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image of Cancer Stem Cells and Angiogenesis: Exploring the Tumor Microenvironment and Therapeutic Strategies in Lung Cancer

Abstract

Tumor microenvironment (TME) plays a particularly important role in the pathogenesis and drug resistance of lung cancer. This article provides a framework that allows us to view lung cancer through the lens of cancer stem cells (CSCs) and angiogenesis, with the aim of enhancing both clinical and laboratory insights. It critically examines the bidirectional interactions between CSCs and other components of the TME, highlighting their combined contributions to tumor aggressiveness and angiogenic processes. We discuss the mechanisms by which CSCs influence angiogenesis, including the release of growth factors and cytokines, while also emphasizing how angiogenic factors, in turn, modulate CSC behavior and help maintain a microenvironment that supports tumor growth. Potential biomarkers and therapeutic targets—such as CD133, ALDH1, and VEGF—are explored as valuable not only for disease management but also for the development of targeted therapies for lung cancer. This article ultimately provides a foundation for researchers to further investigate these interconnected processes and for clinicians to consider therapeutic strategies when managing patients with lung cancer. Given the multifaceted nature of lung cancer biology and the numerous molecules involved, we advocate for a panel-centered approach in both research and clinical management, while underscoring the importance of carefully considering toxicity risks and variability in molecular expression.

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2026-02-09
2026-02-24

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References

  1. Yu Z. Pestell T.G. Lisanti M.P. Pestell R.G. Cancer stem cells. Int. J. Biochem. Cell Biol. 2012 44 12 2144 2151 10.1016/j.biocel.2012.08.022 22981632
    [Google Scholar]
  2. Walcher L. Kistenmacher A.K. Suo H. Kitte R. Dluczek S. Strauß A. Blaudszun A.R. Yevsa T. Fricke S. Kossatz-Boehlert U. Cancer stem cells - Origins and biomarkers: Perspectives for targeted personalized therapies. Front. Immunol. 2020 11 1280 10.3389/fimmu.2020.01280 32849491
    [Google Scholar]
  3. Safa A.R. Cancer stem cells, apoptosis pathways and mechanisms of death resistance. Oncogenomics. Elsevier 2019 89 101 10.1016/B978‑0‑12‑811785‑9.00007‑7
    [Google Scholar]
  4. Yang L. Shi P. Zhao G. Xu J. Peng W. Zhang J. Zhang G. Wang X. Dong Z. Chen F. Cui H. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target. Ther. 2020 5 1 8 10.1038/s41392‑020‑0110‑5
    [Google Scholar]
  5. Zakaria N. Satar N.A. Abu Halim N.H. Ngalim S.H. Yusoff N.M. Lin J. Yahaya B.H. Targeting lung cancer stem cells: Research and clinical impacts. Front. Oncol. 2017 7 80 10.3389/fonc.2017.00080 28529925
    [Google Scholar]
  6. Liu Q. Guo Z. Li G. Zhang Y. Liu X. Li B. Wang J. Li X. Cancer stem cells and their niche in cancer progression and therapy. Cancer Cell Int. 2023 23 1 305 10.1186/s12935‑023‑03130‑2 38041196
    [Google Scholar]
  7. Phi L.T.H. Sari I.N. Yang Y.G. Lee S.H. Jun N. Kim K.S. Lee Y.K. Kwon H.Y. Cancer Stem Cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int. 2018 2018 1 16 10.1155/2018/5416923 29681949
    [Google Scholar]
  8. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021 71 3 209 249 10.3322/caac.21660 33538338
    [Google Scholar]
  9. Siegel R.L. Miller K.D. Wagle N.S. Jemal A. Cancer statistics, 2023. CA Cancer J. Clin. 2023 73 1 17 48 10.3322/caac.21763 36633525
    [Google Scholar]
  10. Schabath M.B. Cote M.L. Cancer progress and priorities: Lung cancer. Cancer Epidemiol. Biomarkers Prev. 2019 28 10 1563 1579 10.1158/1055‑9965.EPI‑19‑0221 31575553
    [Google Scholar]
  11. Sher T. Dy G.K. Adjei A.A. Small cell lung cancer. Mayo Clin. Proc. 2008 83 3 355 367 10.4065/83.3.355 18316005
    [Google Scholar]
  12. Navada S. Lai P. Schwartz A.G. Kalemkerian G.P. Temporal trends in small cell lung cancer: Analysis of the national Surveillance, Epidemiology, and End-Results (SEER) database. J. Clin. Oncol. 2006 24 7082 7082 10.1200/jco.2006.24.18_suppl.7082
    [Google Scholar]
  13. Herbst R.S. Morgensztern D. Boshoff C. The biology and management of non-small cell lung cancer. Nature 2018 553 7689 446 454 10.1038/nature25183 29364287
    [Google Scholar]
  14. Romeo H.E. Barreiro Arcos M.L. Clinical relevance of stem cells in lung cancer. World J. Stem Cells 2023 15 6 576 588 10.4252/wjsc.v15.i6.576 37424954
    [Google Scholar]
  15. Ngaha T.Y.S. Zhilenkova A.V. Essogmo F.E. Uchendu I.K. Abah M.O. Fossa L.T. Sangadzhieva Z.D. Sanikovich D. V.; S Rusanov, A.; N Pirogova, Y.; Boroda, A.; Rozhkov, A.; Kemfang Ngowa, J.D.; N Bagmet, L.; I Sekacheva, M. Angiogenesis in Lung Cancer: Understanding the Roles of Growth Factors. Cancers (Basel) 2023 15 18 4648 10.3390/cancers15184648 37760616
    [Google Scholar]
  16. Codony-Servat J. Verlicchi A. Rosell R. Cancer stem cells in small cell lung cancer. Transl. Lung Cancer Res. 2016 5 1 16 25 26958490
    [Google Scholar]
  17. Hardavella G. George R. Sethi T. Lung cancer stem cells - Characteristics, phenotype. Transl. Lung Cancer Res. 2016 5 3 272 279 10.21037/tlcr.2016.02.01 27413709
    [Google Scholar]
  18. Carney D.N. Gazdar A.F. Minna J.D. Positive correlation between histological tumor involvement and generation of tumor cell colonies in agarose in specimens taken directly from patients with small-cell carcinoma of the lung. Cancer Res. 1980 40 6 1820 1823 6245805
    [Google Scholar]
  19. Carney D.N. Gazdar A.F. Bunn P.A. Guccion J.G. Demonstration of the stem cell nature of clonogenic tumor cells from lung cancer patients. Stem Cells 1982 1 3 149 164 6294885
    [Google Scholar]
  20. Prabavathy D. Swarnalatha Y. Ramadoss N. Lung cancer stem cells—origin, characteristics and therapy. Stem Cell Investig. 2018 5 6 10.21037/sci.2018.02.01 29682513
    [Google Scholar]
  21. Palma A.M. Bushnell G.G. Wicha M.S. Gogna R. Tumor microenvironment interactions with cancer stem cells in pancreatic ductal adenocarcinoma. Advances in Cancer Research. Elsevier 2023 343 372 10.1016/bs.acr.2023.02.007
    [Google Scholar]
  22. Li Y.R. Fang Y. Lyu Z. Zhu Y. Yang L. Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: Implications for novel therapeutic strategies. J. Transl. Med. 2023 21 1 686 10.1186/s12967‑023‑04575‑9 37784157
    [Google Scholar]
  23. Nayak A. Warrier N.M. Kumar P. Cancer stem cells and the tumor microenvironment: Targeting the critical crosstalk through nanocarrier systems. Stem Cell Rev. Rep. 2022 18 7 2209 2233 10.1007/s12015‑022‑10426‑9 35876959
    [Google Scholar]
  24. Albini A. Bruno A. Gallo C. Pajardi G. Noonan D.M. Dallaglio K. Cancer stem cells and the tumor microenvironment: Interplay in tumor heterogeneity. Connect. Tissue Res. 2015 56 5 414 425 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673538/ 10.3109/03008207.2015.1066780 26291921
    [Google Scholar]
  25. Essogmo F.E. Zhilenkova A.V. Tchawe Y.S.N. Owoicho A.M. Rusanov A.S. Boroda A. Pirogova Y.N. Sangadzhieva Z.D. Sanikovich V.D. Bagmet N.N. Sekacheva M.I. Cytokine profile in lung cancer patients: Anti-tumor and oncogenic cytokines. Cancers 2023 15 22 5383 10.3390/cancers15225383 38001643
    [Google Scholar]
  26. Uchendu I. Zhilenkova A. Pirogova Y. Basova M. Bagmet L. Kohanovskaia I. Ngaha Y. Ikebunwa O. Sekacheva M. Cytokines as potential therapeutic targets and their role in the diagnosis and prediction of cancers. Curr. Pharm. Des. 2023 29 32 2552 2567 10.2174/0113816128268111231024054240
    [Google Scholar]
  27. Sanegre S. Lucantoni F. Burgos-Panadero R. de La Cruz-Merino L. Noguera R. Álvaro Naranjo T. Integrating the tumor microenvironment into cancer therapy. Cancers 2020 12 6 1677 10.3390/cancers12061677 32599891
    [Google Scholar]
  28. Pavlova N.N. Zhu J. Thompson C.B. The hallmarks of cancer metabolism: Still emerging. Cell Metab. 2022 34 3 355 377 10.1016/j.cmet.2022.01.007 35123658
    [Google Scholar]
  29. Iqbal W. Alkarim S. AlHejin A. Mukhtar H. Saini K.S. Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis. Oncotarget 2016 7 46 76337 76353 10.18632/oncotarget.10942 27486983
    [Google Scholar]
  30. Takebe N. Miele L. Harris P.J. Jeong W. Bando H. Kahn M. Yang S.X. Ivy S.P. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: Clinical update. Nat. Rev. Clin. Oncol. 2015 12 8 445 464 10.1038/nrclinonc.2015.61 25850553
    [Google Scholar]
  31. Borlongan M.C. Wang H. Profiling and targeting cancer stem cell signaling pathways for cancer therapeutics. Front. Cell Dev. Biol. 2023 11 1125174 10.3389/fcell.2023.1125174 37305676
    [Google Scholar]
  32. Manni W. Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm 2022 3 4 e176 10.1002/mco2.176 36226253
    [Google Scholar]
  33. Guo Q. Zhou Y. Xie T. Yuan Y. Li H. Shi W. Zheng L. Li X. Zhang W. Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting. Genes Dis. 2024 11 3 101043 10.1016/j.gendis.2023.05.024 38292177
    [Google Scholar]
  34. Nishida N. Yano H. Nishida T. Kamura T. Kojiro M. Angiogenesis in cancer. Vasc. Health Risk Manag. 2006 2 3 213 219 10.2147/vhrm.2006.2.3.213 17326328
    [Google Scholar]
  35. Ferrara N. Kerbel R.S. Angiogenesis as a therapeutic target. Nature 2005 438 7070 967 974 10.1038/nature04483 16355214
    [Google Scholar]
  36. Carmeliet P. Jain R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011 473 7347 298 307 10.1038/nature10144 21593862
    [Google Scholar]
  37. Rajput S. Sharma P.K. Malviya R. Fluid mechanics in circulating tumour cells: Role in metastasis and treatment strategies. Med. Drug Discov. 2023 18 100158 10.1016/j.medidd.2023.100158
    [Google Scholar]
  38. Lugano R. Ramachandran M. Dimberg A. Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cell. Mol. Life Sci. 2020 77 9 1745 1770 10.1007/s00018‑019‑03351‑7 31690961
    [Google Scholar]
  39. Ullah A. Shehzadi S. Ullah N. Nawaz T. Iqbal H. Aziz T. Hypoxia a typical target in human lung cancer therapy. Curr. Protein Pept. Sci. 2024 25 5 376 385 10.2174/0113892037252820231114045234 38031268
    [Google Scholar]
  40. Kim H.J. Ji Y.R. Lee Y.M. Crosstalk between angiogenesis and immune regulation in the tumor microenvironment. Arch. Pharm. Res. 2022 45 6 401 416 10.1007/s12272‑022‑01389‑z 35759090
    [Google Scholar]
  41. Zhu Z. Shi L. Dong Y. Zhang Y. Yang F. Wei J. Huo M. Li P. Liu X. Effect of crosstalk among conspirators in tumor microenvironment on niche metastasis of gastric cancer. Am. J. Cancer Res. 2022 12 12 5375 5402 36628284
    [Google Scholar]
  42. Li L. Li J.C. Yang H. Zhang X. Liu L.L. Li Y. Zeng T.T. Zhu Y.H. Li X.D. Li Y. Xie D. Fu L. Guan X.Y. Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis. Proc. Natl. Acad. Sci. USA 2018 115 38 E8948 E8957 10.1073/pnas.1806219115 30158168
    [Google Scholar]
  43. Zamarron B.F. Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int. J. Biol. Sci. 2011 7 5 651 658 10.7150/ijbs.7.651 21647333
    [Google Scholar]
  44. Aguilar-Cazares D. Chavez-Dominguez R. Carlos-Reyes A. Lopez-Camarillo C. Hernadez de la Cruz O.N. Lopez-Gonzalez J.S. Contribution of Angiogenesis to Inflammation and Cancer. Front. Oncol. 2019 9 1399 10.3389/fonc.2019.01399 31921656
    [Google Scholar]
  45. Ribatti D. Crivellato E. Immune cells and angiogenesis. J. Cell. Mol. Med. 2009 13 9a 2822 2833 10.1111/j.1582‑4934.2009.00810.x 19538473
    [Google Scholar]
  46. Peña-Romero A.C. Orenes-Piñero E. Dual effect of immune cells within tumour microenvironment: Pro- and anti-tumour effects and their triggers. Cancers 2022 14 7 1681 10.3390/cancers14071681 35406451
    [Google Scholar]
  47. Ravindran S. Rasool S. Maccalli C. The cross talk between cancer stem cells/cancer initiating cells and tumor microenvironment: The missing piece of the puzzle for the efficient targeting of these cells with immunotherapy. Cancer Microenviron. 2019 12 2-3 133 148 10.1007/s12307‑019‑00233‑1 31758404
    [Google Scholar]
  48. Zhang S. Balch C. Chan M.W. Lai H.C. Matei D. Schilder J.M. Yan P.S. Huang T.H.M. Nephew K.P. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008 68 11 4311 4320 10.1158/0008‑5472.CAN‑08‑0364 18519691
    [Google Scholar]
  49. Vermeulen L. De Sousa E. Melo F. van der Heijden M. Cameron K. de Jong J.H. Borovski T. Tuynman J.B. Todaro M. Merz C. Rodermond H. Sprick M.R. Kemper K. Richel D.J. Stassi G. Medema J.P. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 2010 12 5 468 476 10.1038/ncb2048 20418870
    [Google Scholar]
  50. Plaks V. Kong N. Werb Z. The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2015 16 3 225 238 10.1016/j.stem.2015.02.015 25748930
    [Google Scholar]
  51. Kogan E.A. Shchelokova E.E. Demura T.A. Zharkov N.V. Kichigina O.N. Kovyazina N.V. Mordovina A.I. Zelenchenkova P.I. Meerovich G.A. Reshetov I.V. ALDH1, CD133, CD34-positive cancer stem cells in lung adenocarcinoma in patients who had a new coronavirus infection and retained the persistence of viral proteins in the lung tissue. Russ J. Arch. Pathol. 2024 86 5 5 14 10.17116/patol2024860515
    [Google Scholar]
  52. He Z. Zhang S. Tumor-Associated Macrophages and Their Functional Transformation in the Hypoxic Tumor Microenvironment. Front. Immunol. 2021 12 741305 10.3389/fimmu.2021.741305 34603327
    [Google Scholar]
  53. Pan Y. Yu Y. Wang X. Zhang T. Tumor-associated macro-phages in tumor immunity. Front. Immunol. 2020 11 583084 10.3389/fimmu.2020.583084 33365025
    [Google Scholar]
  54. Yang L. Zhang Y. Tumor-associated macrophages: From basic research to clinical application. J. Hematol. Oncol. 2017 10 1 58 10.1186/s13045‑017‑0430‑2 28241846
    [Google Scholar]
  55. Zhou J. Tang Z. Gao S. Li C. Feng Y. Zhou X. Tumor-associated macrophages: Recent insights and therapies. Front. Oncol. 2020 10 188 10.3389/fonc.2020.00188 32161718
    [Google Scholar]
  56. Guerriero J.L. Sotayo A. Ponichtera H.E. Castrillon J.A. Pourzia A.L. Schad S. Johnson S.F. Carrasco R.D. Lazo S. Bronson R.T. Davis S.P. Lobera M. Nolan M.A. Letai A. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 2017 543 7645 428 432 10.1038/nature21409 28273064
    [Google Scholar]
  57. Movahedi K. Laoui D. Gysemans C. Baeten M. Stangé G. Van den Bossche J. Mack M. Pipeleers D. In’t Veld P. De Baetselier P. Van Ginderachter J.A. Different tumor micro-environments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010 70 14 5728 5739 10.1158/0008‑5472.CAN‑09‑4672 20570887
    [Google Scholar]
  58. Mantovani A. Sica A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr. Opin. Immunol. 2010 22 2 231 237 10.1016/j.coi.2010.01.009 20144856
    [Google Scholar]
  59. Biswas S.K. Metabolic reprogramming of immune cells in cancer progression. Immunity 2015 43 3 435 449 10.1016/j.immuni.2015.09.001 26377897
    [Google Scholar]
  60. Ramos R.N. Amano M.T. Paes Leme A.F. Fox J.W. de Oliveira A.K. Editorial: Tumor microenvironment (TME) and tumor immune microenvironment (TIME): New perspectives for prognosis and therapy. Front. Cell Dev. Biol. 2022 10 971275 10.3389/fcell.2022.971275 36072339
    [Google Scholar]
  61. Wang Z. Liu J.Q. Liu Z. Shen R. Zhang G. Xu J. Basu S. Feng Y. Bai X.F. Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. J. Immunol. 2013 190 5 2415 2423 10.4049/jimmunol.1202535 23345334
    [Google Scholar]
  62. Facciabene A. Peng X. Hagemann I.S. Balint K. Barchetti A. Wang L.P. Gimotty P.A. Gilks C.B. Lal P. Zhang L. Coukos G. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 2011 475 7355 226 230 10.1038/nature10169 21753853
    [Google Scholar]
  63. Vignali D.A.A. Collison L.W. Workman C.J. How regulatory T cells work. Nat. Rev. Immunol. 2008 8 7 523 532 10.1038/nri2343 18566595
    [Google Scholar]
  64. Nishikawa H. Sakaguchi S. Regulatory T cells in tumor immunity. Int. J. Cancer 2010 127 4 759 767 10.1002/ijc.25429 20518016
    [Google Scholar]
  65. Plitas G. Rudensky A.Y. Regulatory T. Cells in Cancer. Annu. Rev. Cancer Biol. 2020 4 1 459 477 10.1146/annurev‑cancerbio‑030419‑033428
    [Google Scholar]
  66. Ha T.Y. The role of regulatory T cells in cancer. Immune Netw. 2009 9 6 209 235 10.4110/in.2009.9.6.209 20157609
    [Google Scholar]
  67. Karpisheh V. Mousavi S.M. Naghavi Sheykholeslami P. Fathi M. Mohammadpour Saray M. Aghebati-Maleki L. Jafari R. Majidi Zolbanin N. Jadidi-Niaragh F. The role of regulatory T cells in the pathogenesis and treatment of prostate cancer. Life Sci. 2021 284 119132 10.1016/j.lfs.2021.119132 33513396
    [Google Scholar]
  68. Nakae S. Komiyama Y. Nambu A. Sudo K. Iwase M. Homma I. Sekikawa K. Asano M. Iwakura Y. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 2002 17 3 375 387 10.1016/S1074‑7613(02)00391‑6 12354389
    [Google Scholar]
  69. Vesely M.D. Kershaw M.H. Schreiber R.D. Smyth M.J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 2011 29 1 235 271 10.1146/annurev‑immunol‑031210‑101324 21219185
    [Google Scholar]
  70. Motz G.T. Coukos G. Deciphering and reversing tumor immune suppression. Immunity 2013 39 1 61 73 10.1016/j.immuni.2013.07.005 23890064
    [Google Scholar]
  71. Batlle E. Clevers H. Cancer stem cells revisited. Nat. Med. 2017 23 10 1124 1134 10.1038/nm.4409 28985214
    [Google Scholar]
  72. Sharma P. Hu-Lieskovan S. Wargo J.A. Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017 168 4 707 723 10.1016/j.cell.2017.01.017 28187290
    [Google Scholar]
  73. Black M. Barsoum I.B. Truesdell P. Cotechini T. Macdonald-Goodfellow S.K. Petroff M. Siemens D.R. Koti M. Craig A.W.B. Graham C.H. Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget 2016 7 9 10557 10567 10.18632/oncotarget.7235 26859684
    [Google Scholar]
  74. Schöniger S. Jasani B. The PD-1/PD-L1 pathway: A perspective on comparative immuno-oncology. Animals 2022 12 19 2661 10.3390/ani12192661 36230402
    [Google Scholar]
  75. Vetsika E.K. Koukos A. Kotsakis A. Myeloid-derived suppressor cells: Major figures that shape the immunosuppressive and angiogenic network in cancer. Cells 2019 8 12 1647 10.3390/cells8121647 31847487
    [Google Scholar]
  76. Wu B. Shi X. Jiang M. Liu H. Cross-talk between cancer stem cells and immune cells: Potential therapeutic targets in the tumor immune microenvironment. Mol. Cancer 2023 22 1 38 10.1186/s12943‑023‑01748‑4 36810098
    [Google Scholar]
  77. Ugel S. Delpozzo F. Desantis G. Papalini F. Simonato F. Sonda N. Zilio S. Bronte V. Therapeutic targeting of myeloid-derived suppressor cells. Curr. Opin. Pharmacol. 2009 9 4 470 481 10.1016/j.coph.2009.06.014 19616475
    [Google Scholar]
  78. Bleve A. Consonni F.M. Porta C. Garlatti V. Sica A. Evolution and targeting of myeloid suppressor cells in cancer: A translational perspective. Cancers 2022 14 3 510 10.3390/cancers14030510 35158779
    [Google Scholar]
  79. Zhao Y. Du J. Shen X. Targeting myeloid-derived suppressor cells in tumor immunotherapy: Current, future and beyond. Front. Immunol. 2023 14 1157537 10.3389/fimmu.2023.1157537 37006306
    [Google Scholar]
  80. Vivier E. Tomasello E. Baratin M. Walzer T. Ugolini S. Functions of natural killer cells. Nat. Immunol. 2008 9 5 503 510 10.1038/ni1582 18425107
    [Google Scholar]
  81. Portale F. Di Mitri D. NK cells in cancer: Mechanisms of dysfunction and therapeutic potential. Int. J. Mol. Sci. 2023 24 11 9521 10.3390/ijms24119521 37298470
    [Google Scholar]
  82. Lorenzo-Herrero S. López-Soto A. Sordo-Bahamonde C. Gonzalez-Rodriguez A.P. Vitale M. Gonzalez S. NK cell-based immunotherapy in cancer metastasis. Cancers 2018 11 1 29 10.3390/cancers11010029 30597841
    [Google Scholar]
  83. Ebeling S. Kowalczyk A. Perez-Vazquez D. Mattiola I. Regulation of tumor angiogenesis by the crosstalk between innate immunity and endothelial cells. Front. Oncol. 2023 13 1171794 10.3389/fonc.2023.1171794 37234993
    [Google Scholar]
  84. Fridlender Z.G. Sun J. Kim S. Kapoor V. Cheng G. Ling L. Worthen G.S. Albelda S.M. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 2009 16 3 183 194 10.1016/j.ccr.2009.06.017 19732719
    [Google Scholar]
  85. Gentles A.J. Newman A.M. Liu C.L. Bratman S.V. Feng W. Kim D. Nair V.S. Xu Y. Khuong A. Hoang C.D. Diehn M. West R.B. Plevritis S.K. Alizadeh A.A. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 2015 21 8 938 945 10.1038/nm.3909 26193342
    [Google Scholar]
  86. Shojaei F. Singh M. Thompson J.D. Ferrara N. Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc. Natl. Acad. Sci. USA 2008 105 7 2640 2645 10.1073/pnas.0712185105 18268320
    [Google Scholar]
  87. Masucci M.T. Minopoli M. Carriero M.V. Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy. Front. Oncol. 2019 9 1146 10.3389/fonc.2019.01146 31799175
    [Google Scholar]
  88. Que H. Fu Q. Lan T. Tian X. Wei X. Tumor-associated neutrophils and neutrophil-targeted cancer therapies. Biochim. Biophys. Acta Rev. Cancer 2022 1877 5 188762 10.1016/j.bbcan.2022.188762 35853517
    [Google Scholar]
  89. Furumaya C. Martinez-Sanz P. Bouti P. Kuijpers T.W. Matlung H.L. Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance. Front. Immunol. 2020 11 2100 10.3389/fimmu.2020.02100 32983165
    [Google Scholar]
  90. Yan M. Zheng M. Niu R. Yang X. Tian S. Fan L. Li Y. Zhang S. Roles of tumor-associated neutrophils in tumor metastasis and its clinical applications. Front. Cell Dev. Biol. 2022 10 938289 10.3389/fcell.2022.938289 36060811
    [Google Scholar]
  91. Dutta A. Bhagat S. Paul S. Katz J.P. Sengupta D. Bhargava D. Neutrophils in cancer and potential therapeutic strategies using neutrophil-derived exosomes. Vaccines 2023 11 6 1028 10.3390/vaccines11061028 37376417
    [Google Scholar]
  92. Andzinski L. Wu C.F. Lienenklaus S. Kröger A. Weiss S. Jablonska J. Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN-β. Int. J. Cancer 2015 136 3 572 583 10.1002/ijc.28957 24806531
    [Google Scholar]
  93. Wu C.F. Andzinski L. Kasnitz N. Kröger A. Klawonn F. Lienenklaus S. Weiss S. Jablonska J. The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung. Int. J. Cancer 2015 137 4 837 847 10.1002/ijc.29444 25604426
    [Google Scholar]
  94. Andzinski L. Kasnitz N. Stahnke S. Wu C.F. Gereke M. von Köckritz-Blickwede M. Schilling B. Brandau S. Weiss S. Jablonska J. Type I. IFNs induce anti‐tumor polarization of tumor associated neutrophils in mice and human. Int. J. Cancer 2016 138 8 1982 1993 10.1002/ijc.29945 26619320
    [Google Scholar]
  95. Wright K. Ly T. Kriet M. Czirok A. Thomas S.M. Cancer-associated fibroblasts: Master tumor microenvironment modifiers. Cancers 2023 15 6 1899 10.3390/cancers15061899 36980785
    [Google Scholar]
  96. Xing F. Saidou J. Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front. Biosci. 2010 15 1 166 179 10.2741/3613 20036813
    [Google Scholar]
  97. Wang F.T. Sun W. Zhang J.T. Fan Y.Z. Cancer associated fibroblast regulation of tumor neo angiogenesis as a therapeutic target in cancer. (Review) Oncol. Lett. 2019 17 3 3055 3065 10.3892/ol.2019.9973 30867734
    [Google Scholar]
  98. Sarkar M. Nguyen T. Gundre E. Ogunlusi O. El-Sobky M. Giri B. Sarkar T.R. Cancer-associated fibroblasts: The chief architect in the tumor microenvironment. Front. Cell Dev. Biol. 2023 11 1089068 10.3389/fcell.2023.1089068 36793444
    [Google Scholar]
  99. Zhang H. Yue X. Chen Z. Liu C. Wu W. Zhang N. Liu Z. Yang L. Jiang Q. Cheng Q. Luo P. Liu G. Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: New opportunities in cancer immunotherapy and advances in clinical trials. Mol. Cancer 2023 22 1 159 10.1186/s12943‑023‑01860‑5 37784082
    [Google Scholar]
  100. Prieto-Fernández L. Montoro-Jiménez I. de Luxan-Delgado B. Otero-Rosales M. Rodrigo J.P. Calvo F. García-Pedrero J.M. Álvarez-Teijeiro S. Dissecting the functions of cancer-associated fibroblasts to therapeutically target head and neck cancer microenvironment. Biomed. Pharmacother. 2023 161 114502 10.1016/j.biopha.2023.114502 37002578
    [Google Scholar]
  101. Fang Z. Meng Q. Xu J. Wang W. Zhang B. Liu J. Liang C. Hua J. Zhao Y. Yu X. Shi S. Signaling pathways in cancer-associated fibroblasts: Recent advances and future perspectives. Cancer Commun. 2023 43 1 3 41 10.1002/cac2.12392 36424360
    [Google Scholar]
  102. Orimo A. Gupta P.B. Sgroi D.C. Arenzana-Seisdedos F. Delaunay T. Naeem R. Carey V.J. Richardson A.L. Weinberg R.A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005 121 3 335 348 10.1016/j.cell.2005.02.034 15882617
    [Google Scholar]
  103. Karnoub A.E. Dash A.B. Vo A.P. Sullivan A. Brooks M.W. Bell G.W. Richardson A.L. Polyak K. Tubo R. Weinberg R.A. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007 449 7162 557 563 10.1038/nature06188 17914389
    [Google Scholar]
  104. Guan J. Chen J. Mesenchymal stem cells in the tumor microenvironment. Biomed. Rep. 2013 1 4 517 521 10.3892/br.2013.103 24648978
    [Google Scholar]
  105. Atiya H. Frisbie L. Pressimone C. Coffman L. Mesenchymal Stem Cells in the Tumor Microenvironment. Adv. Exp. Med. Biol. 2020 1234 31 42 10.1007/978‑3‑030‑37184‑5_3 32040853
    [Google Scholar]
  106. Liu J. Gao J. Liang Z. Gao C. Niu Q. Wu F. Zhang L. Mesenchymal stem cells and their microenvironment. Stem Cell Res. Ther. 2022 13 1 429 10.1186/s13287‑022‑02985‑y 35987711
    [Google Scholar]
  107. Lin W. Huang L. Li Y. Fang B. Li G. Chen L. Xu L. Mesenchymal stem cells and cancer: Clinical challenges and opportunities. BioMed Res. Int. 2019 2019 1 12 10.1155/2019/2820853 31205939
    [Google Scholar]
  108. Ahn S.Y. The role of MSCs in the tumor microenvironment and tumor progression. Anticancer Res. 2020 40 6 3039 3047 10.21873/anticanres.14284 32487597
    [Google Scholar]
  109. Papait A. Stefani F.R. Cargnoni A. Magatti M. Parolini O. Silini A.R. The multifaceted roles of mscs in the tumor microenvironment: Interactions with immune cells and exploitation for therapy. Front. Cell Dev. Biol. 2020 8 447 10.3389/fcell.2020.00447 32637408
    [Google Scholar]
  110. Slama Y. Ah-Pine F. Khettab M. Arcambal A. Begue M. Dutheil F. Gasque P. The dual role of mesenchymal stem cells in cancer pathophysiology: Pro-tumorigenic effects versus therapeutic potential. Int. J. Mol. Sci. 2023 24 17 13511 10.3390/ijms241713511
    [Google Scholar]
  111. Hass R. Role of MSC in the tumor microenvironment. Cancers 2020 12 8 2107 10.3390/cancers12082107 32751163
    [Google Scholar]
  112. Melzer C. Yang Y. Hass R. Interaction of MSC with tumor cells. Cell Commun. Signal. 2016 14 1 20 10.1186/s12964‑016‑0143‑0 27608835
    [Google Scholar]
  113. Quante M. Tu S.P. Tomita H. Gonda T. Wang S.S.W. Takashi S. Baik G.H. Shibata W. DiPrete B. Betz K.S. Friedman R. Varro A. Tycko B. Wang T.C. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 2011 19 2 257 272 10.1016/j.ccr.2011.01.020 21316604
    [Google Scholar]
  114. Chulpanova D.S. Kitaeva K.V. Tazetdinova L.G. James V. Rizvanov A.A. Solovyeva V.V. Application of mesenchymal stem cells for therapeutic agent delivery in anti-tumor treatment. Front. Pharmacol. 2018 9 259 10.3389/fphar.2018.00259 29615915
    [Google Scholar]
  115. Park T.S. Donnenberg V.S. Donnenberg A.D. Zambidis E.T. Zimmerlin L. Dynamic interactions between cancer stem cells and their stromal partners. Curr. Pathobiol. Rep. 2014 2 1 41 52 10.1007/s40139‑013‑0036‑5 24660130
    [Google Scholar]
  116. Leone P. Malerba E. Susca N. Favoino E. Perosa F. Brunori G. Prete M. Racanelli V. Endothelial cells in tumor microenvironment: Insights and perspectives. Front. Immunol. 2024 15 1367875 10.3389/fimmu.2024.1367875 38426109
    [Google Scholar]
  117. García-Caballero M. Sokol L. Cuypers A. Carmeliet P. Metabolic reprogramming in tumor endothelial cells. Int. J. Mol. Sci. 2022 23 19 11052 10.3390/ijms231911052
    [Google Scholar]
  118. Dias S. Choy M. Alitalo K. Rafii S. Vascular endothelial growth factor (VEGF)–C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood 2002 99 6 2179 2184 10.1182/blood.V99.6.2179 11877295
    [Google Scholar]
  119. Nieman K.M. Romero I.L. Van Houten B. Lengyel E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2013 1831 10 1533 1541 10.1016/j.bbalip.2013.02.010 23500888
    [Google Scholar]
  120. Hefetz-Sela S. Scherer P.E. Adipocytes: Impact on tumor growth and potential sites for therapeutic intervention. Pharmacol. Ther. 2013 138 2 197 210 10.1016/j.pharmthera.2013.01.008 23353703
    [Google Scholar]
  121. Herold J. Kalucka J. Angiogenesis in adipose tissue: The interplay between adipose and endothelial cells. Front. Physiol. 2021 11 624903 10.3389/fphys.2020.624903 33633579
    [Google Scholar]
  122. Zhao C. Wu M. Zeng N. Xiong M. Hu W. Lv W. Yi Y. Zhang Q. Wu Y. Cancer-associated adipocytes: Emerging supporters in breast cancer. J. Exp. Clin. Cancer Res. 2020 39 1 156 10.1186/s13046‑020‑01666‑z 32787888
    [Google Scholar]
  123. Kim J.W. Kim J.H. Lee Y.J. The role of adipokines in tumor progression and its association with obesity. Biomedicines 2024 12 1 97 10.3390/biomedicines12010097 38255203
    [Google Scholar]
  124. Park J. Euhus D.M. Scherer P.E. Paracrine and endocrine effects of adipose tissue on cancer development and progression. Endocr. Rev. 2011 32 4 550 570 10.1210/er.2010‑0030 21642230
    [Google Scholar]
  125. Koundouros N. Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br. J. Cancer 2020 122 1 4 22 10.1038/s41416‑019‑0650‑z 31819192
    [Google Scholar]
  126. Umar M.I. Hassan W. Murtaza G. Buabeid M. Arafa E. Irfan H.M. Asmawi M.Z. Huang X. The adipokine component in the molecular regulation of cancer cell survival, proliferation and metastasis. Pathol. Oncol. Res. 2021 27 1609828 10.3389/pore.2021.1609828 34588926
    [Google Scholar]
  127. Zhou X. Zhang J. Lv W. Zhao C. Xia Y. Wu Y. Zhang Q. The pleiotropic roles of adipocyte secretome in remodeling breast cancer. J. Exp. Clin. Cancer Res. 2022 41 1 203 10.1186/s13046‑022‑02408‑z 35701840
    [Google Scholar]
  128. Bocian-Jastrzębska A. Malczewska-Herman A. Kos-Kudła B. Role of leptin and adiponectin in carcinogenesis. Cancers 2023 15 17 4250 10.3390/cancers15174250 37686525
    [Google Scholar]
  129. Wu C. Dong S. Huang R. Chen X. Cancer-associated adipocytes and breast cancer: Intertwining in the tumor microenvironment and challenges for cancer therapy. Cancers 2023 15 3 726 10.3390/cancers15030726 36765683
    [Google Scholar]
  130. Jurj A. Ciocan C. Raduly L. Zanoaga O. Berindan-Neagoe I. Braicu C. Role of Cancer-Associated Adipocytes in the Progression of Breast Cancer. Handbook of Cancer and Immunology. Rezaei N. Cham Springer International Publishing 2022 1 22 10.1007/978‑3‑030‑80962‑1_54‑1
    [Google Scholar]
  131. Ye Y. Yu S. Guo T. Zhang S. Shen X. Han G. Epithelial–mesenchymal transition in non-small cell lung cancer management: Opportunities and challenges. Biomolecules 2024 14 12 1523 10.3390/biom14121523 39766230
    [Google Scholar]
  132. Liao L. Wang Y.X. Fan S.S. Hu Y.Y. Wang X.C. Zhang X. The role and clinical significance of tumor-associated macrophages in the epithelial–mesenchymal transition of lung cancer. Front. Oncol. 2025 15 1571583 10.3389/fonc.2025.1571583
    [Google Scholar]
  133. Sung W.J. Kim H. Park K.K. The biological role of epithelial-mesenchymal transition in lung cancer. (Review) Oncol. Rep. 2016 36 3 1199 1206 10.3892/or.2016.4964 27460444
    [Google Scholar]
  134. Fang J. Lu Y. Zheng J. Jiang X. Shen H. Shang X. Lu Y. Fu P. Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: New insights and therapeutic implications. Cell Death Dis. 2023 14 9 586 10.1038/s41419‑023‑06119‑x 37666809
    [Google Scholar]
  135. Lei Z.N. Teng Q.X. Koya J. Liu Y. Chen Z. Zeng L. The correlation between cancer stem cells and epithelial–mesenchymal transition: Molecular mechanisms and significance in cancer theragnosis. Front. Immunol. 2024 15 1417201 10.3389/fimmu.2024.1417201
    [Google Scholar]
  136. de Visser K.E. Joyce J.A. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023 41 3 374 403 10.1016/j.ccell.2023.02.016 36917948
    [Google Scholar]
  137. Wang Q. Shao X. Zhang Y. Zhu M. Wang F.X.C. Mu J. Li J. Yao H. Chen K. Role of tumor microenvironment in cancer progression and therapeutic strategy. Cancer Med. 2023 12 10 11149 11165 10.1002/cam4.5698 36807772
    [Google Scholar]
  138. Bilotta M.T. Antignani A. Fitzgerald D.J. Managing the TME to improve the efficacy of cancer therapy. Front. Immunol. 2022 13 954992 10.3389/fimmu.2022.954992 36341428
    [Google Scholar]
  139. Tiwari A. Trivedi R. Lin S.Y. Tumor microenvironment: Barrier or opportunity towards effective cancer therapy. J. Biomed. Sci. 2022 29 1 83 10.1186/s12929‑022‑00866‑3 36253762
    [Google Scholar]
  140. Xiao Y. Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther. 2021 221 107753 10.1016/j.pharmthera.2020.107753 33259885
    [Google Scholar]
  141. Fisher R. Pusztai L. Swanton C. Cancer heterogeneity: Implications for targeted therapeutics. Br. J. Cancer 2013 108 3 479 485 10.1038/bjc.2012.581 23299535
    [Google Scholar]
  142. Marino F.Z. Bianco R. Accardo M. Ronchi A. Cozzolino I. Morgillo F. Rossi G. Franco R. Molecular heterogeneity in lung cancer: From mechanisms of origin to clinical implications. Int. J. Med. Sci. 2019 16 7 981 989 10.7150/ijms.34739 31341411
    [Google Scholar]
  143. Cassidy J.W. Bruna A. Tumor heterogeneity. Patient Derived Tumor Xenograft Models. Elsevier 2017 37 55 10.1016/B978‑0‑12‑804010‑2.00004‑7
    [Google Scholar]
  144. de Sousa V.M.L. Carvalho L. Heterogeneity in Lung Cancer. Pathobiology 2018 85 1-2 96 107 10.1159/000487440 29635240
    [Google Scholar]
  145. Lovly C.M. Salama A.K.S. Salgia R. Tumor heterogeneity and therapeutic resistance. Am. Soc. Clin. Oncol. Educ. Book 2016 35 36 e585 e593 10.1200/EDBK_158808 27249771
    [Google Scholar]
  146. Heng W.S. Gosens R. Kruyt F.A.E. Lung cancer stem cells: Origin, features, maintenance mechanisms and therapeutic targeting. Biochem. Pharmacol. 2019 160 121 133 10.1016/j.bcp.2018.12.010 30557553
    [Google Scholar]
  147. Bisht S. Nigam M. Kunjwal S.S. Sergey P. Mishra A.P. Sharifi-Rad J. Cancer stem cells: From an insight into the basics to recent advances and therapeutic targeting. Stem Cells Int. 2022 2022 1 28 10.1155/2022/9653244 35800881
    [Google Scholar]
  148. Aponte P.M. Caicedo A. Stemness in cancer: Stem cells, cancer stem cells, and their microenvironment. Stem Cells Int. 2017 2017 1 17 10.1155/2017/5619472 28473858
    [Google Scholar]
  149. Rudin C.M. Brambilla E. Faivre-Finn C. Sage J. Small-cell lung cancer. Nat. Rev. Dis. Primers 2021 7 1 3 10.1038/s41572‑020‑00235‑0 33446664
    [Google Scholar]
  150. Huber R.M. Tufman A. Update on small cell lung cancer management. Breathe 2012 8 4 314 330 10.1183/20734735.013211
    [Google Scholar]
  151. Key statistics for lung cancer. Available from:https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html
  152. Goodell M.A. Brose K. Paradis G. Conner A.S. Mulligan R.C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 1996 183 4 1797 1806 10.1084/jem.183.4.1797 8666936
    [Google Scholar]
  153. Salcido C.D. Larochelle A. Taylor B.J. Dunbar C.E. Varticovski L. Molecular characterisation of side population cells with cancer stem cell-like characteristics in small-cell lung cancer. Br. J. Cancer 2010 102 11 1636 1644 10.1038/sj.bjc.6605668 20424609
    [Google Scholar]
  154. Watkins D.N. Berman D.M. Burkholder S.G. Wang B. Beachy P.A. Baylin S.B. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003 422 6929 313 317 10.1038/nature01493 12629553
    [Google Scholar]
  155. Guo W. Qiao T. Li T. The role of stem cells in small-cell lung cancer: Evidence from chemoresistance to immunotherapy. Semin. Cancer Biol. 2022 87 160 169 10.1016/j.semcancer.2022.11.006 36371027
    [Google Scholar]
  156. Maiuthed A. Chantarawong W. Chanvorachote P. Lung cancer stem cells and cancer stem cell-targeting natural compounds. Anticancer Res. 2018 38 7 3797 3809 10.21873/anticanres.12663 29970499
    [Google Scholar]
  157. Testa U. Castelli G. Pelosi E. Lung cancers: Molecular characterization, clonal heterogeneity and evolution, and cancer stem cells. Cancers 2018 10 8 248 10.3390/cancers10080248 30060526
    [Google Scholar]
  158. Stratigos M. Matikas A. Voutsina A. Mavroudis D. Georgoulias V. Targeting angiogenesis in small cell lung cancer. Transl. Lung Cancer Res. 2016 5 4 389 400 10.21037/tlcr.2016.08.04 27652203
    [Google Scholar]
  159. Lund E.L. Thorsen C. Pedersen M.W. Junker N. Kristjansen P.E. Relationship between vessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in small cell lung cancer in vivo and in vitro. Clin. Cancer Res. 2000 6 11 4287 4291 11106245
    [Google Scholar]
  160. Lucchi M. Mussi A. Fontanini G. Faviana P. Ribechini A. Angeletti C.A. Small cell lung carcinoma (SCLC): The angiogenic phenomenon. Eur. J. Cardiothorac. Surg. 2002 21 6 1105 1110 10.1016/S1010‑7940(02)00112‑4 12048093
    [Google Scholar]
  161. Zhan P. Wang J. Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: A systematic review with meta-analysis. J. Thorac. Oncol. 2009 4 9 1094 1103 10.1097/JTO.0b013e3181b9e60b
    [Google Scholar]
  162. Tanno S. Ohsaki Y. Nakanishi K. Toyoshima E. Kikuchi K. Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. Lung Cancer 2004 46 1 11 19 10.1016/j.lungcan.2004.03.006 15364128
    [Google Scholar]
  163. Lizárraga-Verdugo E. Avendaño-Félix M. Bermúdez M. Ramos-Payán R. Pérez-Plasencia C. Aguilar-Medina M. Cancer stem cells and its role in angiogenesis and vasculogenic mimicry in gastrointestinal cancers. Front. Oncol. 2020 10 413 10.3389/fonc.2020.00413 32296643
    [Google Scholar]
  164. Zhao Y. Bao Q. Renner A. Camaj P. Eichhorn M. Ischenko I. Angele M. Kleespies A. Jauch K.W. Bruns C. Cancer stem cells and angiogenesis. Int. J. Dev. Biol. 2011 55 4-5 477 482 10.1387/ijdb.103225yz 21732274
    [Google Scholar]
  165. Eid R.A. Alaa Edeen M. Shedid E.M. Kamal A.S.S. Warda M.M. Mamdouh F. Khedr S.A. Soltan M.A. Jeon H.W. Zaki M.S.A. Kim B. Targeting cancer stem cells as the key driver of carcinogenesis and therapeutic resistance. Int. J. Mol. Sci. 2023 24 2 1786 10.3390/ijms24021786 36675306
    [Google Scholar]
  166. Cho Y. Kim Y.K. Cancer stem cells as a potential target to overcome multidrug resistance. Front. Oncol. 2020 10 764 10.3389/fonc.2020.00764 32582535
    [Google Scholar]
  167. Mudra S.E. Sadhukhan P. Ugurlu M.T. Alam S. Hoque M.O. Therapeutic targeting of cancer stem cells in lung, head and neck, and bladder cancers. Cancers 2021 13 20 5098 10.3390/cancers13205098 34680249
    [Google Scholar]
  168. Wang T. Narayanaswamy R. Ren H. Torchilin V.P. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment. Cancer Biol. Ther. 2016 17 6 698 707 10.1080/15384047.2016.1190488 27259361
    [Google Scholar]
  169. Drugs approved for lung cancer. 2025 Available from:https://www.cancer.gov/about-cancer/treatment/drugs/lung
  170. Bodaghi A. Fattahi N. Ramazani A. Biomarkers: Promising and valuable tools towards diagnosis, prognosis and treatment of Covid-19 and other diseases. Heliyon 2023 9 2 e13323 10.1016/j.heliyon.2023.e13323 36744065
    [Google Scholar]
  171. Ahmad A. Imran M. Ahsan H. Biomarkers as biomedical bioindicators: Approaches and techniques for the detection, analysis, and validation of novel biomarkers of diseases. Pharmaceutics 2023 15 6 1630 10.3390/pharmaceutics15061630 37376078
    [Google Scholar]
  172. Sarhadi V.K. Armengol G. Molecular biomarkers in cancer. Biomolecules 2022 12 8 1021 10.3390/biom12081021 35892331
    [Google Scholar]
  173. Min H.Y. Lee H.Y. Molecular targeted therapy for anticancer treatment. Exp. Mol. Med. 2022 54 10 1670 1694 10.1038/s12276‑022‑00864‑3 36224343
    [Google Scholar]
  174. Crisci S. Amitrano F. Saggese M. Muto T. Sarno S. Mele S. Vitale P. Ronga G. Berretta M. Di Francia R. Overview of current targeted anti-cancer drugs for therapy in onco-hematology. Medicina 2019 55 8 414 10.3390/medicina55080414 31357735
    [Google Scholar]
  175. Orzetti S. Tommasi F. Bertola A. Bortolin G. Caccin E. Cecco S. Ferrarin E. Giacomin E. Baldo P. Genetic therapy and molecular targeted therapy in oncology: Safety, pharmacovigilance, and perspectives for research and clinical practice. Int. J. Mol. Sci. 2022 23 6 3012 10.3390/ijms23063012 35328435
    [Google Scholar]
  176. Henry N.L. Hayes D.F. Cancer biomarkers. Mol. Oncol. 2012 6 2 140 146 10.1016/j.molonc.2012.01.010 22356776
    [Google Scholar]
  177. Lopes G.L. Vattimo E.F.Q. Castro G. Junior Identifying activating mutations in the EGFR gene: Prognostic and therapeutic implications in non-small cell lung cancer. J. Bras. Pneumol. 2015 41 4 365 375 10.1590/S1806‑37132015000004531 26398757
    [Google Scholar]
  178. Bethune G. Bethune D. Ridgway N. Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: An overview and update. J. Thorac. Dis. 2010 2 1 48 51 22263017
    [Google Scholar]
  179. Castañeda-González J.P. Chaves J.J. Parra-Medina R. Multiple mutations in the EGFR gene in lung cancer: A systematic review. Transl. Lung Cancer Res. 2022 11 10 2148 2163 https://tlcr.amegroups.org/article/view/67999 10.21037/tlcr‑22‑235 36386461
    [Google Scholar]
  180. Ansar Z. Nasir A. Moatter T. Mutation analysis of epidermal growth factor receptor gene in non-small cell lung cancer for selection of patients eligible for tyrosine kinase inhibitor therapy. J. Cancer Allied Spec. 2023 10 1 10.37029/jcas.v10i1.569
    [Google Scholar]
  181. Rifai N. Gillette M.A. Carr S.A. Protein biomarker discovery and validation: The long and uncertain path to clinical utility. Nat. Biotechnol. 2006 24 8 971 983 10.1038/nbt1235 16900146
    [Google Scholar]
  182. Thatcher B.J. Caputo E. Biomarker discovery. Medical Applications of Mass Spectrometry. Elsevier 2008 505 532 10.1016/B978‑044451980‑1.50024‑0
    [Google Scholar]
  183. Hudler P. Kocevar N. Komel R. Proteomic approaches in biomarker discovery: New perspectives in cancer diagnostics. ScientificWorldJournal 2014 2014 1 18 10.1155/2014/260348 24550697
    [Google Scholar]
  184. Quezada H. Guzmán-Ortiz A.L. Díaz-Sánchez H. Valle-Rios R. Aguirre-Hernández J. Omics-based biomarkers: Current status and potential use in the clinic. Bol. Méd. Hosp. Infant. México 2017 74 3 219 226 10.1016/j.bmhimx.2017.03.003 29382490
    [Google Scholar]
  185. Zhao X. Modur V. Carayannopoulos L.N. Laterza O.F. Biomarkers in Pharmaceutical Research. Clin. Chem. 2015 61 11 1343 1353 10.1373/clinchem.2014.231712 26408531
    [Google Scholar]
  186. Bock C. Epigenetic biomarker development. Epigenomics 2009 1 1 99 110 10.2217/epi.09.6 22122639
    [Google Scholar]
  187. Pepe M.S. Etzioni R. Feng Z. Potter J.D. Thompson M.L. Thornquist M. Winget M. Yasui Y. Phases of biomarker development for early detection of cancer. J. Natl. Cancer Inst. 2001 93 14 1054 1061 10.1093/jnci/93.14.1054 11459866
    [Google Scholar]
  188. Hanash S.M. Baik C.S. Kallioniemi O. Emerging molecular biomarkers—blood-based strategies to detect and monitor cancer. Nat. Rev. Clin. Oncol. 2011 8 3 142 150 10.1038/nrclinonc.2010.220 21364687
    [Google Scholar]
  189. Day R.S. Planning clinically relevant biomarker validation studies using the “number needed to treat” concept. J. Transl. Med. 2016 14 1 117 10.1186/s12967‑016‑0862‑4 27146704
    [Google Scholar]
  190. Mayeux R. Biomarkers: Potential uses and limitations. NeuroRx 2004 1 2 182 188 10.1602/neurorx.1.2.182 15717018
    [Google Scholar]
  191. Pleskač P. Fargeas C.A. Veselska R. Corbeil D. Skoda J. Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease. Cell. Mol. Biol. Lett. 2024 29 1 41 10.1186/s11658‑024‑00554‑0 38532366
    [Google Scholar]
  192. Moreno-Londoño A.P. Robles-Flores M. Functional roles of CD133: More than stemness associated factor regulated by the microenvironment. Stem Cell Rev. Rep. 2024 20 1 25 51 10.1007/s12015‑023‑10647‑6 37922108
    [Google Scholar]
  193. Glumac P.M. LeBeau A.M. The role of CD133 in cancer: A concise review. Clin. Transl. Med. 2018 7 1 e18 29984391
    [Google Scholar]
  194. Vander Griend D.J. Karthaus W.L. Dalrymple S. Meeker A. DeMarzo A.M. Isaacs J.T. The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res. 2008 68 23 9703 9711 10.1158/0008‑5472.CAN‑08‑3084 19047148
    [Google Scholar]
  195. Tan Y. Chen B. Xu W. Zhao W. Wu J. Clinicopathological significance of CD133 in lung cancer: A meta-analysis. Mol. Clin. Oncol. 2014 2 1 111 115 10.3892/mco.2013.195 24649317
    [Google Scholar]
  196. Irollo E. Pirozzi G. CD133: To be or not to be, is this the real question? Am. J. Transl. Res. 2013 5 6 563 581 24093054
    [Google Scholar]
  197. Di Fiore R. Suleiman S. Calleja-Agius J. CD133 as biomarker and therapeutic target in gynecologic malignancies. Gynecological Cancers: An Interdisciplinary Approach. Rezaei N. Canada Springer 2023 37 75 10.1007/16833_2023_139
    [Google Scholar]
  198. Schmohl J. Vallera D. CD133, selectively targeting the root of cancer. Toxins 2016 8 6 165 10.3390/toxins8060165 27240402
    [Google Scholar]
  199. Pospieszna J. Dams-Kozlowska H. Udomsak W. Murias M. Kucinska M. Unmasking the deceptive nature of cancer stem cells: The role of CD133 in revealing their secrets. Int. J. Mol. Sci. 2023 24 13 10910 10.3390/ijms241310910 37446085
    [Google Scholar]
  200. Singh S. Brocker C. Koppaka V. Chen Y. Jackson B.C. Matsumoto A. Thompson D.C. Vasiliou V. Aldehyde dehydro-genases in cellular responses to oxidative/electrophilicstress. Free Radic. Biol. Med. 2013 56 89 101 10.1016/j.freeradbiomed.2012.11.010 23195683
    [Google Scholar]
  201. Wei Y. Li Y. Chen Y. Liu P. Huang S. Zhang Y. Sun Y. Wu Z. Hu M. Wu Q. Wu H. Liu F. She T. Ning Z. ALDH1: A potential therapeutic target for cancer stem cells in solid tumors. Front. Oncol. 2022 12 1026278 10.3389/fonc.2022.1026278 36387165
    [Google Scholar]
  202. Yue H. Hu Z. Hu R. Guo Z. Zheng Y. Wang Y. Zhou Y. ALDH1A1 in cancers: Bidirectional function, drug resistance, and regulatory mechanism. Front. Oncol. 2022 12 918778 10.3389/fonc.2022.918778 35814382
    [Google Scholar]
  203. Rodriguez-Torres M. Allan A.L. Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors. Clin. Exp. Metastasis 2016 33 1 97 113 10.1007/s10585‑015‑9755‑9 26445849
    [Google Scholar]
  204. Clark D.W. Palle K. Aldehyde dehydrogenases in cancer stem cells: Potential as therapeutic targets. Ann. Transl. Med. 2016 4 24 518 518 10.21037/atm.2016.11.82 28149880
    [Google Scholar]
  205. Schaefer T. Lengerke C. SOX2 protein biochemistry in stemness, reprogramming, and cancer: The PI3K/AKT/SOX2 axis and beyond. Oncogene 2020 39 2 278 292 10.1038/s41388‑019‑0997‑x 31477842
    [Google Scholar]
  206. Karachaliou N. Rosell R. Viteri S. The role of SOX2 in small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma of the lung. Transl. Lung Cancer Res. 2013 2 3 172 179 25806230
    [Google Scholar]
  207. Zhang S. Xiong X. Sun Y. Functional characterization of SOX2 as an anticancer target. Signal Transduct. Target. Ther. 2020 5 1 135 10.1038/s41392‑020‑00242‑3
    [Google Scholar]
  208. Montoro-Jiménez I. Granda-Díaz R. Menéndez S.T. Prieto-Fernández L. Otero-Rosales M. Álvarez-González M. García-de-la-Fuente V. Rodríguez A. Rodrigo J.P. Álvarez-Teijeiro S. García-Pedrero J.M. Hermida-Prado F. Combined PIK3CA and SOX2 gene amplification predicts laryngeal cancer risk beyond histopathological grading. Int. J. Mol. Sci. 2024 25 5 2695 10.3390/ijms25052695 38473941
    [Google Scholar]
  209. Niu Z. Jin R. Zhang Y. Li H. Signaling pathways and targeted therapies in lung squamous cell carcinoma: Mechanisms and clinical trials. Signal Transduct. Target. Ther. 2022 7 1 353 10.1038/s41392‑022‑01200‑x
    [Google Scholar]
  210. Jordan A.R. Racine R.R. Hennig M.J.P. Lokeshwar V.B. The role of CD44 in disease pathophysiology and targeted treatment. Front. Immunol. 2015 6 182 10.3389/fimmu.2015.00182 25954275
    [Google Scholar]
  211. Chen C. Zhao S. Karnad A. Freeman J.W. The biology and role of CD44 in cancer progression: Therapeutic implications. J. Hematol. Oncol. 2018 11 1 64 10.1186/s13045‑018‑0605‑5 29747682
    [Google Scholar]
  212. Wang Y.Y. Vadhan A. Chen P.H. Lee Y.L. Chao C.Y. Cheng K.H. Chang Y.C. Hu S.C.S. Yuan S.S.F. CD44 promotes lung cancer cell metastasis through ERK–ZEB1 signaling. Cancers 2021 13 16 4057 10.3390/cancers13164057 34439211
    [Google Scholar]
  213. Chen L. Fu C. Zhang Q. He C. Zhang F. Wei Q. The role of CD44 in pathological angiogenesis. FASEB J. 2020 34 10 13125 13139 10.1096/fj.202000380RR 32830349
    [Google Scholar]
  214. Mohtar M. Syafruddin S. Nasir S. Low T.Y. Revisiting the roles of pro-metastatic EpCAM in cancer. Biomolecules 2020 10 2 255 10.3390/biom10020255 32046162
    [Google Scholar]
  215. Liu Y. Wang Y. Sun S. Chen Z. Xiang S. Ding Z. Huang Z. Zhang B. Understanding the versatile roles and applications of EpCAM in cancers: From bench to bedside. Exp. Hematol. Oncol. 2022 11 1 97 10.1186/s40164‑022‑00352‑4 36369033
    [Google Scholar]
  216. Li D. Guo X. Yang K. Yang Y. Zhou W. Huang Y. Liang X. Su J. Jiang L. Li J. Fu M. He H. Yang J. Shi H. Yang H. Tong A. Chen N. Hu J. Xu Q. Wei Y.Q. Wang W. EpCAM-targeting CAR-T cell immunotherapy is safe and efficacious for epithelial tumors. Sci. Adv. 2023 9 48 eadg9721 10.1126/sciadv.adg9721 38039357
    [Google Scholar]
  217. Xiang L. Su P. Xia S. Liu Z. Wang Y. Gao P. Zhou G. ABCG2 is associated with HER-2 Expression, lymph node metastasis and clinical stage in breast invasive ductal carcinoma. Diagn. Pathol. 2011 6 1 90 https://diagnosticpathology.biomedcentral.com/articles/10.1186/1746-1596-6-90 10.1186/1746‑1596‑6‑90 21943250
    [Google Scholar]
  218. Begicevic R.R. Falasca M. ABC transporters in cancer stem cells: Beyond chemoresistance. Int. J. Mol. Sci. 2017 18 11 2362 10.3390/ijms18112362 29117122
    [Google Scholar]
  219. Goler-Baron V. Sladkevich I. Assaraf Y.G. Inhibition of the PI3K-Akt signaling pathway disrupts ABCG2-rich extracellular vesicles and overcomes multidrug resistance in breast cancer cells. Biochem. Pharmacol. 2012 83 10 1340 1348 10.1016/j.bcp.2012.01.033 22342288
    [Google Scholar]
  220. Mohiuddin I.S. Wei S.J. Kang M.H. Role of OCT4 in cancer stem-like cells and chemotherapy resistance. Biochim. Biophys. Acta Mol. Basis Dis. 2020 1866 4 165432 10.1016/j.bbadis.2019.03.005 30904611
    [Google Scholar]
  221. Zhang Q. Han Z. Zhu Y. Chen J. Li W. The role and specific mechanism of OCT4 in cancer stem cells: A review. Int. J. Stem Cells 2020 13 3 312 325 10.15283/ijsc20097 32840233
    [Google Scholar]
  222. Mou Y. Yue Z. Wang X. Li W. Zhang H. Wang Y. Li R. Sun X. OCT4 remodels the phenotype and promotes angiogenesis of HUVECs by changing the gene expression profile. Int. J. Med. Sci. 2016 13 5 386 394 10.7150/ijms.15057 27226779
    [Google Scholar]
  223. Vasefifar P. Motafakkerazad R. Maleki L.A. Najafi S. Ghrobaninezhad F. Najafzadeh B. Alemohammad H. Amini M. Baghbanzadeh A. Baradaran B. Nanog, as a key cancer stem cell marker in tumor progression. Gene 2022 827 146448 10.1016/j.gene.2022.146448 35337852
    [Google Scholar]
  224. Gawlik-Rzemieniewska N. Bednarek I. The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells. Cancer Biol. Ther. 2016 17 1 1 10 10.1080/15384047.2015.1121348 26618281
    [Google Scholar]
  225. Wang M. Chiou S. Wu C. Targeting cancer stem cells: Emerging role of Nanog transcription factor. OncoTargets Ther. 2013 6 1207 1220 10.2147/OTT.S38114
    [Google Scholar]
  226. Webb T.R. Slavish J. George R.E. Look A.T. Xue L. Jiang Q. Cui X. Rentrop W.B. Morris S.W. Anaplastic lymphoma kinase: Role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev. Anticancer Ther. 2009 9 3 331 356 10.1586/14737140.9.3.331 19275511
    [Google Scholar]
  227. Najafiyan B. Bokaii Hosseini Z. Esmaelian S. Firuzpour F. Rahimipour Anaraki S. Kalantari L. Hheidari A. Mesgari H. Nabi-Afjadi M. Unveiling the potential effects of resveratrol in lung cancer treatment: Mechanisms and nanoparticle-based drug delivery strategies. Biomed. Pharmacother. 2024 172 116207 10.1016/j.biopha.2024.116207 38295754
    [Google Scholar]
  228. Khan M. Lin J. Liao G. Tian Y. Liang Y. Li R. Liu M. Yuan Y. ALK Inhibitors in the Treatment of ALK Positive NSCLC. Front. Oncol. 2019 8 557 10.3389/fonc.2018.00557 30687633
    [Google Scholar]
  229. D’Angelo A. Sobhani N. Chapman R. Bagby S. Bortoletti C. Traversini M. Ferrari K. Voltolini L. Darlow J. Roviello G. Focus on ROS1-positive non-small cell lung cancer (NSCLC): Crizotinib, resistance mechanisms and the newer generation of targeted therapies. Cancers 2020 12 11 3293 10.3390/cancers12113293 33172113
    [Google Scholar]
  230. Iyer S.R. Nusser K. Jones K. Shinde P. Keddy C. Beach C.Z. Aguero E. Force J. Shinde U. Davare M.A. Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors. EMBO Mol. Med. 2023 15 10 e17367 10.15252/emmm.202217367 37587872
    [Google Scholar]
  231. Hussain M.R.M. Baig M. Mohamoud H.S.A. Ulhaq Z. Hoessli D.C. Khogeer G.S. Al-Sayed R.R. Al-Aama J.Y. BRAF gene: From human cancers to developmental syndromes. Saudi J. Biol. Sci. 2015 22 4 359 373 10.1016/j.sjbs.2014.10.002 26150740
    [Google Scholar]
  232. Bottos A. Martini M. Di Nicolantonio F. Comunanza V. Maione F. Minassi A. Appendino G. Bussolino F. Bardelli A. Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia. Proc. Natl. Acad. Sci. USA 2012 109 6 E353 E359 10.1073/pnas.1105026109 22203991
    [Google Scholar]
  233. Anguera G. Majem M. BRAF inhibitors in metastatic non-small cell lung cancer. J. Thorac. Dis. 2018 10 2 589 592 10.21037/jtd.2018.01.129 29607117
    [Google Scholar]
  234. Yan N. Guo S. Zhang H. Zhang Z. Shen S. Li X. BRAF-mutated non-small cell lung cancer: Current treatment status and future perspective. Front. Oncol. 2022 12 863043 10.3389/fonc.2022.863043 35433454
    [Google Scholar]
  235. Takahashi M. Ritz J. Cooper G.M. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985 42 2 581 588 10.1016/0092‑8674(85)90115‑1 2992805
    [Google Scholar]
  236. Takahashi M. Buma Y. Iwamoto T. Inaguma Y. Ikeda H. Hiai H. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 1988 3 5 571 578 3078962
    [Google Scholar]
  237. Saha D. Ryan K.R. Lakkaniga N.R. Acharya B. Garcia N.G. Smith E.L. Frett B. Targeting rearranged during transfection in cancer: A perspective on small-molecule inhibitors and their clinical development. J. Med. Chem. 2021 64 16 11747 11773 10.1021/acs.jmedchem.0c02167 34402300
    [Google Scholar]
  238. Shrivastava V. Gurjar V.K. Jain S. Vaidya A. Sharma A. Rearranged during transfection (RET) inhibitors. Current Molecular Targets of Heterocyclic Compounds for Cancer Therapy. Elsevier 2024 323 376 10.1016/B978‑0‑323‑96121‑9.00013‑9
    [Google Scholar]
  239. Kemper M. Krekeler C. Menck K. Lenz G. Evers G. Schulze A.B. Bleckmann A. Liquid biopsies in lung cancer. Cancers 2023 15 5 1430 10.3390/cancers15051430 36900221
    [Google Scholar]
  240. Gambella A. Senetta R. Collemi G. Vallero S.G. Monticelli M. Cofano F. Zeppa P. Garbossa D. Pellerino A. Rudà R. Soffietti R. Fagioli F. Papotti M. Cassoni P. Bertero L. NTRK Fusions in central nervous system tumors: A rare, but worthy target. Int. J. Mol. Sci. 2020 21 3 753 10.3390/ijms21030753 31979374
    [Google Scholar]
  241. Liu F. Wei Y. Zhang H. Jiang J. Zhang P. Chu Q. NTRK fusion in non-small cell lung cancer: Diagnosis, therapy, and TRK inhibitor resistance. Front. Oncol. 2022 12 864666 10.3389/fonc.2022.864666 35372074
    [Google Scholar]
  242. Klink A.J. Kavati A. Gassama A. Kozlek T. Gajra A. Antoine R. Treatment patterns of real-world patients with TRK fusion cancer treated by us community oncologists. Target. Oncol. 2022 17 5 549 561 10.1007/s11523‑022‑00909‑7 36089643
    [Google Scholar]
  243. Jeon H.M. Lee J. MET: Roles in epithelial-mesenchymal transition and cancer stemness. Ann. Transl. Med. 2017 5 1 5 5 10.21037/atm.2016.12.67 28164090
    [Google Scholar]
  244. Gherardi E. Birchmeier W. Birchmeier C. Woude G.V. Targeting MET in cancer: Rationale and progress. Nat. Rev. Cancer 2012 12 2 89 103 10.1038/nrc3205 22270953
    [Google Scholar]
  245. Iqbal N. Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: Overexpression and therapeutic implications. Mol. Biol. Int. 2014 2014 1 9 10.1155/2014/852748 25276427
    [Google Scholar]
  246. Nami B. Wang Z. HER2 in breast cancer stemness: A negative feedback loop towards trastuzumab resistance. Cancers 2017 9 5 40 10.3390/cancers9050040 28445439
    [Google Scholar]
  247. Ren S. Wang J. Ying J. Mitsudomi T. Lee D.H. Wang Z. Chu Q. Mack P.C. Cheng Y. Duan J. Fan Y. Han B. Hui Z. Liu A. Liu J. Lu Y. Ma Z. Shi M. Shu Y. Song Q. Song X. Song Y. Wang C. Wang X. Wang Z. Xu Y. Yao Y. Zhang L. Zhao M. Zhu B. Zhang J. Zhou C. Hirsch F.R. Consensus for HER2 alterations testing in non-small-cell lung cancer. ESMO Open 2022 7 1 100395 10.1016/j.esmoop.2022.100395 35149428
    [Google Scholar]
  248. Vathiotis I.A. Bafaloukos D. Syrigos K.N. Samonis G. Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond. Cancers 2023 15 4 1286 10.3390/cancers15041286 36831628
    [Google Scholar]
  249. Zhu K. Yang X. Tai H. Zhong X. Luo T. Zheng H. HER2-targeted therapies in cancer: A systematic review. Biomark. Res. 2024 12 1 16 10.1186/s40364‑024‑00565‑1 38308374
    [Google Scholar]
  250. Barrenschee M. Lange C. Cossais F. Egberts J.H. Becker T. Wedel T. Böttner M. Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system. Front. Cell. Neurosci. 2015 9 360 10.3389/fncel.2015.00360 26441531
    [Google Scholar]
  251. Iivanainen E. Paatero I. Heikkinen S.M. Junttila T.T. Cao R. Klint P. Jaakkola P.M. Cao Y. Elenius K. Intra- and extracellular signaling by endothelial neuregulin-1. Exp. Cell Res. 2007 313 13 2896 2909 10.1016/j.yexcr.2007.03.042 17499242
    [Google Scholar]
  252. Jeong H. Kim J. Lee Y. Seo J.H. Hong S.R. Kim A. Neuregulin-1 induces cancer stem cell characteristics in breast cancer cell lines. Oncol. Rep. 2014 32 3 1218 1224 10.3892/or.2014.3330 25018110
    [Google Scholar]
  253. Rosas D. Raez L.E. Russo A. Rolfo C. Neuregulin 1 gene (NRG1). A potentially new targetable alteration for the treatment of lung cancer. Cancers 2021 13 20 5038 10.3390/cancers13205038 34680187
    [Google Scholar]
  254. Ullah A. Razzaq A. Zhou C. Ullah N. Shehzadi S. Aziz T. Alfaifi M.Y. Elbehairi S.E.I. Iqbal H. Biological significance of EphB4 expression in cancer. Curr. Protein Pept. Sci. 2024 25 3 244 255 10.2174/0113892037269589231017055642 37909437
    [Google Scholar]
  255. Ferguson B.D. Carol Tan Y.H. Kanteti R.S. Liu R. Gayed M.J. Vokes E.E. Ferguson M.K. John Iafrate A. Gill P.S. Salgia R. Novel EPHB4 receptor tyrosine kinase mutations and kinomic pathway analysis in lung cancer. Sci. Rep. 2015 5 1 10641 10.1038/srep10641 26073592
    [Google Scholar]
  256. Jiang W.G. Sanders A.J. Katoh M. Ungefroren H. Gieseler F. Prince M. Thompson S.K. Zollo M. Spano D. Dhawan P. Sliva D. Subbarayan P.R. Sarkar M. Honoki K. Fujii H. Georgakilas A.G. Amedei A. Niccolai E. Amin A. Ashraf S.S. Ye L. Helferich W.G. Yang X. Boosani C.S. Guha G. Ciriolo M.R. Aquilano K. Chen S. Azmi A.S. Keith W.N. Bilsland A. Bhakta D. Halicka D. Nowsheen S. Pantano F. Santini D. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin. Cancer Biol. 2015 35 Suppl. S244 S275 10.1016/j.semcancer.2015.03.008 25865774
    [Google Scholar]
  257. Jiang X. Wang J. Deng X. Xiong F. Zhang S. Gong Z. Li X. Cao K. Deng H. He Y. Liao Q. Xiang B. Zhou M. Guo C. Zeng Z. Li G. Li X. Xiong W. The role of microenvironment in tumor angiogenesis. J. Exp. Clin. Cancer Res. 2020 39 1 204 10.1186/s13046‑020‑01709‑5 32993787
    [Google Scholar]
  258. Everts P.A. Lana J.F. Onishi K. Buford D. Peng J. Mahmood A. Fonseca L.F. van Zundert A. Podesta L. Angiogenesis and tissue repair depend on platelet dosing and bioformulation strategies following orthobiological platelet-rich plasma procedures: A narrative review. Biomedicines 2023 11 7 1922 10.3390/biomedicines11071922 37509560
    [Google Scholar]
  259. Fernández-Guarino M. Hernández-Bule M.L. Bacci S. Cellular and Molecular Processes in Wound Healing. Biomedicines 2023 11 9 2526 10.3390/biomedicines11092526 37760967
    [Google Scholar]
  260. Farooq M. Khan A.W. Kim M.S. Choi S. The role of Fibroblast Growth Factor (FGF) signaling in tissue repair and regeneration. Cells 2021 10 11 3242 10.3390/cells10113242 34831463
    [Google Scholar]
  261. Ardizzone A. Bova V. Casili G. Repici A. Lanza M. Giuffrida R. Colarossi C. Mare M. Cuzzocrea S. Esposito E. Paterniti I. Role of basic fibroblast growth factor in cancer: Biological activity, targeted therapies, and prognostic value. Cells 2023 12 7 1002 10.3390/cells12071002 37048074
    [Google Scholar]
  262. Pathak A. Pal A.K. Roy S. Nandave M. Jain K. Role of angiogenesis and its biomarkers in development of targeted tumor therapies. Stem Cells Int. 2024 2024 1 9077926 10.1155/2024/9077926
    [Google Scholar]
  263. Santoni-Rugiu E. Melchior L.C. Urbanska E.M. Jakobsen J.N. de Stricker K. Grauslund M. Sørensen J.B. Intrinsic resistance to EGFR-tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: Differences and similarities with acquired resistance. Cancers 2019 11 7 923 10.3390/cancers11070923 31266248
    [Google Scholar]
  264. Marrocco I. Yarden Y. Resistance of lung cancer to EGFR-specific kinase inhibitors: Activation of bypass pathways and endogenous mutators. Cancers 2023 15 20 5009 10.3390/cancers15205009 37894376
    [Google Scholar]
  265. Fu K. Xie F. Wang F. Fu L. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J. Hematol. Oncol. 2022 15 1 173 10.1186/s13045‑022‑01391‑4 36482474
    [Google Scholar]
  266. Zhong L. Li Y. Xiong L. Wang W. Wu M. Yuan T. Yang W. Tian C. Miao Z. Wang T. Yang S. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives. Signal Transduct. Target. Ther. 2021 6 1 201 10.1038/s41392‑021‑00572‑w
    [Google Scholar]
  267. Wang Z. Li J. Guo J. Wei P. Direct antitumor activity of bevacizumab: An overlooked mechanism? Front. Pharmacol. 2024 15 1394878 10.3389/fphar.2024.1394878 38716237
    [Google Scholar]
  268. Ghalehbandi S. Yuzugulen J. Pranjol M.Z.I. Pourgholami M.H. The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF. Eur. J. Pharmacol. 2023 949 175586 10.1016/j.ejphar.2023.175586 36906141
    [Google Scholar]
  269. Zhao Y. Guo S. Deng J. Shen J. Du F. Wu X. Chen Y. Li M. Chen M. Li X. Li W. Gu L. Sun Y. Wen Q. Li J. Xiao Z. VEGF/VEGFR-targeted therapy and immunotherapy in non-small cell lung cancer: Targeting the tumor microenvironment. Int. J. Biol. Sci. 2022 18 9 3845 3858 10.7150/ijbs.70958 35813484
    [Google Scholar]
  270. Aguiar R.B. Moraes J.Z. Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors. Front. Immunol. 2019 10 1023 10.3389/fimmu.2019.01023 31156623
    [Google Scholar]
  271. Sherbet G.V. Hedgehog (Hh) Signalling in EMT (Epithelial Mesenchyme Transition), CSCs (Cancer Stem Cells) and Angiogenesis.Molecular Approach to Cancer Management. Sherbet G.V. Academic Press 2017 55 64 10.1016/B978‑0‑12‑812896‑1.00006‑4
    [Google Scholar]
  272. Fiedler U. Krissl T. Koidl S. Weiss C. Koblizek T. Deutsch U. Martiny-Baron G. Marmé D. Augustin H.G. Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J. Biol. Chem. 2003 278 3 1721 1727 10.1074/jbc.M208550200 12427764
    [Google Scholar]
  273. Saharinen P. Eklund L. Alitalo K. Therapeutic targeting of the angiopoietin–TIE pathway. Nat. Rev. Drug Discov. 2017 16 9 635 661 10.1038/nrd.2016.278 28529319
    [Google Scholar]
  274. Akwii R.G. Sajib M.S. Zahra F.T. Mikelis C.M. Role of angiopoietin-2 in vascular physiology and pathophysiology. Cells 2019 8 5 471 10.3390/cells8050471 31108880
    [Google Scholar]
  275. Wu S. Savani R.C. Molecular bases for lung development, injury, and repair. The Newborn Lung. Bancalari E. Philadelphia Elsevier 2019 3 29 10.1016/B978‑0‑323‑54605‑8.00001‑5
    [Google Scholar]
  276. Roškar L. Roškar I. Rižner T.L. Smrkolj Š. Diagnostic and therapeutic values of angiogenic factors in endometrial cancer. Biomolecules 2021 12 1 7 10.3390/biom12010007 35053155
    [Google Scholar]
  277. Tsakogiannis D. Nikolakopoulou A. Zagouri F. Stratakos G. Syrigos K. Zografos E. Koulouris N. Bletsa G. Update overview of the role of angiopoietins in lung cancer. Medicina 2021 57 11 1191 10.3390/medicina57111191
    [Google Scholar]
  278. Leong A. Kim M. The angiopoietin-2 and TIE pathway as a therapeutic target for enhancing antiangiogenic therapy and immunotherapy in patients with advanced cancer. Int. J. Mol. Sci. 2020 21 22 8689 10.3390/ijms21228689 33217955
    [Google Scholar]
  279. Kiss E.A. Saharinen P. Anti-angiogenic targets: Angiopoietin and angiopoietin receptors. Tumor Angiogenesis 2019 227 250 10.1007/978‑3‑319‑33673‑2_4
    [Google Scholar]
  280. Liu N. Liu M. Fu S. Wang J. Tang H. Isah A.D. Chen D. Wang X. Ang2-targeted combination therapy for cancer treatment. Front. Immunol. 2022 13 949553 10.3389/fimmu.2022.949553 35874764
    [Google Scholar]
  281. Scheuer W. Thomas M. Hanke P. Sam J. Osl F. Weininger D. Baehner M. Seeber S. Kettenberger H. Schanzer J. Brinkmann U. Weidner K.M. Regula J. Klein C. Anti-tumoral, anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2. MAbs 2016 8 3 562 573 10.1080/19420862.2016.1147640 26864324
    [Google Scholar]
  282. Wu F.T.H. Man S. Xu P. Chow A. Paez-Ribes M. Lee C.R. Pirie-Shepherd S.R. Emmenegger U. Kerbel R.S. Efficacy of cotargeting angiopoietin-2 and the VEGF pathway in the adjuvant postsurgical setting for early breast, colorectal, and renal cancers. Cancer Res. 2016 76 23 6988 7000 10.1158/0008‑5472.CAN‑16‑0888 27651308
    [Google Scholar]
  283. Heil F. Babitzki G. Julien-Laferriere A. Ooi C.H. Hidalgo M. Massard C. Martinez-Garcia M. Le Tourneau C. Kockx M. Gerber P. Rossomanno S. Krieter O. Lahr A. Wild N. Harring S.V. Lechner K. Vanucizumab mode of action: Serial biomarkers in plasma, tumor, and skin-wound-healing biopsies. Transl. Oncol. 2021 14 2 100984 10.1016/j.tranon.2020.100984 33338877
    [Google Scholar]
  284. Hidalgo M. Martinez-Garcia M. Le Tourneau C. Massard C. Garralda E. Boni V. Taus A. Albanell J. Sablin M.P. Alt M. Bahleda R. Varga A. Boetsch C. Franjkovic I. Heil F. Lahr A. Lechner K. Morel A. Nayak T. Rossomanno S. Smart K. Stubenrauch K. Krieter O. First-in-human phase i study of single-agent vanucizumab, A first-in-class bispecific anti-angiopoietin-2/anti-VEGF-a antibody, in adult patients with advanced solid tumors. Clin. Cancer Res. 2018 24 7 1536 1545 10.1158/1078‑0432.CCR‑17‑1588 29217526
    [Google Scholar]
  285. Marin-Acevedo J.A. Kimbrough E.O. Lou Y. Next generation of immune checkpoint inhibitors and beyond. J. Hematol. Oncol. 2021 14 1 45 10.1186/s13045‑021‑01056‑8 33741032
    [Google Scholar]
  286. Qi S. Deng S. Lian Z. Yu K. Novel drugs with high efficacy against tumor angiogenesis. Int. J. Mol. Sci. 2022 23 13 6934 10.3390/ijms23136934 35805939
    [Google Scholar]
  287. Valdembri D. Serini G. The roles of integrins in cancer. Fac. Rev. 2021 10 45 10.12703/r/10‑45 34131655
    [Google Scholar]
  288. Hamidi H. Ivaska J. Every step of the way: Integrins in cancer progression and metastasis. Nat. Rev. Cancer 2018 18 9 533 548 10.1038/s41568‑018‑0038‑z 30002479
    [Google Scholar]
  289. Cooper J. Giancotti F.G. Integrin signaling in cancer: Mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell 2019 35 3 347 367 10.1016/j.ccell.2019.01.007 30889378
    [Google Scholar]
  290. Xiong J. Yan L. Zou C. Wang K. Chen M. Xu B. Zhou Z. Zhang D. Integrins regulate stemness in solid tumor: An emerging therapeutic target. J. Hematol. Oncol. 2021 14 1 177 10.1186/s13045‑021‑01192‑1 34715893
    [Google Scholar]
  291. Weis S.M. Cheresh D.A. αV integrins in angiogenesis and cancer. Cold Spring Harb. Perspect. Med. 2011 1 1 a006478 10.1101/cshperspect.a006478 22229119
    [Google Scholar]
  292. Mezu-Ndubuisi O.J. Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr. Res. 2021 89 7 1619 1626 10.1038/s41390‑020‑01177‑9 33027803
    [Google Scholar]
  293. Garmy-Susini B. Varner J.A. Roles of integrins in tumor angiogenesis and lymphangiogenesis. Lymphat. Res. Biol. 2008 6 3-4 155 163 10.1089/lrb.2008.1011 19093788
    [Google Scholar]
  294. Hynes R.O. A reevaluation of integrins as regulators of angiogenesis. Nat. Med. 2002 8 9 918 921 10.1038/nm0902‑918 12205444
    [Google Scholar]
  295. Cai W. Chen X. Anti-angiogenic cancer therapy based on integrin αvβ3 antagonism. Anticancer. Agents Med. Chem. 2006 6 5 407 428 10.2174/187152006778226530
    [Google Scholar]
  296. Millard M. Odde S. Neamati N. Integrin targeted therapeutics. Theranostics 2011 1 154 188 10.7150/thno/v01p0154 21547158
    [Google Scholar]
  297. Slack R.J. Macdonald S.J.F. Roper J.A. Jenkins R.G. Hatley R.J.D. Emerging therapeutic opportunities for integrin inhibitors. Nat. Rev. Drug Discov. 2022 21 1 60 78 10.1038/s41573‑021‑00284‑4 34535788
    [Google Scholar]
  298. Pang X. He X. Qiu Z. Zhang H. Xie R. Liu Z. Gu Y. Zhao N. Xiang Q. Cui Y. Targeting integrin pathways: Mechanisms and advances in therapy. Signal Transduct. Target. Ther. 2023 8 1 1 10.1038/s41392‑022‑01259‑6 36588107
    [Google Scholar]
  299. Li M. Wang Y. Li M. Wu X. Setrerrahmane S. Xu H. Integrins as attractive targets for cancer therapeutics. Acta Pharm. Sin. B 2021 11 9 2726 2737 10.1016/j.apsb.2021.01.004 34589393
    [Google Scholar]
  300. Vansteenkiste J. Barlesi F. Waller C.F. Bennouna J. Gridelli C. Goekkurt E. Verhoeven D. Szczesna A. Feurer M. Milanowski J. Germonpre P. Lena H. Atanackovic D. Krzakowski M. Hicking C. Straub J. Picard M. Schuette W. O’Byrne K. Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO). Ann. Oncol. 2015 26 8 1734 1740 10.1093/annonc/mdv219 25939894
    [Google Scholar]
  301. Jeong J. Kim J. Combination effect of cilengitide with erlotinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells. Int. J. Mol. Sci. 2022 23 7 3423 10.3390/ijms23073423 35408781
    [Google Scholar]
  302. Hamilton G. Rath B. Burghuber O. Chitinase-3-like-1/YKL-40 as marker of circulating tumor cells. Transl. Lung Cancer Res. 2015 4 3 287 291 26207216
    [Google Scholar]
  303. Shao R. Taylor S.L. Oh D.S. Schwartz L.M. Vascular heterogeneity and targeting: The role of YKL-40 in glioblastoma vascularization. Oncotarget 2015 6 38 40507 40518 10.18632/oncotarget.5943 26439689
    [Google Scholar]
  304. Moustafa H.A.M. Sohaib A.U. Saleem I. Ullah A. Targeting of Ykl-40 as a protumor in personalized medicine: A new dimension in disease understanding. Curr. Gene Ther. 2025 10.2174/0115665232332419250213081510 39976089
    [Google Scholar]
  305. Jefri M. Huang Y.N. Huang W.C. Tai C.S. Chen W.L. YKL-40 regulated epithelial-mesenchymal transition and migration/invasion enhancement in non-small cell lung cancer. BMC Cancer 2015 15 1 590 10.1186/s12885‑015‑1592‑3 26275425
    [Google Scholar]
  306. EU clinical trials register. Available from:https://www.clinicaltrialsregister.eu/.
  307. ClinicalTrials.gov. Available from:https://clinicaltrials.gov/https://clinicaltrials.gov/.
/content/journals/cpb/10.2174/0113892010407798251204054106
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Cancer Stem Cells and Angiogenesis: Exploring the Tumor Microenvironment and Therapeutic Strategies in Lung Cancer
Bentham Science Publishers ; https://doi.org/10.2174/0113892010407798251204054106
/content/journals/cpb/10.2174/0113892010407798251204054106
/content/journals/cpb/10.2174/0113892010407798251204054106
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  • Article Type:     Review Article
Keywords: targeted therapy ; lung cancer ; Angiogenesis ; cancer stem cells ; tumor microenvironment ; biomarkers

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