Skip to main content

Advertisement

SpringerLink
Log in

Metastasis prevention: targeting causes and roots

  • Review
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

The spread of tumor cells from the primary focus, metastasis, is the main cause of cancer mortality. Therefore, anticancer therapy should be focused on the prevention of metastatic disease. Key targets can be conditions in the primary tumor that are favorable for the appearance of metastatic cells and the first steps of the metastatic cascade. Here, we discuss different approaches for targeting metastasis causes (hypoxia, metabolism changes, and tumor microenvironment) and roots (angiogenesis, epithelial-mesenchymal transition, migration, and invasion). Also, we emphasize the challenges of the existing approaches for metastasis prevention and suggest opportunities to overcome them. In conclusion, we highlight the importance of clinical evaluation of the agents showing antimetastatic effects in vivo, especially in patients with early-stage cancers, the identification of metastatic seeds, and the development of therapeutics for their eradication.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  2. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292. doi:https://doi.org/10.1016/j.cell.2011.09.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hapach LA, Mosier JA, Wang W, Reinhart-King CA (2019) Engineered models to parse apart the metastatic cascade. NPJ Precis Oncol 3:20. doi:https://doi.org/10.1038/s41698-019-0092-3

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y (2020) Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 5(1):28. doi:https://doi.org/10.1038/s41392-020-0134-x

    Article  PubMed  PubMed Central  Google Scholar 

  5. Seyfried TN, Huysentruyt LC (2013) On the origin of cancer metastasis. Crit Rev Oncog 18(1–2):43–73. doi:https://doi.org/10.1615/critrevoncog.v18.i1-2.40

    Article  PubMed  PubMed Central  Google Scholar 

  6. Guan X (2015) Cancer metastases: challenges and opportunities. Acta Pharm Sin B 5(5):402–418. doi:https://doi.org/10.1016/j.apsb.2015.07.005

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dillekas H, Rogers MS, Straume O (2019) Are 90% of deaths from cancer caused by metastases? Cancer Med 8(12):5574–5576. doi:https://doi.org/10.1002/cam4.2474

    Article  PubMed  PubMed Central  Google Scholar 

  8. Prophylactic Cranial Irradiation Overview Collaborative G (2018) WITHDRAWN: Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission. Cochrane Database Syst Rev 2:CD002805. doi:https://doi.org/10.1002/14651858.CD002805.pub2

    Article  Google Scholar 

  9. Zhang Y, Zhang Y, Liu Z, Qin Z, Li Y, Zhao J, Ma X, Yang Q, Han N, Zeng X, Guo H, Zhang N (2021) Impact of Postmastectomy Radiotherapy on Locoregional Control and Disease-Free Survival in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy. J Oncol 2021:6632635. doi:https://doi.org/10.1155/2021/6632635

  10. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, D’Amico R (2012) Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 2012 (4):Cd006243. doi:https://doi.org/10.1002/14651858.CD006243.pub2

  11. Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A, Pierce LJ, Manchul L, Chafe S, Nolan MC, Craighead P, Bowen J, McCready DR, Pritchard KI, Gelmon K, Murray Y, Chapman JA, Chen BE, Levine MN (2015) Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med 373(4):307–316. doi:https://doi.org/10.1056/NEJMoa1415340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, Lawton C, Machtay M, Grignon D (2001) Phase III radiation therapy oncology group (RTOG) trial 86 – 10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50(5):1243–1252. doi:https://doi.org/10.1016/s0360-3016(01)01579-6

    Article  CAS  PubMed  Google Scholar 

  13. Loud JT, Murphy J (2017) Cancer Screening and Early Detection in the 21(st) Century. Semin Oncol Nurs 33(2):121–128. doi:https://doi.org/10.1016/j.soncn.2017.02.002

    Article  PubMed  PubMed Central  Google Scholar 

  14. Griffin-Sobel JP (2017) Gastrointestinal Cancers: Screening and Early Detection. Semin Oncol Nurs 33(2):165–171. doi:https://doi.org/10.1016/j.soncn.2017.02.004

    Article  PubMed  Google Scholar 

  15. Eggert JA, Palavanzadeh M, Blanton A (2017) Screening and Early Detection of Lung Cancer. Semin Oncol Nurs 33(2):129–140. doi:https://doi.org/10.1016/j.soncn.2017.03.001

    Article  PubMed  Google Scholar 

  16. Hu Y, Yu X, Xu G, Liu S (2017) Metastasis: an early event in cancer progression. J Cancer Res Clin Oncol 143(5):745–757. doi:https://doi.org/10.1007/s00432-016-2279-0

    Article  CAS  PubMed  Google Scholar 

  17. Rapisuwon S, Vietsch EE, Wellstein A (2016) Circulating biomarkers to monitor cancer progression and treatment. Comput Struct Biotechnol J 14:211–222. doi:https://doi.org/10.1016/j.csbj.2016.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Do HTT, Lee CH, Cho J (2020) Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers. Cancers (Basel) 12(2). doi:https://doi.org/10.3390/cancers12020287

  19. Schegoleva AA, Khozyainova AA, Fedorov AA, Gerashchenko TS, Rodionov EO, Topolnitsky EB, Shefer NA, Pankova OV, Durova AA, Zavyalova MV, Perelmuter VM, Denisov EV (2021) Prognosis of Different Types of Non-Small Cell Lung Cancer Progression: Current State and Perspectives. Cell Physiol Biochem 55(S2):29–48. doi:https://doi.org/10.33594/000000340

    Article  PubMed  Google Scholar 

  20. Menyailo ME, Bokova UA, Ivanyuk EE, Khozyainova AA, Denisov EV (2021) Metastasis Prevention: Focus on Metastatic Circulating Tumor Cells. Mol Diagn Ther 25(5):549–562. doi:https://doi.org/10.1007/s40291-021-00543-5

    Article  PubMed  Google Scholar 

  21. Ejaz U, Akhtar F, Xue J, Wan X, Zhang T, He S (2021) Review: Inhibitory potential of low molecular weight Heparin in cell adhesion; emphasis on tumor metastasis. Eur J Pharmacol 892:173778. doi:https://doi.org/10.1016/j.ejphar.2020.173778

    Article  CAS  PubMed  Google Scholar 

  22. Aguirre-Ghiso JA (2021) Translating the Science of Cancer Dormancy to the Clinic. Cancer Res 81(18):4673–4675. doi:https://doi.org/10.1158/0008-5472.can-21-1407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Guo S, Deng CX (2018) Effect of Stromal Cells in Tumor Microenvironment on Metastasis Initiation. Int J Biol Sci 14(14):2083–2093. doi:https://doi.org/10.7150/ijbs.25720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Joseph JP, Harishankar MK, Pillai AA, Devi A (2018) Hypoxia induced EMT: A review on the mechanism of tumor progression and metastasis in OSCC. Oral Oncol 80:23–32. doi:https://doi.org/10.1016/j.oraloncology.2018.03.004

    Article  CAS  PubMed  Google Scholar 

  25. Ma Z, Xiang X, Li S, Xie P, Gong Q, Goh BC, Wang L (2020) Targeting hypoxia-inducible factor-1, for cancer treatment: Recent advances in developing small-molecule inhibitors from natural compounds. Semin Cancer Biol. doi:https://doi.org/10.1016/j.semcancer.2020.09.011

    Article  PubMed  Google Scholar 

  26. Saxena K, Jolly MK, Balamurugan K (2020) Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis. Transl Oncol 13(11):100845. doi:https://doi.org/10.1016/j.tranon.2020.100845

    Article  PubMed  PubMed Central  Google Scholar 

  27. El-Kenawi AE, El-Remessy AB (2013) Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales. Br J Pharmacol 170(4):712–729. doi:https://doi.org/10.1111/bph.12344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marech I, Leporini C, Ammendola M, Porcelli M, Gadaleta CD, Russo E, De Sarro G, Ranieri G (2016) Classical and non-classical proangiogenic factors as a target of antiangiogenic therapy in tumor microenvironment. Cancer Lett 380(1):216–226. doi:https://doi.org/10.1016/j.canlet.2015.07.028

    Article  CAS  PubMed  Google Scholar 

  29. Qin S, Li A, Yi M, Yu S, Zhang M, Wu K (2019) Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol 12(1):27. doi:https://doi.org/10.1186/s13045-019-0718-5

    Article  PubMed  PubMed Central  Google Scholar 

  30. Blomberg OS, Spagnuolo L, de Visser KE (2018) Immune regulation of metastasis: mechanistic insights and therapeutic opportunities. Dis Model Mech 11(10). doi:https://doi.org/10.1242/dmm.036236

  31. Infantino V, Santarsiero A, Convertini P, Todisco S, Iacobazzi V (2021) Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int J Mol Sci 22(11). doi:https://doi.org/10.3390/ijms22115703

  32. Bergers G, Fendt SM (2021) The metabolism of cancer cells during metastasis. Nat Rev Cancer 21(3):162–180. doi:https://doi.org/10.1038/s41568-020-00320-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Payen VL, Porporato PE, Baselet B, Sonveaux P (2016) Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway. Cell Mol Life Sci 73(7):1333–1348. doi:https://doi.org/10.1007/s00018-015-2098-5

    Article  CAS  PubMed  Google Scholar 

  34. Teoh ST, Lunt SY (2018) Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond. Wiley Interdiscip Rev Syst Biol Med 10(2). doi:https://doi.org/10.1002/wsbm.1406

  35. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T, Konishi I (2003) Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 163(4):1437–1447. doi:https://doi.org/10.1016/s0002-9440(10)63501-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang J, Cheng Q, Zhou Y, Wang Y, Chen X (2013) Slug is a key mediator of hypoxia induced cadherin switch in HNSCC: correlations with poor prognosis. Oral Oncol 49(11):1043–1050. doi:https://doi.org/10.1016/j.oraloncology.2013.08.003

    Article  CAS  PubMed  Google Scholar 

  37. Wei L, Sun JJ, Cui YC, Jiang SL, Wang XW, Lv LY, Xie L, Song XR (2016) Twist may be associated with invasion and metastasis of hypoxic NSCLC cells. Tumour Biol 37(7):9979–9987. doi:https://doi.org/10.1007/s13277-016-4896-2

    Article  CAS  PubMed  Google Scholar 

  38. Bonde AK, Tischler V, Kumar S, Soltermann A, Schwendener RA (2012) Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12:35. doi:https://doi.org/10.1186/1471-2407-12-35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Goebel L, Grage-Griebenow E, Gorys A, Helm O, Genrich G, Lenk L, Wesch D, Ungefroren H, Freitag-Wolf S, Sipos B, Röcken C, Schäfer H, Sebens S (2015) CD4(+) T cells potently induce epithelial-mesenchymal-transition in premalignant and malignant pancreatic ductal epithelial cells-novel implications of CD4(+) T cells in pancreatic cancer development. Oncoimmunology 4(4):e1000083. doi:https://doi.org/10.1080/2162402x.2014.1000083

    Article  PubMed  PubMed Central  Google Scholar 

  40. Shintani Y, Fujiwara A, Kimura T, Kawamura T, Funaki S, Minami M, Okumura M (2016) IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling. J Thorac Oncol 11(9):1482–1492. doi:https://doi.org/10.1016/j.jtho.2016.05.025

    Article  PubMed  Google Scholar 

  41. Sangaletti S, Tripodo C, Santangelo A, Castioni N, Portararo P, Gulino A, Botti L, Parenza M, Cappetti B, Orlandi R, Tagliabue E, Chiodoni C, Colombo MP (2016) Mesenchymal Transition of High-Grade Breast Carcinomas Depends on Extracellular Matrix Control of Myeloid Suppressor Cell Activity. Cell Rep 17(1):233–248. doi:https://doi.org/10.1016/j.celrep.2016.08.075

    Article  CAS  PubMed  Google Scholar 

  42. Dongre A, Weinberg RA (2019) New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20(2):69–84. doi:https://doi.org/10.1038/s41580-018-0080-4

    Article  CAS  PubMed  Google Scholar 

  43. Pearson GW (2019) Control of Invasion by Epithelial-to-Mesenchymal Transition Programs during Metastasis. J Clin Med 8(5). doi:https://doi.org/10.3390/jcm8050646

  44. Ruggiero C, Lalli E (2021) Targeting the cytoskeleton against metastatic dissemination. Cancer Metastasis Rev 40(1):89–140. doi:https://doi.org/10.1007/s10555-020-09936-0

    Article  CAS  PubMed  Google Scholar 

  45. Wu JS, Jiang J, Chen BJ, Wang K, Tang YL, Liang XH (2021) Plasticity of cancer cell invasion: Patterns and mechanisms. Transl Oncol 14(1):100899. doi:https://doi.org/10.1016/j.tranon.2020.100899

    Article  CAS  PubMed  Google Scholar 

  46. Krakhmal NV, Zavyalova MV, Denisov EV, Vtorushin SV, Perelmuter VM (2015) Cancer Invasion: Patterns and Mechanisms. Acta Naturae 7(2):17–28

    Article  CAS  Google Scholar 

  47. Panková K, Rösel D, Novotný M, Brábek J (2010) The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell Mol Life Sci 67(1):63–71. doi:https://doi.org/10.1007/s00018-009-0132-1

    Article  CAS  PubMed  Google Scholar 

  48. Yilmaz M, Christofori G (2010) Mechanisms of motility in metastasizing cells. Mol Cancer Res 8(5):629–642. doi:https://doi.org/10.1158/1541-7786.mcr-10-0139

    Article  CAS  PubMed  Google Scholar 

  49. Chiang SP, Cabrera RM, Segall JE (2016) Tumor cell intravasation. Am J Physiol Cell Physiol 311(1):C1–c14. doi:https://doi.org/10.1152/ajpcell.00238.2015

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zavyalova MV, Denisov EV, Tashireva LA, Savelieva OE, Kaigorodova EV, Krakhmal NV, Perelmuter VM (2019) Intravasation as a Key Step in Cancer Metastasis. Biochem (Mosc) 84(7):762–772. doi:https://doi.org/10.1134/s0006297919070071

    Article  CAS  Google Scholar 

  51. Borriello L, Karagiannis GS, Duran CL, Coste A, Oktay MH, Entenberg D, Condeelis JS (2020) The role of the tumor microenvironment in tumor cell intravasation and dissemination. Eur J Cell Biol 99(6):151098. doi:https://doi.org/10.1016/j.ejcb.2020.151098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hackshaw A, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M (2011) Long-Term Benefits of 5 Years of Tamoxifen: 10-Year Follow-Up of a Large Randomized Trial in Women at Least 50 Years of Age With Early Breast Cancer. J Clin Oncol 29(13):1657–1663. doi:https://doi.org/10.1200/jco.2010.32.2933

    Article  PubMed  Google Scholar 

  53. Burstein HJ (2020) Systemic Therapy for Estrogen Receptor-Positive, HER2-Negative Breast Cancer. N Engl J Med 383(26):2557–2570. doi:https://doi.org/10.1056/NEJMra1307118

    Article  CAS  PubMed  Google Scholar 

  54. Paleari L, Gandini S, Provinciali N, Puntoni M, Colombo N, DeCensi A (2017) Clinical benefit and risk of death with endocrine therapy in ovarian cancer: A comprehensive review and meta-analysis. Gynecol Oncol 146(3):504–513. doi:https://doi.org/10.1016/j.ygyno.2017.06.036

    Article  PubMed  Google Scholar 

  55. Paleari L, DeCensi A (2018) Endocrine therapy in ovarian cancer: where do we stand? Curr Opin Obstet Gynecol 30(1):17–22. doi:https://doi.org/10.1097/gco.0000000000000423

    Article  PubMed  Google Scholar 

  56. Singh M, Zaino RJ, Filiaci VJ, Leslie KK (2007) Relationship of estrogen and progesterone receptors to clinical outcome in metastatic endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol 106(2):325–333. doi:https://doi.org/10.1016/j.ygyno.2007.03.042

    Article  CAS  PubMed  Google Scholar 

  57. Fader AN, Bergstrom J, Jernigan A, Tanner EJ 3, Roche KL, Stone RL, Levinson KL, Ricci S, Wethingon S, Wang TL, Shih IM, Yang B, Zhang G, Armstrong DK, Gaillard S, Michener C, DeBernardo R, Rose PG (2017) Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: Reducing overtreatment without compromising survival? Gynecol Oncol 147(1):85–91. doi:https://doi.org/10.1016/j.ygyno.2017.07.127

  58. Liu L, Zhao T, Zhong Q, Cui J, Xiu X, Li G (2020) The Role of Prophylactic Cranial Irradiation in Patients With Non-small Cell Lung Cancer: An Updated Systematic Review and Meta-Analysis. Front Oncol 10:11. doi:https://doi.org/10.3389/fonc.2020.00011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tang JT, Wang JL, Fang JY (2010) Meta-analysis: perioperative regional liver chemotherapy for improving survival and preventing liver metastases in patients with colorectal carcinoma. J Dig Dis 11(4):208–214. doi:https://doi.org/10.1111/j.1751-2980.2010.00440.x

    Article  PubMed  Google Scholar 

  60. Middleton JD, Stover DG, Hai T (2018) Chemotherapy-Exacerbated Breast Cancer Metastasis: A Paradox Explainable by Dysregulated Adaptive-Response. Int J Mol Sci 19(11). doi:https://doi.org/10.3390/ijms19113333

  61. Blyth BJ, Cole AJ, MacManus MP, Martin OA (2018) Radiation therapy-induced metastasis: radiobiology and clinical implications. Clin Exp Metastasis 35(4):223–236. doi:https://doi.org/10.1007/s10585-017-9867-5

    Article  CAS  PubMed  Google Scholar 

  62. Martin OA, Anderson RL, Narayan K, MacManus MP (2017) Does the mobilization of circulating tumour cells during cancer therapy cause metastasis? Nat Rev Clin Oncol 14(1):32–44. doi:https://doi.org/10.1038/nrclinonc.2016.128

    Article  CAS  PubMed  Google Scholar 

  63. Alieva M, van Rheenen J, Broekman MLD (2018) Potential impact of invasive surgical procedures on primary tumor growth and metastasis. Clin Exp Metastasis 35(4):319–331. doi:https://doi.org/10.1007/s10585-018-9896-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Riggio AI, Varley KE, Welm AL (2021) The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer 124(1):13–26. doi:https://doi.org/10.1038/s41416-020-01161-4

    Article  PubMed  Google Scholar 

  65. Zhao Y, He M, Cui L, Gao M, Zhang M, Yue F, Shi T, Yang X, Pan Y, Zheng X, Jia Y, Shao D, Li J, He K, Chen L (2020) Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1. Br J Cancer 122(11):1638–1648. doi:https://doi.org/10.1038/s41416-020-0825-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, Xue EA, Cheng E, D’Alfonso TM, Jones JG, Anampa J, Rohan TE, Sparano JA, Condeelis JS, Oktay MH (2017) Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med 9(397). doi:https://doi.org/10.1126/scitranslmed.aan0026

  67. Kawamoto A, Yokoe T, Tanaka K, Saigusa S, Toiyama Y, Yasuda H, Inoue Y, Miki C, Kusunoki M (2012) Radiation induces epithelial-mesenchymal transition in colorectal cancer cells. Oncol Rep 27(1):51–57. doi:https://doi.org/10.3892/or.2011.1485

    Article  CAS  PubMed  Google Scholar 

  68. Liu G, Chen Y, Qi F, Jia L, Lu XA, He T, Fu Y, Li L, Luo Y (2015) Specific chemotherapeutic agents induce metastatic behaviour through stromal- and tumour-derived cytokine and angiogenic factor signalling. J Pathol 237(2):190–202. doi:https://doi.org/10.1002/path.4564

    Article  CAS  PubMed  Google Scholar 

  69. Perelmuter VM, Tashireva LA, Savelieva OE, Denisov EV, Kaigorodova EV, Zavyalova MV, Cherdyntseva NV (2019) Mechanisms behind prometastatic changes induced by neoadjuvant chemotherapy in the breast cancer microenvironment. Breast Cancer (Dove Med Press) 11:209–219. doi:https://doi.org/10.2147/bctt.s175161

    Article  CAS  Google Scholar 

  70. Liu ZJ, Semenza GL, Zhang HF (2015) Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B 16(1):32–43. doi:https://doi.org/10.1631/jzus.B1400221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wigerup C, Påhlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169. doi:https://doi.org/10.1016/j.pharmthera.2016.04.009

    Article  CAS  PubMed  Google Scholar 

  72. Wei Z, Shan Y, Tao L, Liu Y, Zhu Z, Liu Z, Wu Y, Chen W, Wang A, Lu Y (2017) Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF-1α synthesis, and decreases breast cancer metastasis. Mol Carcinog 56(10):2317–2331. doi:https://doi.org/10.1002/mc.22686

    Article  CAS  PubMed  Google Scholar 

  73. Xu Y, Jin X, Huang Y, Dong J, Wang H, Wang X, Cao X (2016) Inhibition of peritoneal metastasis of human gastric cancer cells by dextran sulphate through the reduction in HIF-1α and ITGβ1 expression. Oncol Rep 35(5):2624–2634. doi:https://doi.org/10.3892/or.2016.4693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bailey CM, Liu Y, Peng G, Zhang H, He M, Sun D, Zheng P, Liu Y, Wang Y (2020) Liposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer. Nanomedicine 29:102278. doi:https://doi.org/10.1016/j.nano.2020.102278

    Article  CAS  PubMed  Google Scholar 

  75. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R (2021) Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med 385(22):2036–2046. doi:https://doi.org/10.1056/NEJMoa2103425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Shimizu K, Iyoda T, Okada M, Yamasaki S, Fujii SI (2018) Immune suppression and reversal of the suppressive tumor microenvironment. Int Immunol 30(10):445–454. doi:https://doi.org/10.1093/intimm/dxy042

    Article  CAS  PubMed  Google Scholar 

  77. Wang X, Fan S, Pan H, Chen W, Wang H (2019) Cancer immunotherapy for metastasis: past, present and future. Brief Funct Genomics 18(2):140–146. doi:https://doi.org/10.1093/bfgp/ely022

    Article  CAS  PubMed  Google Scholar 

  78. Pan C, Liu H, Robins E, Song W, Liu D, Li Z, Zheng L (2020) Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy. J Hematol Oncol 13(1):29. doi:https://doi.org/10.1186/s13045-020-00862-w

    Article  PubMed  PubMed Central  Google Scholar 

  79. Edwards SC, Hoevenaar WHM, Coffelt SB (2021) Emerging immunotherapies for metastasis. Br J Cancer 124(1):37–48. doi:https://doi.org/10.1038/s41416-020-01160-5

    Article  PubMed  Google Scholar 

  80. Janssen LME, Ramsay EE, Logsdon CD, Overwijk WW (2017) The immune system in cancer metastasis: friend or foe? J Immunother Cancer 5(1):79. doi:https://doi.org/10.1186/s40425-017-0283-9

    Article  PubMed  PubMed Central  Google Scholar 

  81. Zhang C, Gao L, Cai Y, Liu H, Gao D, Lai J, Jia B, Wang F, Liu Z (2016) Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model. Biomaterials 84:1–12. doi:https://doi.org/10.1016/j.biomaterials.2016.01.027

    Article  CAS  PubMed  Google Scholar 

  82. Blake SJ, Stannard K, Liu J, Allen S, Yong MC, Mittal D, Aguilera AR, Miles JJ, Lutzky VP, de Andrade LF, Martinet L, Colonna M, Takeda K, Kühnel F, Gurlevik E, Bernhardt G, Teng MW, Smyth MJ (2016) Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy. Cancer Discov 6(4):446–459. doi:https://doi.org/10.1158/2159-8290.cd-15-0944

    Article  CAS  PubMed  Google Scholar 

  83. López-Soto A, Gonzalez S, Smyth MJ, Galluzzi L (2017) Control of Metastasis by NK Cells. Cancer Cell 32(2):135–154. doi:https://doi.org/10.1016/j.ccell.2017.06.009

    Article  CAS  PubMed  Google Scholar 

  84. Lorenzo-Herrero S, López-Soto A, Sordo-Bahamonde C, Gonzalez-Rodriguez AP, Vitale M, Gonzalez S (2018) NK Cell-Based Immunotherapy in Cancer Metastasis. Cancers (Basel) 11(1). doi:https://doi.org/10.3390/cancers11010029

  85. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S (2019) Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer 18(1):155. doi:https://doi.org/10.1186/s12943-019-1091-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhou T, Liang X, Wang P, Hu Y, Qi Y, Jin Y, Du Y, Fang C, Tian J (2020) A Hepatocellular Carcinoma Targeting Nanostrategy with Hypoxia-Ameliorating and Photothermal Abilities that, Combined with Immunotherapy, Inhibits Metastasis and Recurrence. ACS Nano 14(10):12679–12696. doi:https://doi.org/10.1021/acsnano.0c01453

    Article  CAS  PubMed  Google Scholar 

  87. Song W, Tiruthani K, Wang Y, Shen L, Hu M, Dorosheva O, Qiu K, Kinghorn KA, Liu R, Huang L (2018) Trapping of Lipopolysaccharide to Promote Immunotherapy against Colorectal Cancer and Attenuate Liver Metastasis. Adv Mater 30(52):e1805007. doi:https://doi.org/10.1002/adma.201805007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen Q, Chen J, Yang Z, Xu J, Xu L, Liang C, Han X, Liu Z (2019) Nanoparticle-Enhanced Radiotherapy to Trigger Robust Cancer Immunotherapy. Adv Mater 31(10):e1802228. doi:https://doi.org/10.1002/adma.201802228

    Article  CAS  PubMed  Google Scholar 

  89. Mills KA, Quinn JM, Roach ST, Palisoul M, Nguyen M, Noia H, Guo L, Fazal J, Mutch DG, Wickline SA, Pan H, Fuh KC (2019) p5RHH nanoparticle-mediated delivery of AXL siRNA inhibits metastasis of ovarian and uterine cancer cells in mouse xenografts. Sci Rep 9(1):4762. doi:https://doi.org/10.1038/s41598-019-41122-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shi Y, Lammers T (2019) Combining Nanomedicine and Immunotherapy. Acc Chem Res 52(6):1543–1554. doi:https://doi.org/10.1021/acs.accounts.9b00148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, Chan WCW (2016) Analysis of nanoparticle delivery to tumours. Nat Reviews Mater 1(5):16014. doi:https://doi.org/10.1038/natrevmats.2016.14

    Article  CAS  Google Scholar 

  92. Yan L, Zhao F, Wang J, Zu Y, Gu Z, Zhao Y (2019) A Safe-by-Design Strategy towards Safer Nanomaterials in Nanomedicines. Adv Mater 31(45):e1805391. doi:https://doi.org/10.1002/adma.201805391

    Article  CAS  PubMed  Google Scholar 

  93. Woodman C, Vundu G, George A, Wilson CM (2021) Applications and strategies in nanodiagnosis and nanotherapy in lung cancer. Semin Cancer Biol 69:349–364. doi:https://doi.org/10.1016/j.semcancer.2020.02.009

    Article  CAS  PubMed  Google Scholar 

  94. Luengo A, Gui DY, Vander Heiden MG (2017) Targeting Metabolism for Cancer Therapy. Cell Chem Biol 24(9):1161–1180. doi:https://doi.org/10.1016/j.chembiol.2017.08.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Li J, Eu JQ, Kong LR, Wang L, Lim YC, Goh BC, Wong ALA (2020) Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy. Molecules 25(20). doi:https://doi.org/10.3390/molecules25204831

  96. Mele L, Paino F, Papaccio F, Regad T, Boocock D, Stiuso P, Lombardi A, Liccardo D, Aquino G, Barbieri A, Arra C, Coveney C, La Noce M, Papaccio G, Caraglia M, Tirino V, Desiderio V (2018) A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo. Cell Death Dis 9(5):572. doi:https://doi.org/10.1038/s41419-018-0635-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li J, Gu D, Lee SS, Song B, Bandyopadhyay S, Chen S, Konieczny SF, Ratliff TL, Liu X, Xie J, Cheng JX (2016) Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene 35(50):6378–6388. doi:https://doi.org/10.1038/onc.2016.168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lee HJ, Li J, Vickman RE, Li J, Liu R, Durkes AC, Elzey BD, Yue S, Liu X, Ratliff TL, Cheng JX (2018) Cholesterol Esterification Inhibition Suppresses Prostate Cancer Metastasis by Impairing the Wnt/β-catenin Pathway. Mol Cancer Res 16(6):974–985. doi:https://doi.org/10.1158/1541-7786.mcr-17-0665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhao J, Huang X, Xu Z, Dai J, He H, Zhu Y, Wang H (2017) LDHA promotes tumor metastasis by facilitating epithelial–mesenchymal transition in renal cell carcinoma. Mol Med Rep 16(6):8335–8344. doi:https://doi.org/10.3892/mmr.2017.7637

    Article  CAS  PubMed  Google Scholar 

  100. Zhao H, Yan G, Zheng L, Zhou Y, Sheng H, Wu L, Zhang Q, Lei J, Zhang J, Xin R, Jiang L, Zhang X, Chen Y, Wang J, Xu Y, Li D, Li Y (2020) STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma. Theranostics 10(14):6483–6499. doi:https://doi.org/10.7150/thno.44025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Huang Q, Zhang H, Bai LP, Law BYK, Xiong H, Zhou X, Xiao R, Qu YQ, Mok SWF, Liu L, Wong VKW (2020) Novel ginsenoside derivative 20(S)-Rh2E2 suppresses tumor growth and metastasis in vivo and in vitro via intervention of cancer cell energy metabolism. Cell Death Dis 11(8):621. doi:https://doi.org/10.1038/s41419-020-02881-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Donnem T, Reynolds AR, Kuczynski EA, Gatter K, Vermeulen PB, Kerbel RS, Harris AL, Pezzella F (2018) Non-angiogenic tumours and their influence on cancer biology. Nat Rev Cancer 18(5):323–336. doi:https://doi.org/10.1038/nrc.2018.14

    Article  CAS  PubMed  Google Scholar 

  103. Gill JH, Rockley KL, De Santis C, Mohamed AK (2019) Vascular Disrupting Agents in cancer treatment: Cardiovascular toxicity and implications for co-administration with other cancer chemotherapeutics. Pharmacol Ther 202:18–31. doi:https://doi.org/10.1016/j.pharmthera.2019.06.001

    Article  CAS  PubMed  Google Scholar 

  104. Yamakawa M, Doh SJ, Santosa SM, Montana M, Qin EC, Kong H, Han KY, Yu C, Rosenblatt MI, Kazlauskas A, Chang JH, Azar DT (2018) Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review. Med Res Rev 38(6):1769–1798. doi:https://doi.org/10.1002/med.21496

    Article  PubMed  PubMed Central  Google Scholar 

  105. Bhargava P, Robinson MO (2011) Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr Oncol Rep 13(2):103–111. doi:https://doi.org/10.1007/s11912-011-0154-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bertolini F, Marighetti P, Martin-Padura I, Mancuso P, Hu-Lowe DD, Shaked Y, D’Onofrio A (2011) Anti-VEGF and beyond: shaping a new generation of anti-angiogenic therapies for cancer. Drug Discov Today 16(23–24):1052–1060. doi:https://doi.org/10.1016/j.drudis.2011.08.007

    Article  CAS  PubMed  Google Scholar 

  107. Zhao Y, Adjei AA (2015) Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor. Oncologist 20(6):660–673. doi:https://doi.org/10.1634/theoncologist.2014-0465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 21(9):1804–1809. doi:https://doi.org/10.1093/annonc/mdq020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dai X, Liu D, Liu M, Zhang X, Wang W, Jin F, Qian Y, Wang X, Zhao J, Wu Y, Xiong F, Chang NA, Sun YU, Yang Z, Hoffman RM, Liu Y (2017) Anti-metastatic Efficacy of Traditional Chinese Medicine (TCM) Ginsenoside Conjugated to a VEFGR-3 Antibody on Human Gastric Cancer in an Orthotopic Mouse Model. Anticancer Res 37(3):979–986. doi:https://doi.org/10.21873/anticanres.11407

    Article  CAS  PubMed  Google Scholar 

  110. Ceci C, Atzori MG, Lacal PM, Graziani G (2020) Role of VEGFs/VEGFR-1 Signaling and its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models. Int J Mol Sci 21(4). doi:https://doi.org/10.3390/ijms21041388

  111. Lugano R, Ramachandran M, Dimberg A (2020) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77(9):1745–1770. doi:https://doi.org/10.1007/s00018-019-03351-7

    Article  CAS  PubMed  Google Scholar 

  112. Pal K, Madamsetty VS, Dutta SK, Wang E, Angom RS, Mukhopadhyay D (2019) Synchronous inhibition of mTOR and VEGF/NRP1 axis impedes tumor growth and metastasis in renal cancer. npj Precision Oncology 3(1):31. doi:https://doi.org/10.1038/s41698-019-0105-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Guo F, Cui J (2020) Anti-angiogenesis: Opening a new window for immunotherapy. Life Sci 258:118163. doi:https://doi.org/10.1016/j.lfs.2020.118163

    Article  CAS  PubMed  Google Scholar 

  114. Chambers A, Kundranda M, Rao S, Mahmoud F, Niu J (2021) Anti-angiogenesis Revisited: Combination with Immunotherapy in Solid Tumors. Curr Oncol Rep 23(9):100. doi:https://doi.org/10.1007/s11912-021-01099-7

    Article  PubMed  Google Scholar 

  115. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M (2018) Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 378(24):2288–2301. doi:https://doi.org/10.1056/NEJMoa1716948

    Article  CAS  PubMed  Google Scholar 

  116. Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI (2020) Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 21(12):1563–1573. doi:https://doi.org/10.1016/s1470-2045(20)30436-8

    Article  CAS  PubMed  Google Scholar 

  117. Amin A, Plimack ER, Ernstoff MS, Lewis LD, Bauer TM, McDermott DF, Carducci M, Kollmannsberger C, Rini BI, Heng DYC, Knox J, Voss MH, Spratlin J, Berghorn E, Yang L, Hammers HJ (2018) Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. J Immunother Cancer 6(1):109. doi:https://doi.org/10.1186/s40425-018-0420-0

    Article  PubMed  PubMed Central  Google Scholar 

  118. Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, Nathan MR, Wan E, Frentzas S, Schweiger T, Hegedus B, Hoetzenecker K, Renyi-Vamos F, Kuczynski EA, Vasudev NS, Larkin J, Gore M, Dvorak HF, Paku S, Kerbel RS, Dome B, Reynolds AR (2017) Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J Pathol 241(3):362–374. doi:https://doi.org/10.1002/path.4845

    Article  CAS  PubMed  Google Scholar 

  119. De Bock K, Mazzone M, Carmeliet P (2011) Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nat Reviews Clin Oncol 8(7):393–404. doi:https://doi.org/10.1038/nrclinonc.2011.83

    Article  CAS  Google Scholar 

  120. Bhattacharya A, Li Y, Geng F, Munday R, Zhang Y (2011) The principal urinary metabolite of allyl isothiocyanate, N -acetyl- S -(N -allylthiocarbamoyl)cysteine, inhibits the growth and muscle invasion of bladder cancer. Carcinogenesis 33(2):394–398. doi:https://doi.org/10.1093/carcin/bgr283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Donato C, Kunz L, Castro-Giner F, Paasinen-Sohns A, Strittmatter K, Szczerba BM, Scherrer R, Di Maggio N, Heusermann W, Biehlmaier O, Beisel C, Vetter M, Rochlitz C, Weber WP, Banfi A, Schroeder T, Aceto N (2020) Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells. Cell Rep 32(10):108105. doi:https://doi.org/10.1016/j.celrep.2020.108105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Li X, Li Y, Lu W, Chen M, Ye W, Zhang D (2019) The Tumor Vessel Targeting Strategy: A Double-Edged Sword in Tumor Metastasis. Cells 8(12). doi:https://doi.org/10.3390/cells8121602

  123. Mattheolabakis G, Mikelis CM (2019) Nanoparticle Delivery and Tumor Vascular Normalization: The Chicken or The Egg? Front Oncol 9:1227. doi:https://doi.org/10.3389/fonc.2019.01227

    Article  PubMed  PubMed Central  Google Scholar 

  124. Ayuso-Íñigo B, Méndez-García L, Pericacho M, Muñoz-Félix JM (2021) The Dual Effect of the BMP9-ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement? Cancers (Basel) 2113. doi:https://doi.org/10.3390/cancers13215412

  125. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6(6):553–563. doi:https://doi.org/10.1016/j.ccr.2004.10.011

    Article  CAS  PubMed  Google Scholar 

  126. Kim SJ, Jung KH, Son MK, Park JH, Yan HH, Fang Z, Kang YW, Han B, Lim JH, Hong SS (2017) Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery. Cancer Lett 403:339–353. doi:https://doi.org/10.1016/j.canlet.2017.06.035

    Article  CAS  PubMed  Google Scholar 

  127. Huang N, Liu Y, Fang Y, Zheng S, Wu J, Wang M, Zhong W, Shi M, Xing M, Liao W (2020) Gold Nanoparticles Induce Tumor Vessel Normalization and Impair Metastasis by Inhibiting Endothelial Smad2/3 Signaling. ACS Nano 14(7):7940–7958. doi:https://doi.org/10.1021/acsnano.9b08460

    Article  CAS  PubMed  Google Scholar 

  128. Cao J, Liu X, Yang Y, Wei B, Li Q, Mao G, He Y, Li Y, Zheng L, Zhang Q, Li J, Wang L, Qi C (2020) Decylubiquinone suppresses breast cancer growth and metastasis by inhibiting angiogenesis via the ROS/p53/ BAI1 signaling pathway. Angiogenesis 23(3):325–338. doi:https://doi.org/10.1007/s10456-020-09707-z

    Article  CAS  PubMed  Google Scholar 

  129. Zeng T, Tang Z, Liang L, Suo D, Li L, Li J, Yuan Y, Guan XY, Li Y (2020) PDSS2-Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF-κB. Mol Oncol 14(12):3184–3197. doi:https://doi.org/10.1002/1878-0261.12826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Malek R, Wang H, Taparra K, Tran PT (2017) Therapeutic Targeting of Epithelial Plasticity Programs: Focus on the Epithelial-Mesenchymal Transition. Cells Tissues Organs 203(2):114–127. doi:https://doi.org/10.1159/000447238

    Article  CAS  PubMed  Google Scholar 

  131. Nieszporek A, Skrzypek K, Adamek G, Majka M (2019) Molecular mechanisms of epithelial to mesenchymal transition in tumor metastasis. Acta Biochim Pol 66(4):509–520. doi:https://doi.org/10.18388/abp.2019_2899

    Article  CAS  PubMed  Google Scholar 

  132. Sheen YY, Kim MJ, Park SA, Park SY, Nam JS (2013) Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy. Biomol Ther (Seoul) 21(5):323–331. doi:https://doi.org/10.4062/biomolther.2013.072

    Article  CAS  Google Scholar 

  133. Kim BG, Malek E, Choi SH, Ignatz-Hoover JJ, Driscoll JJ (2021) Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol 14(1):55. doi:https://doi.org/10.1186/s13045-021-01053-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wang J, Xiang H, Lu Y, Wu T (2021) Role and clinical significance of TGF–β1 and TGF–βR1 in malignant tumors (Review). Int J Mol Med 47(4). doi:https://doi.org/10.3892/ijmm.2021.4888

  135. Di L, Liu LJ, Yan YM, Fu R, Li Y, Xu Y, Cheng YX, Wu ZQ (2019) Discovery of a natural small-molecule compound that suppresses tumor EMT, stemness and metastasis by inhibiting TGFβ/BMP signaling in triple-negative breast cancer. J Exp Clin Cancer Res 38(1):134. doi:https://doi.org/10.1186/s13046-019-1130-2

    Article  PubMed  PubMed Central  Google Scholar 

  136. Purow B (2012) Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med Biol 727:305–319. doi:https://doi.org/10.1007/978-1-4614-0899-4_23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Voronkov A, Krauss S (2013) Wnt/beta-catenin signaling and small molecule inhibitors. Curr Pharm Des 19(4):634–664. doi:https://doi.org/10.2174/138161213804581837

    Article  CAS  PubMed  Google Scholar 

  138. Fagard R, Metelev V, Souissi I, Baran-Marszak F (2013) STAT3 inhibitors for cancer therapy: Have all roads been explored? Jakstat 2. e22882. https://doi.org/10.4161/jkst.22882. 1

  139. Arepalli SK, Choi M, Jung JK, Lee H (2015) Novel NF-κB inhibitors: a patent review (2011–2014). Expert Opin Ther Pat 25(3):319–334. doi:https://doi.org/10.1517/13543776.2014.998199

    Article  CAS  PubMed  Google Scholar 

  140. Zou Y, Zhao D, Yan C, Ji Y, Liu J, Xu J, Lai Y, Tian J, Zhang Y, Huang Z (2018) Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo. J Med Chem 61(5):1821–1832. doi:https://doi.org/10.1021/acs.jmedchem.7b01096

    Article  CAS  PubMed  Google Scholar 

  141. Lin Y, Ukaji T, Koide N, Umezawa K (2018) Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review. Int J Mol Sci 19(3). doi:https://doi.org/10.3390/ijms19030729

  142. Yang L, Zhang XY, Li K, Li AP, Yang WD, Yang R, Wang P, Zhao ZH, Cui F, Qin Y, Yang JH, Tao HL, Sun T, Chen S, Yu PH, Liu HJ, Yang C (2019) Protopanaxadiol inhibits epithelial-mesenchymal transition of hepatocellular carcinoma by targeting STAT3 pathway. Cell Death Dis 10(9):630. doi:https://doi.org/10.1038/s41419-019-1733-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lu HY, Zu YX, Jiang XW, Sun XT, Liu TY, Li RL, Wu Q, Zhang YS, Zhao QC (2019) Novel ADAM-17 inhibitor ZLDI-8 inhibits the proliferation and metastasis of chemo-resistant non-small-cell lung cancer by reversing Notch and epithelial mesenchymal transition in vitro and in vivo. Pharmacol Res 148:104406. doi:https://doi.org/10.1016/j.phrs.2019.104406

    Article  CAS  PubMed  Google Scholar 

  144. Barriere G, Fici P, Gallerani G, Fabbri F, Rigaud M (2015) Epithelial Mesenchymal Transition: a double-edged sword. Clin Transl Med 4:14. doi:https://doi.org/10.1186/s40169-015-0055-4

    Article  PubMed  PubMed Central  Google Scholar 

  145. Denisov EV, Jolly MK, Shubin VP, Tsukanov AS, Cherdyntseva NV (2020) Critical Steps in Epithelial-Mesenchymal Transition as Target for Cancer Treatment. In: Bizzarri M (ed) Approaching Complex Diseases: Network-Based Pharmacology and Systems Approach in Bio-Medicine. Springer International Publishing, Cham, pp 213–244. doi:https://doi.org/10.1007/978-3-030-32857-3_10

    Chapter  Google Scholar 

  146. Perelmuter VM, Tashireva LA, Manskikh VN, Denisov EV, Savelieva OE, Kaygorodova EV, Zavyalova MV (2018) Heterogeneity and Plasticity of Immune Inflammatory Responses in the Tumor Microenvironment: Their Role in the Antitumor Effect and Tumor Aggressiveness. Biology Bull Reviews 8(5):431–448. doi:https://doi.org/10.1134/S2079086418050055

    Article  Google Scholar 

  147. Verma RK, Yu W, Shrivastava A, Shankar S, Srivastava RK (2016) α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in human, and transgenic (Kras(G12D), and Kras(G12D)/tp53R270H) mice. Sci Rep 6:32743. doi:https://doi.org/10.1038/srep32743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wang B, Ding Y, Zhao X, Han X, Yang N, Zhang Y, Zhao Y, Zhao X, Taleb M, Miao QR, Nie G (2018) Delivery of small interfering RNA against Nogo-B receptor via tumor-acidity responsive nanoparticles for tumor vessel normalization and metastasis suppression. Biomaterials 175:110–122. doi:https://doi.org/10.1016/j.biomaterials.2018.05.034

    Article  CAS  PubMed  Google Scholar 

  149. Gandalovičová A, Rosel D, Fernandes M, Veselý P, Heneberg P, Čermák V, Petruželka L, Kumar S, Sanz-Moreno V, Brábek J (2017) Migrastatics-Anti-metastatic and Anti-invasion Drugs: Promises and Challenges. Trends Cancer 3(6):391–406. doi:https://doi.org/10.1016/j.trecan.2017.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Fukami S, Tomioka D, Murakami Y, Honda T, Hatakeyama S (2019) Pharmacological profiling of a dual FAK/IGF-1R kinase inhibitor TAE226 in cellular and in vivo tumor models. BMC Res Notes 12(1):347. doi:https://doi.org/10.1186/s13104-019-4389-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Humphries-Bickley T, Castillo-Pichardo L, Hernandez-O’Farrill E, Borrero-Garcia LD, Forestier-Roman I, Gerena Y, Blanco M, Rivera-Robles MJ, Rodriguez-Medina JR, Cubano LA, Vlaar CP, Dharmawardhane S (2017) Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Cancer. Mol Cancer Ther 16(5):805–818. doi:https://doi.org/10.1158/1535-7163.mct-16-0442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Yu X, Liang C, Zhang Y, Zhang W, Chen H (2019) Inhibitory short peptides targeting EPS8/ABI1/SOS1 tri-complex suppress invasion and metastasis of ovarian cancer cells. BMC Cancer 19(1):878. doi:https://doi.org/10.1186/s12885-019-6087-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Chen L, Bi S, Hou J, Zhao Z, Wang C, Xie S (2019) Targeting p21-activated kinase 1 inhibits growth and metastasis via Raf1/MEK1/ERK signaling in esophageal squamous cell carcinoma cells. Cell Communication and Signaling 17(1):31. doi:https://doi.org/10.1186/s12964-019-0343-5

    Article  PubMed  PubMed Central  Google Scholar 

  154. Yoon YJ, Han YM, Choi J, Lee YJ, Yun J, Lee SK, Lee CW, Kang JS, Chi SW, Moon JH, Lee S, Han DC, Kwon BM (2019) Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis. Biochem Pharmacol 163:46–59. doi:https://doi.org/10.1016/j.bcp.2019.01.017

    Article  CAS  PubMed  Google Scholar 

  155. Jung H, Yoon SR, Lim J, Cho HJ, Lee HG (2020) Dysregulation of Rho GTPases in Human Cancers. Cancers (Basel) 12(5). doi:https://doi.org/10.3390/cancers12051179

  156. Tsubaki M, Genno S, Takeda T, Matsuda T, Kimura N, Yamashita Y, Morii Y, Shimomura K, Nishida S (2021) Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells. Biomedicines 9(1). doi:https://doi.org/10.3390/biomedicines9010035

  157. Willier S, Butt E, Grunewald TG (2013) Lysophosphatidic acid (LPA) signalling in cell migration and cancer invasion: a focussed review and analysis of LPA receptor gene expression on the basis of more than 1700 cancer microarrays. Biol Cell 105(8):317–333. doi:https://doi.org/10.1111/boc.201300011

    Article  CAS  PubMed  Google Scholar 

  158. Tan Z, Lei H, Guo M, Chen Y, Zhai X (2021) An updated patent review of autotaxin inhibitors (2017-present). Expert Opin Ther Pat 31(5):421–434. doi:https://doi.org/10.1080/13543776.2021.1867106

    Article  CAS  PubMed  Google Scholar 

  159. Lin YH, Lin YC, Chen CC (2021) Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials. Cells 10(7). doi:https://doi.org/10.3390/cells10071629

  160. Jung HS, Lee SI, Kang SH, Wang JS, Yang EH, Jeon B, Myung J, Baek JY, Park SK (2017) Monoclonal antibodies against autocrine motility factor suppress gastric cancer. Oncol Lett 13(6):4925–4932. doi:https://doi.org/10.3892/ol.2017.6037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Novikov NM, Zolotaryova SY, Gautreau AM, Denisov EV (2021) Mutational drivers of cancer cell migration and invasion. Br J Cancer 124(1):102–114. doi:https://doi.org/10.1038/s41416-020-01149-0

    Article  PubMed  Google Scholar 

  162. Winer A, Adams S, Mignatti P (2018) Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes. Mol Cancer Ther 17(6):1147–1155. doi:https://doi.org/10.1158/1535-7163.mct-17-0646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Voura EB, English JL, Yu HY, Ho AT, Subarsky P, Hill RP, Hojilla CV, Khokha R (2013) Proteolysis during tumor cell extravasation in vitro: metalloproteinase involvement across tumor cell types. PLoS ONE 8(10):e78413. doi:https://doi.org/10.1371/journal.pone.0078413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kapoor C, Vaidya S, Wadhwan V, Kaur G, Pathak A (2016) Seesaw of matrix metalloproteinases (MMPs). J Cancer Res Ther 12(1):28–35. doi:https://doi.org/10.4103/0973-1482.157337

    Article  CAS  PubMed  Google Scholar 

  165. Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG (2020) Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics. Cells 9(5). doi:https://doi.org/10.3390/cells9051313

  166. Levin M, Udi Y, Solomonov I, Sagi I (2017) Next generation matrix metalloproteinase inhibitors - Novel strategies bring new prospects. Biochim Biophys Acta Mol Cell Res 1864(11 Pt A):1927–1939. doi:https://doi.org/10.1016/j.bbamcr.2017.06.009

    Article  CAS  PubMed  Google Scholar 

  167. Botkjaer KA, Kwok HF, Terp MG, Karatt-Vellatt A, Santamaria S, McCafferty J, Andreasen PA, Itoh Y, Ditzel HJ, Murphy G (2016) Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo. Oncotarget 7(13):16773–16792. doi:https://doi.org/10.18632/oncotarget.7780

    Article  PubMed  PubMed Central  Google Scholar 

  168. Ling B, Watt K, Banerjee S, Newsted D, Truesdell P, Adams J, Sidhu SS, Craig AWB (2017) A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast cancer models. Oncotarget 8(35):58372–58385. doi:https://doi.org/10.18632/oncotarget.17702

    Article  PubMed  PubMed Central  Google Scholar 

  169. Winer A, Janosky M, Harrison B, Zhong J, Moussai D, Siyah P, Schatz-Siemers N, Zeng J, Adams S, Mignatti P (2016) Inhibition of Breast Cancer Metastasis by Presurgical Treatment with an Oral Matrix Metalloproteinase Inhibitor: A Preclinical Proof-of-Principle Study. Mol Cancer Ther 15(10):2370–2377. doi:https://doi.org/10.1158/1535-7163.mct-16-0194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Yu CC, Chen CA, Fu SL, Lin HY, Lee MS, Chiou WY, Su YC, Hung SK (2018) Andrographolide enhances the anti-metastatic effect of radiation in Ras-transformed cells via suppression of ERK-mediated MMP-2 activity. PLoS ONE 13(10):e0205666. doi:https://doi.org/10.1371/journal.pone.0205666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Peeney D, Jensen SM, Castro NP, Kumar S, Noonan S, Handler C, Kuznetsov A, Shih J, Tran AD, Salomon DS, Stetler-Stevenson WG (2020) TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer. Carcinogenesis 41(3):313–325. doi:https://doi.org/10.1093/carcin/bgz172

    Article  CAS  PubMed  Google Scholar 

  172. Laronha H, Caldeira J (2020) Structure and Function of Human Matrix Metalloproteinases. Cells 9(5). doi:https://doi.org/10.3390/cells9051076

  173. Rejhová A, Opattová A, Čumová A, Slíva D, Vodička P (2018) Natural compounds and combination therapy in colorectal cancer treatment. Eur J Med Chem 144:582–594. doi:https://doi.org/10.1016/j.ejmech.2017.12.039

    Article  CAS  PubMed  Google Scholar 

  174. Salehi B, Zucca P, Sharifi-Rad M, Pezzani R, Rajabi S, Setzer WN, Varoni EM, Iriti M, Kobarfard F, Sharifi-Rad J (2018) Phytotherapeutics in cancer invasion and metastasis. Phytother Res 32(8):1425–1449. doi:https://doi.org/10.1002/ptr.6087

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms. Ekaterina Khitrinskaya for the preparation of the figure.

Funding

This work was supported by the Russian Science Foundation [grant number 20-75-10060].

Author information

Authors and Affiliations

  1. Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, 634009, Tomsk, Russia

    A. A. Schegoleva, A. A. Khozyainova, T. S. Gerashchenko & Evgeny V. Denisov

  2. Laboratory of Epidemiology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, 634009, Tomsk, Russia

    L. D. Zhuikova

Authors
  1. A. A. Schegoleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. A. Khozyainova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. S. Gerashchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. D. Zhuikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Evgeny V. Denisov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AAS performed the literature search and prepared the parts about metastatic cascade and targeting metastasis causes. AAK and TSG prepared the information about antimetastatic effects of chemo- and radiotherapy and targeting metastasis roots. LDZ wrote challenges and opportunities. EVD contributed to the conception and design and revised the review article. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Evgeny V. Denisov.

Ethics declarations

Conflict of interest

We declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schegoleva, A.A., Khozyainova, A.A., Gerashchenko, T.S. et al. Metastasis prevention: targeting causes and roots. Clin Exp Metastasis 39, 505–519 (2022). https://doi.org/10.1007/s10585-022-10162-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-022-10162-x

Keywords

Search

Navigation