# Hallmarks of perineural invasion in pancreatic ductal adenocarcinoma: new biological dimensions **Authors:** Yaquan Sun, Wei Jiang, Xiang Liao, Dongqing Wang PMC · DOI: 10.3389/fonc.2024.1421067 · Frontiers in Oncology · 2024-07-25 ## TL;DR This review explores perineural invasion in pancreatic cancer, its impact on prognosis, and new research directions. ## Contribution The paper provides a detailed overview of PNI mechanisms and highlights novel technologies for future investigation. ## Key findings - Perineural invasion is common in early PDAC and linked to poor outcomes. - PNI involves complex interactions between cancer cells, nerves, and the tumor environment. - New technologies are emphasized for better understanding and treatment of PNI in PDAC. ## Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor with a high metastatic potential. Perineural invasion (PNI) occurs in the early stages of PDAC with a high incidence rate and is directly associated with a poor prognosis. It involves close interaction among PDAC cells, nerves and the tumor microenvironment. In this review, we detailed discuss PNI-related pain, six specific steps of PNI, and treatment of PDAC with PNI and emphasize the importance of novel technologies for further investigation. ## Linked entities - **Diseases:** pancreatic ductal adenocarcinoma (MONDO:0005184) ## Full-text entities - **Genes:** Cdc42 (cell division cycle 42) [NCBI Gene 12540], SRC (SRC proto-oncogene, non-receptor tyrosine kinase) [NCBI Gene 6714] {aka ASV, SRC1, THC6, c-SRC, p60-Src}, Lag3 (lymphocyte-activation gene 3) [NCBI Gene 16768] {aka CD223, LAG-3, Ly66}, Cxcr4 (C-X-C motif chemokine receptor 4) [NCBI Gene 12767] {aka CD184, CXC-R4, CXCR-4, Cmkar4, LESTR, PB-CKR}, Artn (artemin) [NCBI Gene 11876] {aka neublastin}, Trpv1 (transient receptor potential cation channel, subfamily V, member 1) [NCBI Gene 193034] {aka OTRPC1, TRPV1alpha, TRPV1beta, VR-1, Vr1}, ZHX2 (zinc fingers and homeoboxes 2) [NCBI Gene 22882] {aka AFR1, RAF}, PIK3CG (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma) [NCBI Gene 5294] {aka IMD97, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma}, NGF (nerve growth factor) [NCBI Gene 4803] {aka Beta-NGF, HSAN5, NGFB}, ROBO1 (roundabout guidance receptor 1) [NCBI Gene 6091] {aka CPHD8, DUTT1, NORS, NYS8, SAX3}, Foxp3 (forkhead box P3) [NCBI Gene 20371] {aka JM2, scurfin, sf}, Mettl3 (methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit) [NCBI Gene 56335] {aka 2310024F18Rik, M6A, Spo8}, L1cam (L1 cell adhesion molecule) [NCBI Gene 16728] {aka CD171, L1, N-CAM-L1, NCAM-L1}, Ephb2 (Eph receptor B2) [NCBI Gene 13844] {aka Cek5, Drt, ETECK, Erk, Hek5, Nuk}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, SEMA3D (semaphorin 3D) [NCBI Gene 223117] {aka Sema-Z2, coll-2}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, KIF14 (kinesin family member 14) [NCBI Gene 9928] {aka MCPH20, MKS12}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, NODAL (nodal growth differentiation factor) [NCBI Gene 4838] {aka HTX5}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, LGALS1 (galectin 1) [NCBI Gene 3956] {aka GAL1, GBP}, CCR2 (C-C motif chemokine receptor 2) [NCBI Gene 729230] {aka CC-CKR-2, CCR-2, CCR2A, CCR2B, CD192, CKR2}, Kras (Kras proto-oncogene, GTPase) [NCBI Gene 16653] {aka K-Ras, K-Ras 2, K-ras, Ki-ras, Kras-2, Kras2}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, Calca (calcitonin/calcitonin-related polypeptide, alpha) [NCBI Gene 12310] {aka CA, CGRP-1, CGRP1, Calc, Calc1, Cgrp}, Pdcd1 (programmed cell death 1) [NCBI Gene 18566] {aka Ly101, PD-1, Pdc1}, PTK2 (protein tyrosine kinase 2) [NCBI Gene 5747] {aka FADK, FADK 1, FAK, FAK1, FRNK, PPP1R71}, SDC3 (syndecan 3) [NCBI Gene 9672] {aka SDCN, SYND3}, MAG (myelin associated glycoprotein) [NCBI Gene 4099] {aka GMA, S-MAG, SIGLEC-4A, SIGLEC4, SIGLEC4A, SPG75}, Adrb2 (adrenergic receptor, beta 2) [NCBI Gene 11555] {aka Adrb-2, Badm, Gpcr7}, MAP2K1 (mitogen-activated protein kinase kinase 1) [NCBI Gene 5604] {aka CFC3, MAPKK1, MEK1, MEL, MKK1, PRKMK1}, PTN (pleiotrophin) [NCBI Gene 5764] {aka HARP, HB-GAM, HBBM, HBGF-8, HBGF8, HBNF}, TRPV1 (transient receptor potential cation channel subfamily V member 1) [NCBI Gene 7442] {aka VR1}, KLRB1 (killer cell lectin like receptor B1) [NCBI Gene 3820] {aka CD161, CLEC5B, NKR, NKR-P1, NKR-P1A, NKRP1A}, GDNF (glial cell derived neurotrophic factor) [NCBI Gene 2668] {aka ATF, ATF1, ATF2, HFB1-GDNF, HSCR3}, ITGB1 (integrin subunit beta 1) [NCBI Gene 3688] {aka CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA}, SLIT2 (slit guidance ligand 2) [NCBI Gene 9353] {aka SLIL3, Slit-2}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, RET (ret proto-oncogene) [NCBI Gene 5979] {aka CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, MTC1}, CSF1 (colony stimulating factor 1) [NCBI Gene 1435] {aka CSF-1, MCSF, PG-M-CSF}, CX3CL1 (C-X3-C motif chemokine ligand 1) [NCBI Gene 6376] {aka ABCD-3, C3Xkine, CXC3, CXC3C, NTN, NTT}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, DCX (doublecortin) [NCBI Gene 1641] {aka DBCN, DC, LISX, SCLH, XLIS}, Mdk (midkine) [NCBI Gene 17242] {aka MK, Mek}, Ngf (nerve growth factor) [NCBI Gene 18049] {aka Ngfb, beta-NGF}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, HGF (hepatocyte growth factor) [NCBI Gene 3082] {aka DFNB39, F-TCF, HGFB, HPTA, SF}, ARHGDIB (Rho GDP dissociation inhibitor beta) [NCBI Gene 397] {aka D4, GDIA2, GDID4, LYGDI, Ly-GDI, RAP1GN1}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, NTRK1 (neurotrophic receptor tyrosine kinase 1) [NCBI Gene 4914] {aka MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA}, BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, CX3CR1 (C-X3-C motif chemokine receptor 1) [NCBI Gene 1524] {aka CCRL1, CMKBRL1, CMKDR1, GPR13, GPRV28, V28}, Ccl5 (C-C motif chemokine ligand 5) [NCBI Gene 20304] {aka MuRantes, RANTES, SISd, Scya5, TCP228}, NCAM1 (neural cell adhesion molecule 1) [NCBI Gene 4684] {aka CD56, MSK39, NCAM}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, GFRA3 (GDNF family receptor alpha 3) [NCBI Gene 2676] {aka GDNFR3}, Gfra3 (glial cell line derived neurotrophic factor family receptor alpha 3) [NCBI Gene 14587] {aka GFRalpha3} - **Diseases:** Pancreatic (MESH:D010195), bleeding (MESH:D006470), PNI (MESH:D052958), TAMs (MESH:D000072716), demyelination (MESH:D003711), peripheral nerve injury (MESH:D059348), hypoxia (MESH:D000860), mitochondrial function (MESH:D028361), prostate cancer (MESH:D011471), lung cancer (MESH:D008175), paralysis (MESH:D010243), emaciation (MESH:D004614), nerves (MESH:C537568), diarrhea (MESH:D003967), Cancer (MESH:D009369), sensory abnormalities (MESH:D012678), head and neck pancreatic cancer (MESH:D006258), melanoma (MESH:D008545), abdominal and back pain (MESH:D015746), Metastasis (MESH:D009362), fibrosis (MESH:D005355), inflammation (MESH:D007249), neuroinflammation (MESH:D000090862), death (MESH:D003643), nerve pain (MESH:D009437), colon cancer (MESH:D015179), Pain (MESH:D010146), nerve injury (MESH:D000080902), Pancreatic cancer (MESH:D010190), neurodegeneration (MESH:D019636), neurogenic inflammation (MESH:D020078), pancreatic neuroendocrine tumors (MESH:D018358), neurotoxic (MESH:D020258), PDAC (MESH:D021441), jaundice (MESH:D007565), numbness (MESH:D006987) - **Chemicals:** calcium (MESH:D002118), gemcitabine (MESH:D000093542), Glutamate (MESH:D018698), capsaicin (MESH:D002211), sodium (MESH:D012964), prostaglandin (MESH:D011453), lactate (MESH:D019344), lipid (MESH:D008055), epinephrine B2 (-), adrenaline (MESH:D004837), NE (MESH:D009638), polysialic acid (MESH:C021319), polysaccharide (MESH:D011134), ACh (MESH:D000109), RTX (MESH:C024353), HNK (MESH:C005499), Tanezumab (MESH:C549319), ARRY-470 (MESH:C000609083), serine (MESH:D012694), Magnolol (MESH:C005498), Catecholamine (MESH:D002395), N6-methyladenosine (MESH:C010223), m6A (MESH:C005955), DE (MESH:D004054), PHA-848125 (MESH:C550092), glycosaminoglycans (MESH:D006025), glucose (MESH:D005947), iodine-125 (MESH:C000614960), ethanol (MESH:D000431) - **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090] - **Cell lines:** Capan-2 — Homo sapiens (Human), Pancreatic ductal adenocarcinoma, Cancer cell line (CVCL_0026), MiaPACA2 — Homo sapiens (Human), Pancreatic undifferentiated carcinoma, Cancer cell line (CVCL_0428), DU-145 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0105), PANC1 — Homo sapiens (Human), Pancreatic ductal adenocarcinoma, Cancer cell line (CVCL_0480), T3M4 — Homo sapiens (Human), Pancreatic ductal adenocarcinoma, Cancer cell line (CVCL_4056), ASPC1 — Homo sapiens (Human), Pancreatic ductal adenocarcinoma, Cancer cell line (CVCL_0152) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC11307098/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC11307098/full.md ## References 150 references — full list in the complete paper: https://tomesphere.com/paper/PMC11307098/full.md --- Source: https://tomesphere.com/paper/PMC11307098