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2000
Volume 25, Issue 9
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576

Abstract

Pancreatic cancer is a highly malignant form of cancer that distinguishes itself from other gastrointestinal tumors through significant fibrosis and unique perineural invasion. These characteristics underscore the complexity of neural regulation within the pancreatic cancer Tumor Microenvironment (TME). This review aimed to explore the regulatory mechanisms and crosstalk among stromal cells and their factors within the pancreatic cancer microenvironment. We begin by reviewing the major components of the pancreatic cancer microenvironment, analyzing interactions among crucial cell types, such as Cancer-associated Fibroblasts (CAFs) and immune cells, and revealing the dynamic changes between tumor cells and surrounding nerves, immune, and stromal cells. We discuss the role of neural factors, including the Nerve Growth Factor (NGF) and Brain-derived Neurotrophic Factor (BDNF), in the progression of pancreatic cancer and the mechanisms by which the sympathetic and parasympathetic nervous systems regulate tumor cell growth, migration, and invasion. Interactions among stromal cells, cytokines, and neural factors in the pancreatic cancer microenvironment promote fibrosis and perineural invasion. A deeper understanding of the regulation and crosstalk among components in the pancreatic cancer microenvironment offers new perspectives for inhibiting fibrosis and perineural invasion in pancreatic cancer.

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References

  1. YoshiharaK. ShahmoradgoliM. MartínezE. VegesnaR. KimH. Torres-GarciaW. TreviñoV. ShenH. LairdP.W. LevineD.A. CarterS.L. GetzG. Stemke-HaleK. MillsG.B. VerhaakR.G.W. Inferring tumour purity and stromal and immune cell admixture from expression data.Nat. Commun.201341261210.1038/ncomms3612 24113773
    [Google Scholar]
  2. LiuJ. LichtenbergT. HoadleyK.A. PoissonL.M. LazarA.J. CherniackA.D. KovatichA.J. BenzC.C. LevineD.A. LeeA.V. OmbergL. WolfD.M. ShriverC.D. ThorssonV. HuH. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics.Cell2018173400416
    [Google Scholar]
  3. LaklaiH. MiroshnikovaY.A. PickupM.W. CollissonE.A. KimG.E. BarrettA.S. HillR.C. LakinsJ.N. SchlaepferD.D. MouwJ.K. LeBleuV.S. RoyN. NovitskiyS.V. JohansenJ.S. PoliV. KalluriR. Iacobuzio-DonahueC.A. WoodL.D. HebrokM. HansenK. MosesH.L. WeaverV.M. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.Nat. Med.201622549750510.1038/nm.4082 27089513
    [Google Scholar]
  4. OliveK.P. JacobetzM.A. DavidsonC.J. GopinathanA. McIntyreD. HonessD. MadhuB. GoldgrabenM.A. CaldwellM.E. AllardD. FreseK.K. DeNicolaG. FeigC. CombsC. WinterS.P. Ireland-ZecchiniH. ReicheltS. HowatW.J. ChangA. DharaM. WangL. RückertF. GrützmannR. PilarskyC. IzeradjeneK. HingoraniS.R. HuangP. DaviesS.E. PlunkettW. EgorinM. HrubanR.H. WhitebreadN. McGovernK. AdamsJ. Iacobuzio-DonahueC. GriffithsJ. TuvesonD.A. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.Science200932459331457146110.1126/science.1171362 19460966
    [Google Scholar]
  5. JacobetzM.A. ChanD.S. NeesseA. BapiroT.E. CookN. FreseK.K. FeigC. NakagawaT. CaldwellM.E. ZecchiniH.I. LolkemaM.P. JiangP. KulttiA. ThompsonC.B. ManevalD.C. JodrellD.I. FrostG.I. ShepardH.M. SkepperJ.N. TuvesonD.A. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.Gut201362111212010.1136/gutjnl‑2012‑302529 22466618
    [Google Scholar]
  6. JiangX. AbiatariI. KongB. ErkanM. De OliveiraT. GieseN.A. MichalskiC.W. FriessH. KleeffJ. ancreatic islet and stellate cells are the main sources of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 in pancreatic cancer, Pancreatology. Off.J. Int. Assoc. Pancreatol.20099165172
    [Google Scholar]
  7. SongY. WangJ. XuJ. GaoY. XuZ. Circ_0018909 knockdown inhibits the development of pancreatic cancer via the miR‐545‐3p/FASN axis and reduces macrophage polarization to M2.J. Biochem. Mol. Toxicol.2023374e2329310.1002/jbt.23293 36541402
    [Google Scholar]
  8. HabtezionA. EdderkaouiM. PandolS.J. Macrophages and pancreatic ductal adenocarcinoma.Cancer Lett.2016381121121610.1016/j.canlet.2015.11.049 26708507
    [Google Scholar]
  9. SenturkZ.N. AkdagI. DenizB. Sayi-YazganA. Pancreatic cancer: Emerging field of regulatory B-cell-targeted immunotherapies.Front. Immunol.202314115255110.3389/fimmu.2023.1152551 37033931
    [Google Scholar]
  10. ChenM.L. PittetM.J. GorelikL. FlavellR.A. WeisslederR. von BoehmerH. KhazaieK. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo .Proc. Natl. Acad. Sci. USA2005102241942410.1073/pnas.0408197102 15623559
    [Google Scholar]
  11. ChakkeraM. FooteJ.B. FarranB. NagarajuG.P. Breaking the stromal barrier in pancreatic cancer: Advances and challenges.Biochim. Biophys. Acta Rev. Cancer20241879118906510.1016/j.bbcan.2023.189065 38160899
    [Google Scholar]
  12. HenkeE. NandigamaR. ErgünS. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy.Front. Mol. Biosci.2020616010.3389/fmolb.2019.00160 32118030
    [Google Scholar]
  13. HoseinA.N. BrekkenR.A. MaitraA. Pancreatic cancer stroma: an update on therapeutic targeting strategies.Nat. Rev. Gastroenterol. Hepatol.202017848750510.1038/s41575‑020‑0300‑1 32393771
    [Google Scholar]
  14. WenigerM. HonselmannK. LissA. The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship.Cancers (Basel)201810931610.3390/cancers10090316 30200666
    [Google Scholar]
  15. ThomasD. RadhakrishnanP. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis.Mol. Cancer20191811410.1186/s12943‑018‑0927‑5 30665410
    [Google Scholar]
  16. LiangD. ShiS. XuJ. ZhangB. QinY. JiS. XuW. LiuJ. LiuL. LiuC. LongJ. NiQ. YuX. New insights into perineural invasion of pancreatic cancer: More than pain.Biochim. Biophys. Acta201618652111122 26794395
    [Google Scholar]
  17. TeffK.L. Visceral nerves: vagal and sympathetic innervation.JPEN J. Parenter. Enteral Nutr.200832556957110.1177/0148607108321705 18753395
    [Google Scholar]
  18. DeshmukhS.D. WillmannJ.K. JeffreyR.B. Pathways of extrapancreatic perineural invasion by pancreatic adenocarcinoma: evaluation with 3D volume-rendered MDCT imaging.AJR Am. J. Roentgenol.2010194366867410.2214/AJR.09.3285 20173143
    [Google Scholar]
  19. ChatterjeeD. KatzM.H. RashidA. WangH. IugaA.C. VaradhacharyG.R. WolffR.A. LeeJ.E. PistersP.W. CraneC.H. GomezH.F. AbbruzzeseJ.L. FlemingJ.B. WangH. Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma.Am. J. Surg. Pathol.201236340941710.1097/PAS.0b013e31824104c5 22301497
    [Google Scholar]
  20. XuW. LiuJ. ZhangJ. LuJ. GuoJ. Tumor microenvironment crosstalk between tumors and the nervous system in pancreatic cancer: Molecular mechanisms and clinical perspectives.Biochim. Biophys. Acta Rev. Cancer20241879118903210.1016/j.bbcan.2023.189032 38036106
    [Google Scholar]
  21. RenzB.W. TakahashiR. TanakaT. MacchiniM. HayakawaY. DantesZ. MaurerH.C. ChenX. JiangZ. WestphalenC.B. IlmerM. ValentiG. MohantaS.K. HabenichtA.J.R. MiddelhoffM. ChuT. NagarK. TailorY. CasadeiR. Di MarcoM. KleespiesA. FriedmanR.A. RemottiH. ReichertM. WorthleyD.L. NeumannJ. WernerJ. IugaA.C. OliveK.P. WangT.C. β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.Cancer Cell20183317590.e710.1016/j.ccell.2017.11.007 29249692
    [Google Scholar]
  22. SinhaS. FuY.Y. GrimontA. KetchamM. LafaroK. SaglimbeniJ.A. AskanG. BaileyJ.M. MelchorJ.P. ZhongY. JooM.G. Grbovic-HuezoO. YangI.H. BasturkO. BakerL. ParkY. KurtzR.C. TuvesonD. LeachS.D. PasrichaP.J. PanI.N. PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk.Cancer Res.20177781868187910.1158/0008‑5472.CAN‑16‑0899 28386018
    [Google Scholar]
  23. FlammigerA. BinderM. The role of T-cell phenotype and T-cell receptor rearrangement in the diagnosis of T-cell malignancies: author’s reply.Leuk. Lymphoma20155612345510.3109/10428194.2015.1050667 25971906
    [Google Scholar]
  24. SalomanJ.L. AlbersK.M. LiD. HartmanD.J. CrawfordH.C. MuhaE.A. RhimA.D. DavisB.M. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.Proc. Natl. Acad. Sci. USA2016113113078308310.1073/pnas.1512603113 26929329
    [Google Scholar]
  25. WhiteR.A. WangT.C. Nerves on tr[ac]k to support pancreatic cancer metabolism.Cell Res.202131438138210.1038/s41422‑020‑00462‑w 33536521
    [Google Scholar]
  26. RenzB.W. TanakaT. SunagawaM. TakahashiR. JiangZ. MacchiniM. DantesZ. ValentiG. WhiteR.A. MiddelhoffM.A. IlmerM. ObersteinP.E. AngeleM.K. DengH. HayakawaY. WestphalenC.B. WernerJ. RemottiH. ReichertM. TailorY.H. NagarK. FriedmanR.A. IugaA.C. OliveK.P. WangT.C. Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness.Cancer Discov.20188111458147310.1158/2159‑8290.CD‑18‑0046 30185628
    [Google Scholar]
  27. ParteckeL.I. KädingA. TrungD.N. DiedrichS. SendlerM. WeissF. KühnJ.P. MayerleJ. BeyerK. von BernstorffW. HeideckeC.D. KeßlerW. Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFα in a murine pancreatic cancer model.Oncotarget2017814225012251210.18632/oncotarget.15019 28160574
    [Google Scholar]
  28. RibattiD. CrivellatoE. Mast cells, angiogenesis and cancer.Adv. Exp. Med. Biol.201171627028810.1007/978‑1‑4419‑9533‑9_14 21713661
    [Google Scholar]
  29. OverallC.M. KleifeldO. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.Nat. Rev. Cancer20066322723910.1038/nrc1821 16498445
    [Google Scholar]
  30. MengL. LiuB. JiR. JiangX. YanX. XinY. Targeting the BDNF/TrkB pathway for the treatment of tumors.Oncol. Lett.201917220312039 30675270
    [Google Scholar]
  31. TakahashiR. IjichiH. FujishiroM. The role of neural signaling in the pancreatic cancer microenvironment.Cancers202214174269
    [Google Scholar]
  32. KamiyaA. HiyamaT. FujimuraA. YoshikawaS. Sympathetic and parasympathetic innervation in cancer: Therapeutic implications. Clinic. autonomic res. off. j. Clinic.Autonomic Res. Soc.202131165178
    [Google Scholar]
  33. DemirI.E. FriessH. CeyhanG.O. Nerve-cancer interactions in the stromal biology of pancreatic cancer.Front. Physiol.201239710.3389/fphys.2012.00097 22529816
    [Google Scholar]
  34. ShweikiD. ItinA. SofferD. KeshetE. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.Nature1992359639884384510.1038/359843a0 1279431
    [Google Scholar]
  35. ZhangY. KiraneA. HuangH. SorrelleN.B. BurrowsF.J. DellingerM.T. BrekkenR.A. Cyclooxygenase-2 Inhibition Potentiates the Efficacy of Vascular Endothelial Growth Factor Blockade and Promotes an Immune Stimulatory Microenvironment in Preclinical Models of Pancreatic Cancer.Mol. Cancer Res.201917234835510.1158/1541‑7786.MCR‑18‑0427 30333153
    [Google Scholar]
  36. GruberR. PanayiotouR. NyeE. Spencer-DeneB. StampG. BehrensA. YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK–STAT3 Signaling.Gastroenterology2016151352653910.1053/j.gastro.2016.05.006 27215660
    [Google Scholar]
  37. RozengurtE. Sinnett-SmithJ. EiblG. Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival.Signal Transduct. Target. Ther.2018311110.1038/s41392‑017‑0005‑2 29682330
    [Google Scholar]
  38. StalneckerC.A. GroverK.R. EdwardsA.C. ColemanM.F. YangR. DeLibertyJ.M. PapkeB. GoodwinC.M. PierobonM. PetricoinE.F.III GautamP. WennerbergK. CoxA.D. DerC.J. HurstingS.D. BryantK.L. Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors.Cancer Res.202282458659810.1158/0008‑5472.CAN‑21‑1443 34921013
    [Google Scholar]
  39. KoshibaT. HosotaniR. MiyamotoY. IdaJ. TsujiS. NakajimaS. KawaguchiM. KobayashiH. DoiR. HoriT. FujiiN. ImamuraM. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression.Clin. Cancer Res.20006935303535 10999740
    [Google Scholar]
  40. MoriT. DoiR. KoizumiM. ToyodaE. ItoD. KamiK. MasuiT. FujimotoK. TamamuraH. HiramatsuK. FujiiN. ImamuraM. CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer.Mol. Cancer Ther.200431293710.1158/1535‑7163.29.3.1 14749473
    [Google Scholar]
  41. QinR. RenW. YaG. WangB. HeJ. RenS. JiangL. ZhaoS. Role of chemokines in the crosstalk between tumor and tumor-associated macrophages.Clin. Exp. Med.20222351359137310.1007/s10238‑022‑00888‑z 36173487
    [Google Scholar]
  42. OuyangH. GoreJ. DeitzS. KorcM. microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions.Oncogene201433384664467410.1038/onc.2013.405 24096486
    [Google Scholar]
  43. CaveD.D. Di GuidaM. CostaV. SevillanoM. FerranteL. HeeschenC. CoronaM. CucciardiA. LonardoE. TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation.Oncogene202039214271428510.1038/s41388‑020‑1289‑1 32291413
    [Google Scholar]
  44. YangX.P. LiuS.L. XuJ.F. CaoS.G. LiY. ZhouY.B. Pancreatic stellate cells increase pancreatic cancer cells invasion through the hepatocyte growth factor/c-Met/survivin regulated by P53/P21.Exp. Cell Res.20173571798710.1016/j.yexcr.2017.04.027 28461158
    [Google Scholar]
  45. BierieB. MosesH. TGF-β and cancer.Cytokine Growth Factor Rev.2006171-2294010.1016/j.cytogfr.2005.09.006 16289860
    [Google Scholar]
  46. MancinoM. StrizziL. WechselbergerC. WatanabeK. GonzalesM. HamadaS. NormannoN. SalomonD.S. BiancoC. Regulation of human cripto‐1 gene expression by TGF‐β1 and BMP‐4 in embryonal and colon cancer cells.J. Cell. Physiol.2008215119220310.1002/jcp.21301 17941089
    [Google Scholar]
  47. LevyL. HillC. Alterations in components of the TGF-β superfamily signaling pathways in human cancer.Cytokine Growth Factor Rev.2006171-2415810.1016/j.cytogfr.2005.09.009 16310402
    [Google Scholar]
  48. ChuX. YangY. TianX. Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs.Int. J. Mol. Sci.20222317951210.3390/ijms23179512 36076911
    [Google Scholar]
  49. LiX. ZhouJ. WangX. LiC. MaZ. WanQ. PengF. Pancreatic cancer and fibrosis: Targeting metabolic reprogramming and crosstalk of cancer-associated fibroblasts in the tumor microenvironment.Front. Immunol.202314115231210.3389/fimmu.2023.1152312 37033960
    [Google Scholar]
  50. ThakerP.H. HanL.Y. KamatA.A. ArevaloJ.M. TakahashiR. LuC. JenningsN.B. Armaiz-PenaG. BanksonJ.A. RavooriM. MerrittW.M. LinY.G. MangalaL.S. KimT.J. ColemanR.L. LandenC.N. LiY. FelixE. SanguinoA.M. NewmanR.A. LloydM. GershensonD.M. KundraV. Lopez-BeresteinG. LutgendorfS.K. ColeS.W. SoodA.K. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.Nat. Med.200612893994410.1038/nm1447 16862152
    [Google Scholar]
  51. LutgendorfS.K. ColeS. CostanzoE. BradleyS. CoffinJ. JabbariS. RainwaterK. RitchieJ.M. YangM. SoodA.K. Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines.Clin. Cancer Res.200391245144521 14555525
    [Google Scholar]
  52. PalmaC. Tachykinins and their receptors in human malignancies.Curr. Drug Targets2006781043105210.2174/138945006778019282 16918332
    [Google Scholar]
  53. MayordomoC. García-RecioS. AmetllerE. Fernández-NogueiraP. Pastor-ArroyoE.M. VinyalsL. CasasI. GascónP. AlmendroV. Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2.J. Cell. Physiol.201222741358136610.1002/jcp.22848 21604273
    [Google Scholar]
  54. MancinoM. AmetllerE. GascónP. AlmendroV. The neuronal influence on tumor progression.Biochim. Biophys. Acta201118162105118 21616127
    [Google Scholar]
  55. JiangJ. BaiJ. QinT. WangZ. HanL. NGF from pancreatic stellate cells induces pancreatic cancer proliferation and invasion by PI3K/AKT/GSK signal pathway.J. Cell. Mol. Med.202024105901591010.1111/jcmm.15265 32294802
    [Google Scholar]
  56. HanL. JiangJ. XueM. QinT. XiaoY. WuE. ShenX. MaQ. MaJ. Sonic hedgehog signaling pathway promotes pancreatic cancer pain via nerve growth factor.Reg. Anesth. Pain Med.202045213714410.1136/rapm‑2019‑100991 31792027
    [Google Scholar]
  57. BoillyB. FaulknerS. JoblingP. HondermarckH. Nerve Dependence: From Regeneration to Cancer.Cancer Cell201731334235410.1016/j.ccell.2017.02.005 28292437
    [Google Scholar]
  58. PundavelaJ. DemontY. JoblingP. LinczL.F. RoselliS. ThorneR.F. BondD. BradshawR.A. WalkerM.M. HondermarckH. ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer.Am. J. Pathol.2014184123156316210.1016/j.ajpath.2014.08.009 25285721
    [Google Scholar]
  59. PundavelaJ. RoselliS. FaulknerS. AttiaJ. ScottR.J. ThorneR.F. ForbesJ.F. BradshawR.A. WalkerM.M. JoblingP. HondermarckH. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer.Mol. Oncol.2015981626163510.1016/j.molonc.2015.05.001 26009480
    [Google Scholar]
  60. DobrenisK. GauthierL.R. BarrocaV. MagnonC. Granulocyte colony‐stimulating factor off‐target effect on nerve outgrowth promotes prostate cancer development.Int. J. Cancer2015136498298810.1002/ijc.29046 24975135
    [Google Scholar]
  61. WangK. DemirI.E. D’HaeseJ.G. TieftrunkE. KujundzicK. SchornS. XingB. KehlT. FriessH. CeyhanG.O. The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer.Carcinogenesis201435110311310.1093/carcin/bgt312 24067900
    [Google Scholar]
  62. BixbyJ.L. HarrisW.A. Molecular mechanisms of axon growth and guidance.Annu. Rev. Cell Biol.19917111715910.1146/annurev.cb.07.110191.001001 1687312
    [Google Scholar]
  63. KoziczakM. HolbroT. HynesN.E. Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins.Oncogene200423203501350810.1038/sj.onc.1207331 15116089
    [Google Scholar]
  64. Reis-FilhoJ.S. SimpsonP.T. TurnerN.C. LambrosM.B. JonesC. MackayA. GrigoriadisA. SarrioD. SavageK. DexterT. IravaniM. FenwickK. WeberB. HardissonD. SchmittF.C. PalaciosJ. LakhaniS.R. AshworthA. FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas.Clin. Cancer Res.200612226652666210.1158/1078‑0432.CCR‑06‑1164 17121884
    [Google Scholar]
  65. ShalabiS. BelayachiA. LarrivéeB. Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment.Front. Immunol.202415128462910.3389/fimmu.2024.1284629 38375479
    [Google Scholar]
  66. MagnonC. HallS.J. LinJ. XueX. GerberL. FreedlandS.J. FrenetteP.S. Autonomic nerve development contributes to prostate cancer progression.Science20133416142123636110.1126/science.1236361 23846904
    [Google Scholar]
  67. ZhaoC.M. HayakawaY. KodamaY. MuthupalaniS. WestphalenC.B. AndersenG.T. FlatbergA. JohannessenH. FriedmanR.A. RenzB.W. SandvikA.K. BeisvagV. TomitaH. HaraA. QuanteM. LiZ. GershonM.D. KanekoK. FoxJ.G. WangT.C. ChenD. Denervation suppresses gastric tumorigenesis.Sci. Transl. Med.20146250250ra11510.1126/scitranslmed.3009569 25143365
    [Google Scholar]
  68. ShiX. YoungC.D. ZhouH. WangX.J. Transforming Growth Factor-β Signaling in Fibrotic Diseases and Cancer-Associated Fibroblasts.Biomolecules20201012166610.3390/biom10121666 33322749
    [Google Scholar]
  69. MaoX. XuJ. WangW. LiangC. HuaJ. LiuJ. ZhangB. MengQ. YuX. ShiS. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.Mol. Cancer202120113110.1186/s12943‑021‑01428‑1 34635121
    [Google Scholar]
  70. BiffiG. OniT.E. SpielmanB. HaoY. ElyadaE. ParkY. PreallJ. TuvesonD.A. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.Cancer Discov.20199228230110.1158/2159‑8290.CD‑18‑0710 30366930
    [Google Scholar]
  71. BughdaR. DimouP. D’SouzaR.R. KlampatsaA. Fibroblast Activation Protein (FAP)-Targeted CAR-T Cells: Launching an Attack on Tumor Stroma.ImmunoTargets Ther.20211031332310.2147/ITT.S291767 34386436
    [Google Scholar]
  72. NajafiM. FarhoodB. MortezaeeK. Extracellular matrix (ECM) stiffness and degradation as cancer drivers.J. Cell. Biochem.201912032782279010.1002/jcb.27681 30321449
    [Google Scholar]
  73. MartinezJ.A. KobayashiM. KrishnanA. WebberC. ChristieK. GuoG. SinghV. ZochodneD.W. Intrinsic facilitation of adult peripheral nerve regeneration by the Sonic hedgehog morphogen.Exp. Neurol.201527149350510.1016/j.expneurol.2015.07.018 26210874
    [Google Scholar]
  74. GrotheC. MeisingerC. ClausP. In vivo expression and localization of the fibroblast growth factor system in the intact and lesioned rat peripheral nerve and spinal ganglia.J. Comp. Neurol.2001434334235710.1002/cne.1181 11331533
    [Google Scholar]
  75. ChouH.J. LaiD.M. HuangC.W. McLennanI.S. WangH.D. WangP.Y. BMP4 is a peripherally-derived factor for motor neurons and attenuates glutamate-induced excitotoxicity in vitro .PLoS One201383e5844110.1371/journal.pone.0058441 23472198
    [Google Scholar]
  76. ReussB. von Bohlen und HalbachO. Fibroblast growth factors and their receptors in the central nervous system.Cell Tissue Res.2003313213915710.1007/s00441‑003‑0756‑7 12845521
    [Google Scholar]
  77. MiarkaL. HauserC. HelmO. HoldhofD. BeckingerS. EgbertsJ.H. GundlachJ.P. LenkL. RahnS. MikulitsW. TrauzoldA. SebensS. The hepatic microenvironment and TRAIL-R2 Impact outgrowth of liver metastases in pancreatic cancer after surgical resection.201911745
    [Google Scholar]
  78. SeikeT. FujitaK. YamakawaY. KidoM.A. TakiguchiS. TeramotoN. IguchiH. NodaM. Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis.Clin. Exp. Metastasis2011281132510.1007/s10585‑010‑9354‑8 20953899
    [Google Scholar]
  79. ZhangY. HeH. HeL. ShiB. IL-6 Accelerates the Proliferation and Metastasis of Pancreatic Cancer Cells via the miR-455-5p/IGF-1R Axis.Cancer Biother. Radiopharm.2022 36595346
    [Google Scholar]
  80. KarneviE. AnderssonR. RosendahlA.H. Tumour‐educated macrophages display a mixed polarisation and enhance pancreatic cancer cell invasion.Immunol. Cell Biol.201492654355210.1038/icb.2014.22 24662521
    [Google Scholar]
  81. CharlesN.A. HollandE.C. GilbertsonR. GlassR. KettenmannH. The brain tumor microenvironment.Glia20115981169118010.1002/glia.21136 21446047
    [Google Scholar]
  82. OlsonP. ChuG.C. PerryS.R. Nolan-StevauxO. HanahanD. Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma.Proc. Natl. Acad. Sci.2011108E1275E128410.1073/pnas.1111079108 22084065
    [Google Scholar]
  83. MizukamiY. Bone marrow-derived proangiogenic cells in pancreatic cancer.J. Gastroenterol. Hepatol.201227232610.1111/j.1440‑1746.2011.07012 22320912
    [Google Scholar]
  84. EguchiS. KimuraK. KageyamaK. TaniN. TanakaR. NishioK. ShinkawaH. OhiraG. AmanoR. TanakaS. YamamotoA. TakemuraS. YashiroM. KuboS. Optimal Organ for Patient-derived Xenograft Model in Pancreatic Cancer and Microenvironment that Contributes to Success.Anticancer Res.20224252395240410.21873/anticanres.15718 35489770
    [Google Scholar]
  85. ChenM.L. YuanT.T. ChuangC.F. HuangY.T. ChungI.C. HuangW.C. A Novel Enolase-1 Antibody Targets Multiple Interacting Players in the Tumor Microenvironment of Advanced Prostate Cancer.Mol. Cancer Ther.20222181337134710.1158/1535‑7163.MCT‑21‑0285 35700013
    [Google Scholar]
  86. PotoR. CristinzianoL. ModestinoL. de PaulisA. MaroneG. LoffredoS. GaldieroM.R. VarricchiG. Neutrophil Extracellular Traps, Angiogenesis and Cancer.Biomedicines202210243110.3390/biomedicines10020431 35203640
    [Google Scholar]
  87. LinX. QiuW. XiaoY. MaJ. XuF. ZhangK. GaoY. ChenQ. LiY. LiH. QianA. MiR-199b-5p Suppresses Tumor Angiogenesis Mediated by Vascular Endothelial Cells in Breast Cancer by Targeting ALK1.Front. Genet.202010139710.3389/fgene.2019.01397 32082362
    [Google Scholar]
  88. OstapoffK.T. AwasthiN. Kutluk CenikB. HinzS. DredgeK. SchwarzR.E. BrekkenR.A. PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer.Mol. Cancer Ther.20131271190120110.1158/1535‑7163.MCT‑12‑1123 23696215
    [Google Scholar]
  89. SzymuraS. ChaS. WangL. ZhangT. DongZ. AndersonA. OhE. WangZ. LeeV. ParshotthamS. RaoS. OlsemJ.B. CrumptonB.N. LeeH.C. ManasanchE.E. NeelapuS.S. ThomasS.K. KwakL.W. Early Intervention and Favorable Biologic Effects of Personalized Neoantigen Vaccines on the Tumor Immune Microenvironment in Smoldering Waldenstrom Macroglobulinemia.Blood2023142Suppl. 121221210.1182/blood‑2023‑182448
    [Google Scholar]
  90. BaruchE.N. NagarajanP. Gleber-NettoF.O. RaoX. XieT. AkhterS. AdewaleA. ShajedulI. MattsonB.J. FerrarottoR. WongM.K. DaviesM.A. JindalS. BasuS. HarwoodC. LeighI. AjamiN. FutrealA. CastilloM. GunaratneP. GoepfertR.P. KhushalaniN. WangJ. WatowichS. CalinG.A. MigdenM.R. VermeerP. D’SilvaN. YanivD. BurksJ.K. GomezJ. DoughertyP.M. TsaiK.Y. AllisonJ.P. SharmaP. WargoJ. MyersJ.N. GrossN.D. AmitM. Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by interleukin-6 blockadeResearch square2023
    [Google Scholar]
  91. Villalobos-AyalaK. LaverdeV. PermuthJ. KerrW. MalafaM. YatesC. GhansahT. Abstract C043: SHIP-1: Therapeutic target to reduce health disparities in African Americans with pancreatic cancer.Cancer Epidemiol. Biomarkers Prev.20233212_SupplementC043C04310.1158/1538‑7755.DISP23‑C043
    [Google Scholar]
  92. MarkosyanN. KimI.K. AroraC. QuinonesL. ChengN. StangerB.Z. VonderheideR.H. Abstract B033: Tumor cell-intrinsic mPGES-1-PGE2-EP4 signaling is a major immunosuppressive pathway in pancreatic cancer.Cancer Res.2024842_SupplementB033B03310.1158/1538‑7445.PANCA2023‑B033
    [Google Scholar]
  93. ZhuL. LiJ. GuoZ. KwokH.F. ZhaoQ. Synergistic combination of targeted nano-nuclear-reactors and anti-PD-L1 nanobodies evokes persistent T cell immune activation for cancer immunotherapy.J. Nanobiotechnology202220152110.1186/s12951‑022‑01736‑8 36496381
    [Google Scholar]
  94. BahwalS.A. ChenJ.J. eL. HaoT. ChenJ. CarruthersV.B. LaiJ. ZhouX. Attenuated Toxoplasma gondii enhances the antitumor efficacy of anti-PD1 antibody by altering the tumor microenvironment in a pancreatic cancer mouse model.J. Cancer Res. Clin. Oncol.2022148102743275710.1007/s00432‑022‑04036‑8 35556163
    [Google Scholar]
  95. ZhangB. LiuJ. LiH. HuangB. ZhangB. SongB. BaoC. LiuY. WangZ. Integrated multi-omics identified the novel intratumor microbiome-derived subtypes and signature to predict the outcome, tumor microenvironment heterogeneity, and immunotherapy response for pancreatic cancer patients.Front. Pharmacol.202314124475210.3389/fphar.2023.1244752 37745080
    [Google Scholar]
  96. LinC.Y. HuangK.Y. KaoS.H. LinM.S. LinC.C. YangS.C. ChungW.C. ChangY.H. CheinR.J. YangP.C. Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response.Sci. Adv.20239eade994410.1126/sciadv.ade9944 37027467
    [Google Scholar]
  97. LinJ. LuF. WuY. HuangH. PanY. The cellular trajectories of tumor-associated macrophages decipher the heterogeneity of pancreatic cancer.Funct. Integr. Genomics202323434310.1007/s10142‑023‑01266‑y 37991591
    [Google Scholar]
  98. LeJ. GaoH. LeY. RichardsW. RadigS. BledayR. ClancyT. ZhuZ. Abstract 5111: VentX-modulated tumor associated macrophages revert immune suppression in tumor microenvironment and promote efficacy of gemcitabine against pancreatic cancer.Cancer Res.2023837_Supplement5111511110.1158/1538‑7445.AM2023‑5111
    [Google Scholar]
  99. HosonumaM. YoshimuraK. Association between pH regulation of the tumor microenvironment and immunological state.Front. Oncol.202313117556310.3389/fonc.2023.1175563 37492477
    [Google Scholar]
  100. YiJ. LinY. YicongW. ChengyanL. ShulinZ. WenjunC. Effect of macrophages on biological function of ovarian cancer cells in tumor microenvironment in vitro .Arch. Gynecol. Obstet.202030241009101710.1007/s00404‑020‑05719‑8 32748054
    [Google Scholar]
  101. WangZ. WangS. JiaZ. HuY. CaoD. YangM. LiuL. GaoL. QiuS. YanW. LiY. LuoJ. GengY. ZhangJ. LiZ. WangX. LiM. ShaoR. LiuY. YKL-40 derived from infiltrating macrophages cooperates with GDF15 to establish an immune suppressive microenvironment in gallbladder cancer.Cancer Lett.202356321618410.1016/j.canlet.2023.216184 37088328
    [Google Scholar]
  102. ChenS. WangM. LuT. LiuY. HongW. HeX. ChengY. LiuJ. WeiY. WeiX. JMJD6 in tumor-associated macrophage regulates macrophage polarization and cancer progression via STAT3/IL-10 axis.Oncogene202342372737275010.1038/s41388‑023‑02781‑9 37567973
    [Google Scholar]
  103. WangX. SembaT. ManyamG.C. WangJ. ShaoS. BertucciF. FinettiP. KrishnamurthyS. PhiL.T. PearsonT. BurksJ.K. CohenE.N. ReubenJ.M. YangF. MinH. NavinN. IwaseT. ShenY. ZhangX. TripathyD. UenoN.T. Abstract PD10-08: Remodeling the inflammatory breast cancer tumor microenvironment to enhance immunotherapy: Novel therapeutic development.Cancer Res.202282PD10PD0810.1158/1538‑7445.SABCS21‑PD10‑08
    [Google Scholar]
  104. YamaguchiK. FujiiE. MitsunagaS. SawadaN. IkedaM. FujitomoT. MizunoH. KayukawaY. MakikawaM. AokiK. ImaokaH. SasakiM. WatanabeK. KatoA. TsunodaH. TeraoK. OchiaiA. Abstract 6145: Increased PD-L1 expression levels were observed on both tumor cells and macrophages by tocilizumab plus gemcitabine/nab-paclitaxel treatment in gemcitabine/nab-paclitaxel-refractory metastatic pancreatic cancer patients.Cancer Res.20228212_Supplement6145614510.1158/1538‑7445.AM2022‑6145
    [Google Scholar]
  105. ParkJ.E. KooJ. LeeH.K. KimT.H. Abstract 1448: Combination therapy of anti-sense oligonucleotide targeting TGF-beta2 (TASO) and IL-2 (Proleukin) has anti-cancer effect in solid cancer.Cancer Res.20218113_Supplement1448144810.1158/1538‑7445.AM2021‑1448
    [Google Scholar]
  106. ConiglioS.J. EugeninE. DobrenisK. StanleyE.R. WestB.L. SymonsM.H. SegallJ.E. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling.Mol. Med.201218351952710.2119/molmed.2011.00217 22294205
    [Google Scholar]
  107. WattersJ.J. SchartnerJ.M. BadieB. Microglia function in brain tumors.J. Neurosci. Res.200581344745510.1002/jnr.20485 15959903
    [Google Scholar]
  108. LiW. GraeberM.B. The molecular profile of microglia under the influence of glioma.Neuro-oncol.201214895897810.1093/neuonc/nos116 22573310
    [Google Scholar]
  109. WesolowskaA. KwiatkowskaA. SlomnickiL. DembinskiM. MasterA. SliwaM. FranciszkiewiczK. ChouaibS. KaminskaB. Microglia-derived TGF-β as an important regulator of glioblastoma invasion—an inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor.Oncogene200827791893010.1038/sj.onc.1210683 17684491
    [Google Scholar]
  110. ZhengY. RenS. ZhangY. LiuS. MengL. LiuF. GuL. AiN. SangM. Circular RNA circWWC3 augments breast cancer progression through promoting M2 macrophage polarization and tumor immune escape via regulating the expression and secretion of IL-4.Cancer Cell Int.202222126410.1186/s12935‑022‑02686‑9 35996149
    [Google Scholar]
  111. LiuW. LongQ. ZhangW. ZengD. HuB. LiuS. ChenL. miRNA-221-3p derived from M2-polarized tumor-associated macrophage exosomes aggravates the growth and metastasis of osteosarcoma through SOCS3/JAK2/STAT3 axis.Aging (Albany NY)20211315197601977510.18632/aging.203388 34388111
    [Google Scholar]
  112. HanH. DingG. WangS. MengJ. LvY. YangW. ZhangH. WenX. ZhaoW. Long Non-Coding, RNA Long non-coding RNA LOC339059 attenuates il-6/stat3-signaling-mediated pdl1 expression and macrophage m2 polarization by interacting with c-myc in gastric cancer.Cancers202315531310.3390/cancers15225313 38001573
    [Google Scholar]
  113. MormileR. Leukocyte Telomere Length and Pancreatic Cancer Survival: a Consequence of Activation of IL-6 Signaling Pathway in the Carcinogenic Process?J. Gastrointest. Cancer202051272072110.1007/s12029‑020‑00364‑5 31975049
    [Google Scholar]
  114. LiuX. HuangfuY. WangJ. KongP. TianW. LiuP. FangC. LiS. NieY. FengZ. HuangP. ShiS. ZhangC. DongA. WangW. Supramolecular polymer-nanomedicine hydrogel loaded with tumor associated macrophage-reprogramming polyTLR7/8a nanoregulator for enhanced anti-angiogenesis therapy of orthotopic hepatocellular carcinoma.Adv. Sci.202310e2300637
    [Google Scholar]
  115. WangL. GuoW. GuanH. YanN. CaiX. ZhuL. Tramadol suppresses growth of orthotopic liver tumors via promoting M1 macrophage polarization in the tumor microenvironment.Naunyn Schmiedebergs Arch. Pharmacol.2023 38041778
    [Google Scholar]
  116. SongS. ZhaoY. WangX. TongX. ChenX. XiongQ. M2 macrophages-derived exosomal miR-3917 promotes the progression of lung cancer via targeting GRK6.Biol. Chem.2023404415710.1515/hsz‑2022‑0162 36261031
    [Google Scholar]
  117. YangX. LinJ. WangG. XuD. Targeting proliferating tumor-infiltrating macrophages facilitates spatial redistribution of CD8+ T cells in pancreatic cancer.Cancers202214147410.3390/cancers14061474 35326625
    [Google Scholar]
  118. CavelO. ShomronO. ShabtayA. VitalJ. Trejo-LeiderL. WeizmanN. KrelinY. FongY. WongR.J. AmitM. GilZ. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor.Cancer Res.201272225733574310.1158/0008‑5472.CAN‑12‑0764 22971345
    [Google Scholar]
  119. SchwartzM. ZhangY. RosenblattJ.D. B cell regulation of the anti-tumor response and role in carcinogenesis.J. Immunother. Cancer2016414010.1186/s40425‑016‑0145‑x 27437104
    [Google Scholar]
  120. OlkhanudP.B. DamdinsurenB. BodogaiM. GressR.E. SenR. WejkszaK. MalchinkhuuE. WerstoR.P. BiragynA. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells.Cancer Res.201171103505351510.1158/0008‑5472.CAN‑10‑4316 21444674
    [Google Scholar]
  121. FarhoodB. NajafiM. MortezaeeK. CD8 + cytotoxic T lymphocytes in cancer immunotherapy: A review.J. Cell. Physiol.201923468509852110.1002/jcp.27782 30520029
    [Google Scholar]
  122. BeattyG.L. PatersonY. IFN-γ-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4+ T cells requires tumor responsiveness to IFN-γ.J. Immunol.200116642276228210.4049/jimmunol.166.4.2276 11160282
    [Google Scholar]
  123. JorgovanovicD. SongM. WangL. ZhangY. Roles of IFN-γ in tumor progression and regression: a review.Biomark. Res.2020814910.1186/s40364‑020‑00228‑x 33005420
    [Google Scholar]
  124. JarnickiA.G. LysaghtJ. TodrykS. MillsK.H.G. Suppression of antitumor immunity by IL-10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells.J. Immunol.2006177289690410.4049/jimmunol.177.2.896 16818744
    [Google Scholar]
  125. HungK. HayashiR. Lafond-WalkerA. LowensteinC. PardollD. LevitskyH. The central role of CD4(+) T cells in the antitumor immune response.J. Exp. Med.1998188122357236810.1084/jem.188.12.2357 9858522
    [Google Scholar]
  126. NumasakiM. FukushiJ. OnoM. NarulaS.K. ZavodnyP.J. KudoT. RobbinsP.D. TaharaH. LotzeM.T. Interleukin-17 promotes angiogenesis and tumor growth.Blood200310172620262710.1182/blood‑2002‑05‑1461 12411307
    [Google Scholar]
  127. KonrathS.H. O’BrienE.H. HsingC. Changes in dispositional empathy in American college students over time: a meta-analysis, Personality and social psychology review: an official journal of the Society for Personality and Social Psychology.Inc201115180198
    [Google Scholar]
  128. PidalaJ. AnasettiC. JimH. Quality of life after allogeneic hematopoietic cell transplantation.Blood2009114171910.1182/blood‑2008‑10‑182592 19336756
    [Google Scholar]
  129. KangH.Y. KimH.J. ParkT.K. JeeS.H. NamC.M. ParkH.W. Economic burden of smoking in Korea.Tob. Control2003121374410.1136/tc.12.1.37 12612360
    [Google Scholar]
  130. PetersonB.S. ChoiH.A. HaoX. AmatJ.A. ZhuH. WhitemanR. LiuJ. XuD. BansalR. Morphologic features of the amygdala and hippocampus in children and adults with Tourette syndrome.Arch. Gen. Psychiatry200764111281129110.1001/archpsyc.64.11.1281 17984397
    [Google Scholar]
  131. HanQ. SangJ. FanX. WangX. ZengL. ZhangX. ZhangK. LiN. LvY. LiuZ. Association of LIN28B polymorphisms with chronic hepatitis B virus infection.Virol. J.20201718110.1186/s12985‑020‑01353‑7 32571380
    [Google Scholar]
  132. KramannR. SchneiderR.K. The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis.Blood2018131192111211910.1182/blood‑2018‑02‑834820 29572380
    [Google Scholar]
  133. KlempanT.A. ErnstC. DelevaV. LabonteB. TureckiG. Characterization of QKI gene expression, genetics, and epigenetics in suicide victims with major depressive disorder.Biol. Psychiatry200966982483110.1016/j.biopsych.2009.05.010 19545858
    [Google Scholar]
  134. JhaB. GajendraS. Histoplasma capsulatum in a peripheral blood smear in a non-HIV patient.Ann. Hematol.201796470971010.1007/s00277‑016‑2906‑5 28011982
    [Google Scholar]
  135. LajiliS. DeghrigueM. Bel Haj AmorH. MullerC.D. BouraouiA. In vitro immunomodulatory activity and in vivo anti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red alga Laurencia obtusa.Pharm. Biol.201654112486249510.3109/13880209.2016.1160937 27096253
    [Google Scholar]
  136. ChenS.J. ChungJ.G. ChungY.C. ChouS.T. In vitro antioxidant and antiproliferative activity of the stem extracts from Graptopetalum paraguayense.Am. J. Chin. Med.200836236938310.1142/S0192415X08005837 18457367
    [Google Scholar]
  137. HilsenrothM.J. Incoming editorial: Bigger, purple, pragmatic, and parsimony.Psychotherapy (Chic.)20114811310.1037/a0022236 21401267
    [Google Scholar]
  138. GrakouiA. ShoukryN.H. WoollardD.J. HanJ.H. HansonH.L. GhrayebJ. MurthyK.K. RiceC.M. WalkerC.M. HCV persistence and immune evasion in the absence of memory T cell help.Science2003302564565966210.1126/science.1088774 14576438
    [Google Scholar]
  139. Landers-RamosR.Q. SappR.M. VandeWaterE. MackoJ. RobinsonS. WangY. ChinE.R. SpangenburgE.E. PriorS.J. HagbergJ.M. Investigating the extremes of the continuum of paracrine functions in CD34 −/CD31 + CACs across diverse populations.Am. J. Physiol. Heart Circ. Physiol.20173121H162H17210.1152/ajpheart.00342.2016 27793853
    [Google Scholar]
  140. McLellanJ.S. RayW.C. PeeplesM.E. Structure and function of respiratory syncytial virus surface glycoproteins.Curr. Top. Microbiol. Immunol.20133728310410.1007/978‑3‑642‑38919‑1_4 24362685
    [Google Scholar]
  141. TadićB. MijatovićS. JanićevićS. SpasojevićD. RodgersG.J. The critical Barkhausen avalanches in thin random-field ferromagnets with an open boundary.Sci. Rep.201991634010.1038/s41598‑019‑42802‑w 31004121
    [Google Scholar]
  142. RaghavK.P.S. BlumenscheinG.R. Jr Motesanib and advanced NSCLC: experiences and expectations.Expert Opin. Investig. Drugs201120685986910.1517/13543784.2011.579103 21534718
    [Google Scholar]
  143. BellesoeurA. CartonE. AlexandreJ. GoldwasserF. HuillardO. Axitinib in the treatment of renal cell carcinoma: design, development, and place in therapy.Drug Des. Devel. Ther.2017112801281110.2147/DDDT.S109640 29033542
    [Google Scholar]
  144. MorabitoA. PiccirilloM.C. CostanzoR. SandomenicoC. CarillioG. DanieleG. GiordanoP. BryceJ. CarotenutoP. La RoccaA. Di MaioM. NormannoN. RoccoG. PerroneF. Vandetanib: An overview of its clinical development in NSCLC and other tumors, Drugs of today.Drugs Today20104668369810.1358/dot.2010.46.9.1516989 20967300
    [Google Scholar]
  145. GanH.K. SerugaB. KnoxJ.J. Sunitinib in solid tumors.Expert Opin. Investig. Drugs200918682183410.1517/13543780902980171 19453268
    [Google Scholar]
  146. DietrichJ. WangD. BatchelorT.T. Cediranib: profile of a novel anti-angiogenic agent in patients with glioblastoma.Expert Opin. Investig. Drugs200918101549155710.1517/13543780903183528 19671039
    [Google Scholar]
  147. KeatingG.M. SantoroA. Sorafenib.Drugs200969222324010.2165/00003495‑200969020‑00006 19228077
    [Google Scholar]
  148. ScottE.N. MeinhardtG. JacquesC. LaurentD. ThomasA.L. Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours.Expert Opin. Investig. Drugs200716336737910.1517/13543784.16.3.367 17302531
    [Google Scholar]
  149. SloanB. ScheinfeldN.S. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy.Curr. Opin. Investig. Drugs2008913241335 19037839
    [Google Scholar]
  150. KeatingG.M. Bevacizumab: a review of its use in advanced cancer.Drugs201474161891192510.1007/s40265‑014‑0302‑9 25315029
    [Google Scholar]
  151. PooleR.M. VaidyaA. Ramucirumab: first global approval.Drugs20147491047105810.1007/s40265‑014‑0244‑2 24916147
    [Google Scholar]
  152. GayaA. TseV. A preclinical and clinical review of aflibercept for the management of cancer.Cancer Treat. Rev.201238548449310.1016/j.ctrv.2011.12.008 22264850
    [Google Scholar]
  153. HakamadaK. Cancer stroma‐targeting therapy: A new tool for fighting pancreatic cancer?Ann. Gastroenterol. Surg.20193212012110.1002/ags3.12244 30923780
    [Google Scholar]
  154. YouG.H. WangY.J. ZhangL.Y. ZhangM. Research progression in neural invasion model of pancreatic cancer.Zhonghua Zhong Liu Za Zhi2020424346350 32375453
    [Google Scholar]
  155. RobatelS. SchenkM. Current limitations and novel perspectives in pancreatic cancer treatment.Cancers202214498510.3390/cancers14040985
    [Google Scholar]
  156. JiangS. FagmanJ.B. MaY. LiuJ. VihavC. EngstromC. LiuB. ChenC. A comprehensive review of pancreatic cancer and its therapeutic challenges.Aging (Albany NY)202214187635764910.18632/aging.204310 36173644
    [Google Scholar]
  157. SelvaggiF. MelchiorreE. CasariI. CinalliS. CinalliM. AcetoG.M. CotelleseR. GarajovaI. FalascaM. Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance.Cancers (Basel)20221423579310.3390/cancers14235793 36497277
    [Google Scholar]
  158. CarterE.P. CoetzeeA.S. Tomas BortE. WangQ. KocherH.M. GroseR.P. Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer.Cells202110484710.3390/cells10040847 33918004
    [Google Scholar]
  159. NguyenT.M. NgocD.T.M. ChoiJ.H. LeeC.H. Unveiling the Neural Environment in Cancer: Exploring the Role of Neural Circuit Players and Potential Therapeutic Strategies.Cells20231215199610.3390/cells12151996 37566075
    [Google Scholar]
  160. XieY. MuC. KazybayB. SunQ. KutzhanovaA. NazarbekG. XuN. NurtayL. WangQ. AminA. LiX. Network pharmacology and experimental investigation of Rhizoma polygonati extract targeted kinase with herbzyme activity for potent drug delivery.Drug Deliv.20212812187219710.1080/10717544.2021.1977422 34662244
    [Google Scholar]
  161. MuraliC. MudgilP. GanC.Y. TaraziH. El-AwadyR. AbdallaY. AminA. MaqsoodS. Camel whey protein hydrolysates induced G2/M cellcycle arrest in human colorectal carcinoma.Sci. Rep.2021111706210.1038/s41598‑021‑86391‑z 33782460
    [Google Scholar]
  162. AbdallaY. AbdallaA. HamzaA.A. AminA. Safranal Prevents Liver Cancer Through Inhibiting Oxidative Stress and Alleviating Inflammation.Front. Pharmacol.20221277750010.3389/fphar.2021.777500 35177980
    [Google Scholar]
  163. AbduS. JuaidN. AminA. MoulayM. MiledN. Effects of sorafenib and quercetin alone or in combination in treating hepatocellular carcinoma: In vitro and in vivo approaches.Molecules2022272210.3390/molecules27228082 36432184
    [Google Scholar]
  164. NelsonD.R. HroutA.A. AlzahmiA.S. ChaiboonchoeA. AminA. Salehi-AshtianiK. Molecular mechanisms behind safranal’s toxicity to HepG2 cells from dual omics.Antioxidants2022116112510.3390/antiox11061125 35740022
    [Google Scholar]
  165. Al-AkhrasM.A.H. AljarrahK. Al-KhateebH. JaradatA. Al-omariA. Al-NasserA. MasadehM.M. AminA. HamzaA. MohammedK. Al OlamaM. DaoudS. Introducing Cichorium Pumilum as a potential therapeutical agent against drug-induced benign breast tumor in rats.Electromagn. Biol. Med.201231429930910.3109/15368378.2012.662193 22812448
    [Google Scholar]
  166. AbdallaA. MuraliC. AminA. Safranal Inhibits Angiogenesis via Targeting HIF-1α/VEGF Machinery: In vitro and ex vivo insights.Front. Oncol.20221178917210.3389/fonc.2021.789172 35211395
    [Google Scholar]
  167. AbduS. JuaidN. AminA. MoulayM. MiledN. Therapeutic effects of crocin alone or in combination with sorafenib against hepatocellular carcinoma: In vivo and in vitro insights.Antioxidants2022119164510.3390/antiox11091645 36139719
    [Google Scholar]
  168. Al HroutA. Cervantes-GraciaK. ChahwanR. AminA. Modelling liver cancer microenvironment using a novel 3D culture system.Sci. Rep.2022121800310.1038/s41598‑022‑11641‑7 35568708
    [Google Scholar]
  169. Abdel-latifR. HeebaG.H. HassaninS.O. WazS. AminA. TLRs-JNK/NF-κB pathway underlies the protective effect of the sulfide salt against liver toxicity.Front. Pharmacol.20221385006610.3389/fphar.2022.850066 35517830
    [Google Scholar]
  170. BotrosS.R. MatoukA.I. AminA. HeebaG.H. Comparative effects of incretin-based therapy on doxorubicin-induced nephrotoxicity in rats: The role of SIRT1/Nrf2/NF-κB/TNF-α signaling pathways.Front. Pharmacol.202415135302910.3389/fphar.2024.1353029 38440177
    [Google Scholar]
  171. BouabdallahS. Al-MaktoumA. AminA. Steroidal saponins: Naturally occurring compounds as inhibitors of the hallmarks of cancer.Cancers20231515390010.3390/cancers15153900 37568716
    [Google Scholar]
  172. OthmanE.M. HabibH.A. ZahranM.E. AminA. HeebaG.H. Mechanistic protective effect of cilostazol in cisplatin-induced testicular damage via regulation of oxidative stress and TNF-α/NF-κB/Caspase-3 Pathways.Int. J. Mol. Sci.202324161265110.3390/ijms241612651 37628836
    [Google Scholar]
  173. HamzaA.A. HeebaG.H. HassaninS.O. ElwyH.M. BekhitA.A. AminA. Hibiscus-cisplatin combination treatment decreases liver toxicity in rats while increasing toxicity in lung cancer cells via oxidative stress- apoptosis pathway.Biomed. pharmacoth. Biomed. pharmacotherapie.2023165115148
    [Google Scholar]
  174. Safarzadeh KozaniP. Safarzadeh KozaniP. RahbarizadehF. Addressing the obstacles of CAR T cell migration in solid tumors: wishing a heavy traffic.Crit. Rev. Biotechnol.20224271079109810.1080/07388551.2021.1988509 34957875
    [Google Scholar]
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