
- Xiong J, Zhou L, Yang M, Lim Y, Zhu YH, Fu DL, et al. . ProBDNF and its Receptors Are Upregulated in Glioma and Inhibit the Growth of Glioma Cells in vitro . Neuro Oncol (2013) 15(8):990–1007. doi: 10.1093/neuonc/not039
- Liu T, Sun B, Zhao X, Gu Q, Dong X, Yao Z, et al. . HER2/neu Expression Correlates With Vasculogenic Mimicry in Invasive Breast Carcinoma. J Cell Mol Med (2013) 17(1):116–22. doi: 10.1111/j.1582-4934.2012.01653.x
- Racordon D, Valdivia A, Mingo G, Erices R, Aravena R, Santoro F, et al. . Structural and Functional Identification of Vasculogenic Mimicry in vitro . Sci Rep (2017) 7(1):6985. doi: 10.1038/s41598-017-07622-w
- Wilson CM, Naves T, Vincent F, Melloni B, Bonnaud F, Lalloué F, et al. . Sortilin Mediates the Release and Transfer of Exosomes in Concert With Two Tyrosine Kinase Receptors. J Cell Sci (2014) 127(Pt 18):3983–97. doi: 10.1242/jcs.149336
- Gao F, Griffin N, Faulkner S, Li X, King SJ, Jobling P, et al. . The Membrane Protein Sortilin Can Be Targeted to Inhibit Pancreatic Cancer Cell Invasion. Am J Pathol (2020) 190(9):1931–42. doi: 10.1016/j.ajpath.2020.05.018
- Zhou X, Gu R, Han X, Wu G, Liu J. Cyclin-Dependent Kinase 5 Controls Vasculogenic Mimicry Formation in Non-Small Cell Lung Cancer via the FAK-AKT Signaling Pathway. Biochem Biophys Res Commun (2021) 546:201. doi: 10.1016/j.bbrc.2021.01.064
- Xiao Y, Cheng L, Xie HJ, Ju RJ, Wang X, Fu M, et al. . Vinorelbine Cationic Liposomes Modified With Wheat Germ Agglutinin for Inhibiting Tumor Metastasis in Treatment of Brain Glioma. Artif Cells Nanomed Biotechnol (2018) 46(sup3):S524–37. doi: 10.1080/21691401.2018.1501377
- Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic Mimicry and Tumor Angiogenesis. Am J Pathol (2000) 156(2):361–81. doi: 10.1016/S0002-9440(10)64739-6
- Shen Y, Quan J, Wang M, Li S, Yang J, Lv M, et al. . Tumor Vasculogenic Mimicry Formation as an Unfavorable Prognostic Indicator in Patients With Breast Cancer. Oncotarget (2017) 8(34):56408–16. doi: 10.18632/oncotarget.16919
- Zhang S, Li M, Gu Y, Liu Z, Xu S, Cui Y, et al. . Thalidomide Influences Growth and Vasculogenic Mimicry Channel Formation in Melanoma. J Exp Clin Cancer Res (2008) 27(1):60. doi: 10.1186/1756-9966-27-60
- Cong R, Sun Q, Yang L, Gu H, Zeng Y, Wang B. Effect of Genistein on Vasculogenic Mimicry Formation by Human Uveal Melanoma Cells. J Exp Clin Cancer Res (2009) 28(1):124. doi: 10.1186/1756-9966-28-124
- Serwe A, Rudolph K, Anke T, Erkel G. Inhibition of TGF-β Signaling, Vasculogenic Mimicry and Proinflammatory Gene Expression by Isoxanthohumol. Invest New Drugs (2012) 30(3):898–915. doi: 10.1007/s10637-011-9643-3
- Hu A, Huang JJ, Jin XJ, Li JP, Tang YJ, Huang XF, et al. . Curcumin Suppresses Invasiveness and Vasculogenic Mimicry of Squamous Cell Carcinoma of the Larynx Through the Inhibition of JAK-2/STAT-3 Signaling Pathway. Am J Cancer Res (2014) 5(1):278–88.
- Liang Y, Huang M, Li J, Sun X, Jiang X, Li L, et al. . Curcumin Inhibits Vasculogenic Mimicry Through the Downregulation of Erythropoietin-Producing Hepatocellular Carcinoma-A2, Phosphoinositide 3-Kinase and Matrix Metalloproteinase-2. Oncol Lett (2014) 8(4):1849–55. doi: 10.3892/ol.2014.2401
- Chiablaem K, Lirdprapamongkol K, Keeratichamroen S, Surarit R, Svasti J. Curcumin Suppresses Vasculogenic Mimicry Capacity of Hepatocellular Carcinoma Cells Through STAT3 and PI3K/AKT Inhibition. Anticancer Res (2014) 34(4):1857–64.
- Chen LX, He YJ, Zhao SZ, Wu JG, Wang JT, Zhu LM, et al. . Inhibition of Tumor Growth and Vasculogenic Mimicry by Curcumin Through Down-Regulation of the EphA2/PI3K/MMP Pathway in a Murine Choroidal Melanoma Model. Cancer Biol Ther (2011) 11(2):229–35. doi: 10.4161/cbt.11.2.13842
- Sicard AA, Dao T, Suarez NG, Annabi B. Diet-Derived Gallated Catechins Prevent TGF-β-Mediated Epithelial-Mesenchymal Transition, Cell Migration and Vasculogenic Mimicry in Chemosensitive ES-2 Ovarian Cancer Cells. Nutr Cancer (2021) 73(1):169–80. doi: 10.1080/01635581.2020.1733624
- Yeo C, Han DS, Lee HJ, Lee EO. Epigallocatechin-3-Gallate Suppresses Vasculogenic Mimicry Through Inhibiting the Twist/VE-Cadherin/AKT Pathway in Human Prostate Cancer PC-3 Cells. Int J Mol Sci (2020) 21(2):439. doi: 10.3390/ijms21020439
- Hettiarachchi SS, Dunuweera SP, Dunuweera AN, Rajapakse RMG. Synthesis of Curcumin Nanoparticles From Raw Turmeric Rhizome. ACS Omega (2021) 6(12):8246–52. doi: 10.1021/acsomega.0c06314
- Li K, Teng C, Min Q. Advanced Nanovehicles-Enabled Delivery Systems of Epigallocatechin Gallate for Cancer Therapy. Front Chem (2020) 8:573297. doi: 10.3389/fchem.2020.573297
- Luo Q, Wang J, Zhao W, Peng Z, Liu X, Li B, et al. . Vasculogenic Mimicry in Carcinogenesis and Clinical Applications. J Hematol Oncol (2020) 13(1):19. doi: 10.1186/s13045-020-00858-6
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