Lub Nervous System: Orchestra Conductor hauv Cancer, Regeneration, Inflammation and Immunity
May 15, 2023
Abstract
Txawm hais tias lub luag haujlwm ntawm cov hlab ntsha hauv stimulating cellular kev loj hlob thiab kev nthuav tawm tau ntev tau piav nyob rau hauv cov ntaub so ntswg regeneration cov kev tshawb fawb txog rau thaum tsis ntev los no ib tug zoo xws li cov trophic muaj nuj nqi ntawm paj hlwb nyob rau hauv cov kab mob twb tsis pom zoo. Txawm li cas los xij, kev tshawb fawb tsis ntev los no hauv oncology tau pom tias kev loj hlob thiab kev nthuav tawm ntawm cov qog nqaij hlav kuj xav tau kev nkag mus ntawm cov hlab ntsha hauv cov qog microenvironment. Cov paj hlwb tsim ntau yam neuro signaling pathways, uas orchestrate pib mob qog noj ntshav, kev loj hlob, thiab metastases.
Ib yam li ntawd, cov hlab ntsha tau nce ntxiv hauv lawv cov kev tswj hwm kev ua haujlwm hauv kev tiv thaiv kab mob thiab mob. Lub luag haujlwm orchestrator ntawm cov hlab ntsha hauv cellular thiab molecular kev sib cuam tshuam thaum lub sij hawm rov tsim dua tshiab, mob qog noj ntshav, tiv thaiv kab mob, thiab o muaj peev xwm tshiab rau kev tsom lossis txhim kho neuro signaling hauv tib neeg kev noj qab haus huv thiab kab mob.
Kev sib raug zoo ntawm kev loj hlob ntawm tes thiab kev tiv thaiv kab mob yog ze heev. Lub cev tiv thaiv kab mob yuav tsum muaj kev loj hlob ntawm tes thiab sib txawv los tsim cov kab mob tiv thaiv kab mob uas tawm tsam cov kab mob txawv teb chaws. Thaum lub cev tau txais kev tiv thaiv kab mob los ntawm cov stimuli sab nraud, lub cev tiv thaiv kab mob xws li T hlwb, B hlwb, thiab macrophages yuav tsum tau sib npaug thiab nthuav tawm sai sai los tawm tsam cov kab mob hauv lub sijhawm. Kev loj hlob ntawm tes yog tswj hwm los ntawm ntau yam, suav nrog kev noj zaub mov, yam tseem ceeb ntawm kev loj hlob, kev taw qhia txoj hauv kev, thiab lwm yam. Cov khoom no kuj muaj qhov cuam tshuam ncaj qha lossis tsis ncaj rau kev loj hlob thiab kev loj hlob ntawm lub cev tiv thaiv kab mob. Piv txwv li, qee yam kev loj hlob xws li epidermal growth factor (EGF), fibroblast growth factor (FGF), thiab lwm yam, tuaj yeem txhawb kev loj hlob ntawm tes thiab kev loj hlob. Tsis tas li ntawd, qee cov cytokines (xws li interleukins, interferons, thiab lwm yam) tuaj yeem ua kom muaj kev loj hlob thiab kev sib txawv ntawm lub cev tiv thaiv kab mob.
Yog li ntawd, kev loj hlob ntawm tes thiab kev tiv thaiv kab mob cuam tshuam rau ib leeg, thiab kev tswj hwm ntawm kev loj hlob ntawm tes ua lub luag haujlwm tseem ceeb hauv kev ua tiav lossis tsis ua tiav ntawm kev tiv thaiv kab mob, kev ceev thiab kev ua haujlwm ntawm cov kab mob tshem tawm, thiab lwm yam. Los ntawm qhov kev xav no, peb txoj kev tiv thaiv tib neeg tseem ceeb heev, yog li peb yuav tsum txhim kho peb txoj kev tiv thaiv. Cistanche muaj txiaj ntsig zoo rau kev txhim kho kev tiv thaiv. Cistanche muaj ntau yam khoom siv roj ntsha, xws li polysaccharides, ob lub nceb, Huangli, thiab lwm yam, cov khoom xyaw no tuaj yeem txhawb nqa ntau lub hlwb ntawm lub cev tiv thaiv kab mob thiab ua kom lawv lub cev tiv thaiv kab mob.
Nyem qhov txiaj ntsig kev noj qab haus huv ntawm cistanche
KEYWORDS
mob qog noj ntshav, tiv thaiv kab mob, mob, paj hlwb, paj hlwb, thiab kev tsim dua tshiab.
1|Taw qhia
Lub paj hlwb peripheral (PNS) muaj cov hlab ntsha sab nraud ntawm lub hauv nruab nrab lub paj hlwb (CNS), suav nrog cov hlab ntsha uas xaiv cranial, cov hauv paus hniav txha caj qaum, kev hnov lus thiab autonomic ganglia, somatic nerves, thiab neuromuscular junctions. Lub luag haujlwm ntawm PNS tau xav tias yuav txwv tsis pub ntau lub luag haujlwm tseem ceeb, suav nrog kev tswj hwm ntawm cov leeg nqaij striated, kev xa cov ntaub ntawv tsis pom kev rau CNS, thiab kev tswj hwm kev ua haujlwm. Cov hlab ntsha peripheral kuj tau pom zoo hauv kev raug mob thiab kab mob. Kev lig kev cai, peripheral paj tsis ua haujlwm suav nrog peripheral neuropathies, peripheral paj raug mob, thiab neuromuscular teeb meem, xws li amyotrophic lateral sclerosis, muscular dystrophy, myasthenia gravis, thiab spinal muscular atrophy.
Nyob rau hauv xyoo tas los no, thaj tsam ntawm mob qog noj ntshav neuroscience tau tshwm sim thiab tau hais txog lub luag haujlwm ntawm cov hlab ntsha tshaj li cov kab mob peripheral paj hlwb thiab rau ntau yam ntawm cov kab mob hauv nruab nrog cev.1,2Nerves tau tshwm sim los ua kev txhawb nqa kev loj hlob thiab kev nthuav tawm thiab txawm tias lawv cov txheej txheem ntawm kev txiav txim siab xav tau. kom paub meej, cov paj hlwb tshwm sim los txhawb ntau yam kev taw qhia txoj hauv kev hauv cov qog nqaij hlav qog noj ntshav thiab lwm cov cellular Cheebtsam ntawm cov qog microenvironment (TME). nrog cov hlab ntsha thiab cov qog innervation, uas tam sim no yuav tsum tau suav hais tias yog ib qho cim ntawm kev mob qog noj ntshav.3 Ntau qhov dav, cov paj hlwb tau piav qhia ntau ntxiv rau lawv cov kev tswj hwm hauv kev tiv thaiv kab mob thiab mob. Cov kab mob los ntawm cov kab mob plab hnyuv inflammatory 4 mus rau endometriosis 5 muaj posited neural etiologies, tsawg kawg yog ib feem. Interestingly, lub luag hauj lwm ntawm cov hlab ntsha nyob rau hauv stimulating cellular loj hlob thiab kev nthuav tawm tau ntev tau txuam nrog cov tsiaj regeneration, qhov twg cov hlab ntsha yog tsim nyog rau lub reconstitution ntawm poob lub cev qhov chaw, 6 thiab tsis ntev los no extension ntawm lub tswv yim ntawm paj dependence los ntawm regeneration rau mob qog noj ntshav thiab tiv thaiv kab mob. ib qho tseem ceeb heev.7
Hauv qhov kev tshuaj xyuas no, peb tsom ntsoov muab qhov kev xav ntawm exonerate biology thiab lub luag haujlwm ntawm cov hlab ntsha sab nraud ntawm lub paj hlwb hauv kev noj qab haus huv thiab kab mob. Peb yuav xub qhia txog cov kev paub tam sim no txog cov paj hlwb nyob hauv kev tsim dua tshiab thiab lub luag haujlwm ntawm cov hlab ntsha hauv ob qho tib si mob qog noj ntshav thiab tiv thaiv kab mob. Qhov sib txawv zoo sib xws hauv paj hlwb kev ua ub no ntawm kev mob qog noj ntshav, kev tsim kho tshiab, thiab kev tiv thaiv kab mob hais txog qhov cuam tshuam trophic ntawm cov hlab ntsha thiab qhia tias kev tsom mus rau cov hlab ntsha thiab neuro signaling yog ib qho kev cog lus kho mob rau kev kho mob ntawm ntau yam tib neeg cov kab mob.
2|NYIAJ NTAWM REGENERATION NTAWM NERVES
2.1|Lub luag haujlwm ntawm cov hlab ntsha hauv kev tsim dua tshiab
Cov paj hlwb kev koom tes nyob rau hauv limb regeneration tau pib pom nyob rau hauv lub salamander, uas muaj cov cuab yeej zoo kawg li rau regenerate appendages (nkhaus thiab tail) tom qab amputation. Pib nrog kev tsim ntawm lub paj hlwb, hu ua blastema, kev tsim kho ntawm cov ceg thiab tus Tsov tus tw tshwm sim tsuas yog ob peb lub lis piam thiab yuav tsum tau nkag mus rau hauv cov hlab ntsha hauv blastema. Denervation ntawm stump tiv thaiv kev tsim thiab kev loj hlob ntawm blastema, thiab nyob rau hauv qhov tsis muaj cov hlab ntsha, es tsis txhob ntawm regeneration, yooj yim qhov txhab kho yuav siv qhov chaw. Nerve dependence nyob rau hauv regeneration yog thawj zaug tshaj tawm nyob rau hauv nruab nrab ntawm lub xyoo pua 19th nyob rau hauv lub ntsiab lus ntawm salamander limb regeneration thiab tom qab ntawd tau pom tias kuj siv rau cov ntaub so ntswg uas tsis yog appendages thiab lwm hom. Nyob rau hauv lub regeneration ntawm amphibian lens, neural retina, thiab forebrain, regeneration tsuas yog tshwm sim nyob rau hauv lub xub ntiag ntawm olfactory paj projections.8
Nyob rau hauv cov ntses, fin, thiab barbel regeneration kuj yuav tsum tau innervation rau tsim ib tug regenerative blastema thiab kev loj hlob reconstitution ntawm ib tug tag nrho functional qauv. , 11 thiab nyob rau hauv tus lej tip regeneration (cov seem ntawm cov limb regeneration nyob rau hauv amphibians), denervation kuj blocks regeneration.12,13
2.2|Cov molecular bases rau paj dependence nyob rau hauv regeneration
Kev nkag siab ntawm cov paj hlwb kev koom tes hauv kev tsim dua tshiab ntawm qib molecular feem ntau tseem yuav tau piav qhia.
Ntawm qhov tod tes, blastema hlwb tsim cov tshuaj neurotrophic uas nyiam cov hlab ntsha hauv cov qauv tsim dua tshiab, thiab ntawm qhov tod tes, cov hlab ntsha tso tawm ntau yam mitogenic yam thiab neurotransmitters uas txhawb nqa neuro signaling hauv blastema hlwb. Neuregulin thiab paj hlwb kev loj hlob (NGF) tau pom tias yuav pab txhawb innervation thaum lub sij hawm lub plawv regeneration11 thiab nyob rau hauv tus lej tip regeneration, ib tug Wntmediated mechanism, yog tsim nyog los nyiam cov hlab ntsha uas txhawb blastema cell loj hlob.13 Immune hlwb, thiab nyob rau hauv particular macrophages, kuj yuav pab tau. mus rau attraction ntawm paj hlwb rau lub blastema. Macrophages secrete neurotrophic yam uas tuaj yeem txhawb cov paj hlwb, 14 thiab cov txheej txheem no zoo li ua si hauv kev tsim dua tshiab.15
Qhov tseem ceeb, cov paj hlwb loj hlob tau pom tias zais ntau yam kev loj hlob thiab cov neurotransmitters los ntawm cov paj hlwb. Transferrin, 16 tshuaj P, 17 fibroblast kev loj hlob yam (FGFs) thiab pob txha morphogenetic protein2 (BMP2), 18 platelet-derived growth factor (PDGF) thiab oncostatin, 19 thiab morphogenetic factor nAG (ib qho kev txiav txim ntawm txoj hauj lwm proximodistal) 20, 21 tau pom tias txhua tus tau raug tso tawm los ntawm cov hlab ntsha thaum lub sijhawm rov tsim dua tshiab thiab nquag txhawb kev loj hlob ntawm kev tsim dua tshiab. Cov paj hlwb kuj ua rau muaj qhov overexpression ntawm histone deacetylase 1 (HDAC1) uas ua rau kev loj hlob ntawm cov hlwb regenerative.22 Denervation ua rau lub deprivation ntawm cov saum toj no-pob paj-tso molecules thiab uas ua rau muaj kev puas tsuaj los yog muaj zog txo nyob rau hauv regenerative capacities. Nco ntsoov, tej zaum, daim ntawv teev cov trophic yam tso tawm los ntawm cov hlab ntsha yog tsis tag, nrog rau lwm cov molecular players tseem yuav nrhiav tau.
Qhov tseem ceeb, lub cellular complexity ntawm paj hlwb yuav tsum tau coj mus rau hauv tus account nyob rau hauv lub molecular mechanisms ntawm paj dependence. Tseeb tiag, cov hlab ntsha peripheral tsis yog ua los ntawm cov neurons nkaus xwb tab sis kuj suav nrog kev txhawb nqa Schwann hlwb, uas tseem koom nrog kev cuam tshuam ntawm cov hlab ntsha hauv kev tsim dua tshiab los ntawm kev tsim khoom ncaj qha thiab tso tawm trophic yam xws li PDGF.19-21
2.3|Nerves raws li qhov chaw ntawm qia / progenitor cells
Ib cag ntawm kev tso tawm ntawm cov molecules los ntawm cov hlab ntsha xaus hauv cov hlwb blastema, ib qho tseem ceeb ntawm cov paj hlwb nyob hauv kev tsim dua tshiab tsis ntev los no tau pom. Nyob rau hauv tus lej tip regeneration thiab kho daim tawv nqaij, peripheral qab haus huv muab ib tug reservoir ntawm mesenchymal precursor hlwb uas ncaj qha mus rau regeneration.23 Neural crest-derived mesenchymal precursor hlwb nyob rau hauv lub endoneurium yuav migrate mus rau lub blastema thiab tom qab ntawd evolve mus rau hauv progenitors ntawm nonneural hlwb, pab txhawb. kev loj hlob thiab kev sib txawv ntawm cov blastema, thiab tshwj xeeb tshaj yog cov pob txha.23
Ib yam li ntawd, neural crest-derived paj hlwb mesenchymal hlwb tau pab txhawb rau lub dermis thaum lub sij hawm ntawm daim tawv nqaij kho mob.23 Cov kev tshawb pom no txhawb nqa tus qauv uas cov hlab ntsha peripheral ncaj qha ua rau cov hlwb ua ntej los txhawb kev kho thiab rov tsim cov ntaub so ntswg raug mob.
Ua ke, tsis tsuas yog cov hlab ntsha txhawb kev tsim kho dua tshiab los ntawm paracrine-based molecular kev sib cuam tshuam, tab sis lawv kuj tuaj yeem muab lub hauv paus ntawm cov hlwb ua ntej uas ncaj qha rau kev tsim dua tshiab. Qhov kev ua haujlwm ntawm ob leeg ntawm cov hlab ntsha no muab lawv tso rau hauv lub luag haujlwm tseem ceeb hauv kev ua yeeb yam rau cov cellular thiab molecular kev sib cuam tshuam ua si thaum lub sijhawm rov tsim dua tshiab thiab, raws li peb yuav piav qhia hauv tshooj tom ntej, muaj qhov sib xws ntawm lub luag haujlwm thiab cov txheej txheem ntawm kev ua ntawm cov hlab ntsha hauv kev tsim dua tshiab thiab mob qog noj ntshav. (Daim duab 1).
3|LUB ROOJ NTAWM NERVES IN CANCER
3.1|Qhov tseem ceeb ntawm cov hlab ntsha hauv qog noj ntshav
Cov kev tshawb fawb yav dhau los tau taw qhia txog kev qhia thiab kev koom tes ntawm cov neurotrophic kev loj hlob yam, xws li NGF24 thiab lwm yam neurotrophins, 25 nrog rau cov neurotransmitter signaling26 hauv cov qog loj hlob. Perineural ntxeem tau (kev cuam tshuam ntawm cov hlab ntsha los ntawm cov qog nqaij hlav cancer) tau paub ntau xyoo, 27 tab sis lub luag haujlwm ntawm cov hlab ntsha hauv cov qog nqaij hlav tsis tau lees paub txog thaum tsis ntev los no. Nerve dependence nyob rau hauv regeneration yog tsis quav ntsej los ntawm cov neeg mob qog noj ntshav txawm hais tias muaj kev tshwm sim, ua thaum ntxov li 1950s, qhov denervation tuaj yeem ua rau qeeb qeeb lossis txawm tias raug ntes ntawm qog loj hlob hauv tsev menyuam, 28 pheochromocytoma29, thiab cov qog nqaij hlav hauv nas.30 Txawm li cas los xij, kev tshawb fawb txog kev mob qog noj ntshav ntawm lub luag haujlwm ntawm cov hlab ntsha nrawm hauv xyoo 2013 thaum qhov cuam tshuam ntawm denervation ntawm kev loj hlob ntawm prostate cancer tau tshaj tawm.31 Cov kws sau ntawv pom tias denervation ntawm sympathetic (adrenergic) thiab parasympathetic (cholinergic) cov hlab ntsha txo ob leeg qog nqaij hlav thiab tsim. ntawm metastases hauv nas. Beta-adrenergic thiab cholinergic signaling nyob rau hauv cov qog hlwb, txawm tias qhib los ntawm liberation ntawm noradrenaline thiab acetylcholine los ntawm sympathetic thiab parasympathetic qab haus huv, raws li, ua rau lub stimulation ntawm beta-adrenergic thiab cholinergic receptors thiab thaum kawg coj mus rau kev loj hlob. ib qho kev tshawb fawb cais, cov paj hlwb muaj siab kuj tau pom tias yog cov inducers ntawm angio-metabolic hloov, los ntawm kev tso tawm ntawm noradrenaline, ua rau cov vascularization ntawm prostate hlav, yog li txhawb tag nrho cov qog loj hlob thiab kev nthuav tawm.32
Interestingly, no paj dependence nyob rau hauv prostate cancer piav qhov ntev-saib qhov tseeb hais tias cov txiv neej uas muaj tus txha caj qaum raug mob muaj ib tug txo qis ntawm prostate cancer, 33 raws li tus txha caj qaum raug mob induces functional denervation, thiab qhov tseem ceeb tseem ceeb ntawm neural signaling nyob rau hauv prostate cancer yog tam sim no lees paub. .34 Tiv thaiv kom tsis txhob muaj kev nkag siab ntawm cov paj hlwb thiab cov hlab ntsha parasympathetic hauv prostate, lossis tsom mus rau lawv txoj kev taw qhia, tam sim no tau raug soj ntsuam hauv kev sim tshuaj nrog beta-blockers (antagonists ntawm beta-adrenergic receptors). ntawm beta-blockers tuaj yeem txo cov neeg tuag hauv prostate cancer.35 Qhov zoo siab, kev kho mob ntawm lub luag haujlwm ntawm cov hlab ntsha hauv kev mob qog noj ntshav mus dhau kev kho mob, vim cov hlab ntsha tuaj yeem siv los txheeb xyuas cov qog nqaij hlav prostate lub neej (uas yuav tsum muaj kev cuam tshuam kev kho mob hnyav) los ntawm indolent. Cov qog nqaij hlav hauv prostate (uas tsuas yog xav tau kev soj ntsuam zoo xwb). Nerve infiltration yog qhov tseeb siab dua hauv kev pheej hmoo mob qog noj ntshav prostate piv nrog cov kev pheej hmoo qis prostate cancer31 thiab perineural invasion, uas cuam tshuam nrog paj hlwb infiltration, tsis ntev los no tau pom tias yog ib qho kev kwv yees ntawm kev mob metastatic hauv prostate cancer.36
Tsis tas li ntawd, raws li cov hlab ntsha hauv cov qog nqaij hlav tuaj yeem pom tau los ntawm kev siv cov magnetic resonance imaging (MRI), cov paj hlwb txiav txim siab los ntawm MRI tuaj yeem yog ib txoj hauv kev tsis zoo los txheeb xyuas cov qog nqaij hlav qog nqaij hlav hauv lub sijhawm kuaj mob.37 Yog li, hauv cov lus kho mob, paj hlwb. Kev koom tes tuaj yeem siv rau kev tsim kho mob qog noj ntshav, txhawm rau kwv yees cov txiaj ntsig ntawm tus neeg mob, thiab hauv kev kho mob rau kev tiv thaiv lossis cuam tshuam nrog neuron signaling. Raws li yuav tau piav qhia hauv qab no, nws kuj tseem yuav pom tias cov kev tshawb pom no thiab kev kho mob ntawm cov qog nqaij hlav prostate tuaj yeem txuas mus rau lwm yam, yog tias tsis yog tag nrho, tib neeg cov qog.
Tom qab mob qog noj ntshav prostate, qhov kev cuam tshuam ntawm cov hlab ntsha hauv cov qog nqaij hlav tau tshaj tawm hauv kev mob plab hnyuv. Hauv kev mob qog noj ntshav, raws li kev phais thiab tshuaj denervation, lub paj hlwb tau pom tias tsim nyog rau cov qog pib thiab kev loj hlob.38 Denervation thwmsim, nrog rau kev siv cov inhibitors lossis molecular targeting tiv thaiv cholinergic signaling, qhia lub luag hauj lwm ntawm parasympathetic hlab ntsha hauv Kev nce qib ntawm kev mob qog noj ntshav.38,39 Txaus siab, lub voj voog feedforward tau pom nyob rau hauv uas cov qog nqaij hlav hauv plab tsim thiab tso tawm NGF los txhawb cov qog innervation thiab rov qab los, cholinergic signaling activates proliferation thiab nthuav tawm ntawm gastric cancer qia hlwb los ntawm Yap- thiab Wnt-mediated pathways.39
Nyob rau hauv basal cell carcinoma ntawm daim tawv nqaij, phais ablation ntawm lub paj hlwb nyob rau hauv cov hauv paus plaub hau suppresses qog tsim, thiab cov hlab ntsha ntawm lub paj hlwb txhawb cov qia cell proliferation los ntawm ib tug mechanism uas muaj feem xyuam rau lub activation ntawm paj hlwb-derived hedgehog signaling.40 Qhov tseem ceeb, qhov no qhia tau hais tias lub luag hauj lwm ntawm stimulatory. paj hlwb hauv kev mob qog noj ntshav tsis yog tas rau cov hlab ntsha uas tsis muaj zog (sympathetic thiab parasympathetic) tab sis cov hlab ntsha ntawm lub paj hlwb tseem koom nrog.
Kev txhim kho mob qog noj ntshav pancreatic zoo nkaus li nyob rau hauv qhov sib npaug ntawm cov paj hlwb uas hnov lus41,42 thiab sympathetic nerves43 txhawb kev loj hlob ntawm pancreatic cancer hlwb, los ntawm neurokinin receptor thiab beta-adrenergic signaling, feem, whereas parasympathetic qab haus huv inhibit cancer kev loj hlob los ntawm cholinergic signaling.44 Nyob rau hauv lub Kev tswj hwm kev ua haujlwm ntawm lub plawv, qhov zoo piv rau hom kev tswj hwm tsis zoo los ntawm kev sib raug zoo nrog rau cov hlab ntsha parasympathetic tau tsim zoo, 45 thiab tib lub hauv paus ntsiab lus ntawm kev tawm tsam neural cuam tshuam kuj tseem siv tau rau kev mob qog noj ntshav. Nco ntsoov, ob qho tib si cov paj hlwb thiab cov hlab ntsha loj tau nce hauv cov qog nqaij hlav pancreatic, thiab cov kev hloov pauv no yuav muaj txiaj ntsig zoo li prognostic biomarkers.46
Hauv kev mob qog noj ntshav mis, qhov cuam tshuam sib txawv ntawm kev sib raug zoo piv rau parasympathetic innervation kuj tseem ua si. Kev siv cov noob caj noob ces nyob rau hauv tus nas, kev loj hlob ntawm cov qog nqaij hlav cancer mis thiab kev loj hlob tau nrawm dua tom qab stimulation ntawm sympathetic qab haus huv hauv cov qog ntawm lub mis tab sis raug txo qis tom qab stimulation ntawm parasympathetic nerves.47 Kuj tseem muaj kev ua siab ntev thiab txo qis parasympathetic paj ntom ntom hauv cov qog uas cuam tshuam nrog cov txiaj ntsig tsis zoo. thiab muaj feem cuam tshuam nrog kev qhia ntau dua ntawm cov tshuaj tiv thaiv kab mob molecules.47 Cov ntaub ntawv no qhia tau tias zoo ib yam li mob qog noj ntshav pancreatic, cov paj hlwb sib txawv yuav muaj qhov sib txawv, thiab tej zaum yuav cuam tshuam rau kev loj hlob ntawm lub mis; seb qhov no siv tau rau lwm hom mob qog noj ntshav yuav tsum tau qhia meej
Txawm hais tias mob qog nqaij hlav hlwb tshwm sim hauv CNS, qhov cuam tshuam ntawm cov neurons ntawm lub hlwb kev loj hlob tau tshwm sim. Neuronal hlwb tau pom los txhawb kev loj hlob ntawm glioma los ntawm kev tso tawm ntawm synaptic protein neuroligin-3 (NLGN3) uas txhawb nqa glioma cell proliferation los ntawm PI3K-mTOR signaling pathway.48
NLGN3 tso tawm yog txhawb los ntawm neural kev ua haujlwm48 thiab tuaj yeem tsom rau hauv cov qauv tsiaj kom txo qis kev loj hlob ntawm glioma hlwb.49 Kev tso tawm ntawm lwm cov proteins, xws li pleiotrophin los ntawm cov hlwb neural, tuaj yeem txhawb nqa glioma cell invasion50 thiab rov qab los, glioma hlwb kuj tuaj yeem cuam tshuam. neuron kev ua ub no.51 Ib lub tswv yim uas cuam tshuam lub hlwb mob qog noj ntshav thiab cov teeb liab synaptic yog nyob ntawm qhov muaj kev hloov pauv ntawm tus tsav tsheb hauv PI3K gene, kos ib qho tseem ceeb ntawm kev sib txuas ntawm genomic instability ntawm mob qog noj ntshav thiab ua kom cov neural signals.52 Cov kev tshawb fawb no hauv hlwb mob cancer txuas ntxiv mus. Kev ua qauv qhia tias cov hlwb neuronal thiab macromolecules yog qhov tseem ceeb hauv kev mob qog noj ntshav thiab tuaj yeem raug tsom rau hauv kev kho mob yav tom ntej.
3.2|Lub hlwb raws li qhov ua tau ntawm cov qog progenitor hlwb
Ib txoj kev tshawb fawb tsis ntev los no tau txheeb xyuas tias qee cov hlwb neural progenitor uas tsim nyob rau hauv thaj tsam subventricular - thaj chaw neurogenic ntawm lub hlwb - tuaj yeem hla cov ntshav-hlwb thaiv thiab nkag mus rau hauv kev ncig.53 Cov hlwb no tuaj yeem nkag mus thiab nyob hauv cov qog prostate uas lawv tsim cov adrenergic neurons tshiab uas pab txhawb rau kev txhawb nqa ntawm prostate cancer kev loj hlob thiab kev nthuav tawm.53 Qhov kev qhia tshiab no, uas lub hlwb yog ib qho ntawm cov hlwb progenitor uas koom nrog cov qog nqaij hlav, zoo ib yam li cov kev tshawb pom tsis ntev los no hauv kev tsim kho tshiab taw qhia rau peripheral. paj hlwb ua ib qhov chaw ntawm mesenchymal qia thiab progenitor hlwb uas koom nrog hauv kev loj hlob ntawm cov regenerate.23
3.3|Lub luag haujlwm ntawm Nerves hauv kev tiv thaiv kab mob qog noj ntshav thiab o
Kev sib tham ntawm cov hlab ntsha thiab lub cev tiv thaiv kab mob yog xav tias yuav koom nrog kev tiv thaiv kab mob qog noj ntshav thiab mob. Kev sib cuam tshuam ntawm Neuroimmune, los ntawm cov hlab ntsha mus rau lub cev tiv thaiv kab mob thiab rov ua haujlwm tau zoo, 54 thiab lawv cov kev cuam tshuam rau kev mob qog noj ntshav tau raug tshuaj xyuas.55 Tsis yog ntau yam neuro signaling, thiab tshwj xeeb tshaj yog adrenergic signaling, yog tsim nyog rau tiam ntawm lub cev tiv thaiv kab mob. cov pob txha pob txha, 56 tab sis kuj yog qhov infiltration thiab ua kom lub cev tiv thaiv kab mob hauv TME tuaj yeem tau tsav los ntawm adrenergic signaling thiab pab txhawb rau metastasis.26 Kev sib cuam tshuam ntawm innervation thiab o kuj tau piav qhia los ntawm qhov tseeb tias cov hlab ntsha vagus modulates nco T hlwb, ua rau inhibition ntawm myeloid-derived suppressor cell loj hlob nyob rau hauv tus po, thiab txhawb kev mob qog noj ntshav los ntawm kev tawm tsam ntawm cytotoxic T cells.57 Ua ke, hais txog kev sib cuam tshuam ntawm neuroimmune hauv kev mob qog noj ntshav, zoo li tsuas yog lub taub ntawm cov dej khov nab kuab xwb. tshawb nrhiav txog niaj hnub no, thiab cov xyoo tom ntej yuav tsum pom qhov nthuav dav ntawm qhov kev tshawb fawb no.
Zuag qhia tag nrho, lub luag haujlwm ntawm cov hlab ntsha hauv kev mob qog noj ntshav thiab cov txiaj ntsig kho mob tau tshwm sim, nrog kev sib tw zoo sib xws ntawm cov kev tswj xyuas kev cuam tshuam ntawm cov hlab ntsha hauv kev tsim dua tshiab thiab mob qog noj ntshav (Daim duab 1). Nws yuav tsum raug sau tseg tias kuj tseem muaj qhov sib txawv ntawm lub luag haujlwm ntawm cov hlab ntsha hauv kev tsim dua tshiab tiv thaiv kab mob qog noj ntshav, vim tias qhov sib npaug ntawm stimulatory thiab inhibitory neural teebmeem yeej tsis tau piav qhia hauv kev tsim dua tshiab. Txawm hais tias ob lub luag haujlwm ntawm cov hlab ntsha hauv kev tsim dua tshiab tsis tau piav qhia vim tias lawv tsis muaj nyob lossis vim tias nws tau ploj mus txog tam sim no tseem yuav tau piav qhia. Txawm li cas los xij, lub tswv yim ntawm kev vam khom paj hlwb tam sim no tau txuas ntxiv mus rau mob qog noj ntshav, thiab dhau ntawm cov qog nqaij hlav uas tau piav qhia saum toj no, innervation ntawm TME tau tshaj tawm hauv cov neeg mob qog noj ntshav, xws li hauv cov thyroid (58) thiab esophageal (59) mob qog noj ntshav.
4|Lub luag haujlwm ntawm cov hlab ntsha hauv cov hlab ntsha thiab kev tiv thaiv kab mob
4.1|Neuroimmunology
Neuroimmunology feem ntau tsom rau CNS thiab cuam tshuam txog cov kab mob neuroinflammatory, xws li ntau yam sclerosis, nrog rau lub luag haujlwm ntawm neuroimmune kev sib cuam tshuam hauv cov kab mob neurodegenerative thiab neuropsychiatric.58 Neuroimmune kev sib cuam tshuam hauv CNS tuaj yeem muaj ob qho kev cuam tshuam thiab lub luag haujlwm hauv lub hlwb kev loj hlob thiab rov qab los ntawm kev raug mob. Ntau tus kab mob sclerosis yog ib qho piv txwv classic ntawm kev cuam tshuam ntawm kev ua haujlwm tsis zoo ntawm lub cev tiv thaiv kab mob, uas T lymphocytes thiab lwm yam inflammatory mediators tawm tsam myelin sheath hauv CNS.59 Neuroimmune kev sib cuam tshuam hauv CNS txuas mus rau microglia thiab cov kab ke ntxiv, nrog rau lub luag haujlwm hauv cov kab mob neurodegenerative. , suav nrog Alzheimer's disease.60 Tsis ntev los no, kev tshawb fawb txog kev sib cuam tshuam ntawm neuroimmune cuam tshuam nrog PNS tau los ua ntej.61
4.2|Hla kev sib tham ntawm peripheral neurons thiab lub cev tiv thaiv kab mob
Raws li kev tawm tsam oncology, kev tshawb fawb ntawm lub plab zom mov (GI) tau lees paub ntev lub luag haujlwm ntawm cov neurons, suav nrog cov kab mob enteric paj hlwb (ENS), hauv cov kab mob hauv plab, xws li kab mob plab hnyuv (IBD), thiab ua haujlwm rau kev piav qhia. Cov hauv paus ntsiab lus tseem ceeb cuam tshuam rau peripheral neuroimmunology.4 Lub GI ib puag ncig yog qhov tshwj xeeb los ntawm qhov ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom ntom. . Neuroimmune cross-hais lus hauv plab yog qhov tseem ceeb rau kev saib xyuas lub cev ib txwm muaj thiab homeostasis nrog rau kev koom tes hauv ntau yam kev cuam tshuam hauv plab nrog rau kev kis kab mob, kev tsis haum zaub mov, thiab IBD.63.
Hauv plab, ENS neurons thiab neurites yog entangled thiab sib txuas lus nrog lub cev tiv thaiv kab mob xws li macrophages. Ib qho piv txwv rau lub plab physiology yog tias ob lub cev tiv thaiv kab mob thiab cov neurons paub txog kev phom sij thiab sib txuas lus. PNS thiab lub cev tiv thaiv kab mob ua haujlwm rau cov kab mob txaus ntshai, cov kab mob tsis zoo, thiab lwm yam stimuli. Daim duab 2 qhia txog qhov yooj yim, pragmatic saib ntawm homeostasis thiab cuam tshuam txog biology. Daim duab 2A qhia txog lub plab homeostatic nrog tolerogenic kev sib txuas lus ntawm cov neurons thiab lub cev tiv thaiv kab mob. Peb xaiv lub xeev tolerogenic los ntawm kev sau npe, I0 lossis N0. Thaum cov neurons thiab / lossis lub cev tiv thaiv kab mob tau txais kev txhawb nqa inflammatory, lawv hloov mus rau lub xeev inflammatory peb depict li I1 lossis N1. Yog hais tias qhov inflammatory stimulus luv luv los yog inconsequential, neurons thiab lub cev tiv thaiv kab mob yuav rov qab mus rau lub hauv paus thiab homeostasis. Tab sis txwv tsis pub, kev hloov kho thawj zaug thiab pib kab mob pib.
Raws li tus kab mob loj hlob zuj zus, lub cev tiv thaiv kab mob muaj lub luag haujlwm loj hauv kev tsav tsheb o thiab kis kab mob thiab tuaj yeem nrhiav cov neurons ntxiv rau hauv lub xeev tus kab mob raws li hauv daim duab 2B. Raws li tus kab mob kis mus ntxiv thiab tej zaum yuav raug kho nrog, piv txwv li, cov tshuaj tiv thaiv TNF, cov tshuaj tiv thaiv kab mob raug coj rov qab mus rau I0 xeev, tab sis yog tias cov kab mob enteric neuron aberration tsis raug daws, cov neurons tuaj yeem coj cov hlwb tiv thaiv kab mob. rov qab mus rau lub xeev qhib I1 raws li pom hauv daim duab 2C. Kev ua kom muaj kev tiv thaiv kab mob neural tuaj yeem muaj peev xwm kho IBD uas yog refractory rau lwm yam, feem ntau tiv thaiv kab mob, kev kho mob.
ENS neurons uas cuam tshuam rau lub plab tsis muaj zog muaj xws li cov kab mob hauv nruab nrab ntawm cov kab mob hauv nruab nrog cev, vasoactive plab hnyuv peptide neurons uas ua rau cov mucosa, thiab cholinergic neurons uas cuam tshuam rau macrophages hauv cov leeg nqaij sab nraud.62 Canonical enteric neuropeptides, xws li calcitonin gene-related peptide, thiab neurotransmitters. txoj hauv kev, suav nrog cholinergic, cuam tshuam lub cev tiv thaiv kab mob uas muaj peev xwm tiv thaiv kab mob.61 Acetylcholine yog ib qho tseem ceeb neurotransmitter rau kev sib txuas lus ntawm extrinsic/intrinsic neurons thiab ENS rau lub cev tiv thaiv kab mob. Cov muscarinic GPCRs thiab nicotinic ligand-gated ion channels tau nthuav tawm nyob rau hauv cov qauv sib txawv nyob rau hauv cov subsets ntawm neurons thiab lub cev tiv thaiv kab mob ua kom muaj kev taw qhia tshwj xeeb. Nws tau nthuav tawm ntawm ntau hom neuronal thiab tshwj xeeb tshaj yog ntawm cov hlab ntsha peripheral suav nrog ENS. Ntau qhov kev tshawb fawb ua ntej tau lees paub qhov kev kho mob muaj peev xwm ntawm lub hom phiaj alpha 7 nicotinic acetylcholine receptor-mediated anti-inflammatory teebmeem los ntawm kev hloov kho ntawm proinflammatory cytokines.64 Ib leeg lossis hauv kev sib xyaw ua ke, neuropeptide thiab / lossis neurotransmitter modulation tuaj yeem kho neuroimmune homeostasis nrog cov txiaj ntsig zoo rau kev tiv thaiv IBD. .
Sab nraud ntawm GI system, neuroimmune cross tham muaj lub luag haujlwm dav dav hauv kev saib xyuas lub xeev tolerogenic, nrog rau ntau yam kab mob. Lub luag haujlwm ntawm PNS thiab lub cev tiv thaiv kab mob raws li cov xaim hluav taws xob rau cov teeb liab txaus ntshai yog tshwm sim nrog cov ntaub so ntswg, nrog rau cov tawv nqaij, rov ua kom lub cev tiv thaiv kab mob, cov nociceptors, thiab cov neurons hnov qab uas ua haujlwm txhawm rau txheeb xyuas ntau yam kev ceeb toom txaus ntshai. Innate lymphoid cells thiab PNS sib txuas lus thiab txiav txim siab txog lub xeev ntawm cov neeg nyob hauv lub cev tiv thaiv kab mob, suav nrog macrophages, thiab fibroblasts.65 Qhov tseeb, kev sib cuam tshuam ntawm cov neuroimmune tshwm sim ua lub luag haujlwm tseem ceeb hauv psoriasis, kab mob ntev ntawm daim tawv nqaij, nrog rau kev ua haujlwm ntawm nociceptive neurons.66 Neuroimmune kev sib cuam tshuam hauv cov kab mob tsis txwv rau ntawm daim tawv nqaij thiab GI system. Piv txwv li, PNS plays lub luag haujlwm tseem ceeb hauv pathophysiology ntawm endometriosis, ib qho mob tsis txaus ntseeg.67 Cov paj hlwb uas nyob ib puag ncig thiab innervate endometriotic lesions tsis tsuas yog tsav cov mob ntev thiab debilitating cuam tshuam nrog endometriosis tab sis kuj pab txhawb kev loj hlob phenotype los ntawm secreting neurotrophic yam tseem ceeb thiab cuam tshuam nrog ib puag ncig lub cev tiv thaiv kab mob.
5|TXOJ HAUJ LWM: KEV PAB CUAM KEV PAB CUAM
Lub luag haujlwm ntawm lub paj hlwb hauv kev noj qab haus huv thiab kab mob tau nthuav dav, thiab kev tshawb nrhiav tshiab ntawm cov neuroscience ntawm tib neeg cov kab mob tau qhib qhov chaw tshiab hauv biomedicine. Los ntawm kev rov tsim dua tshiab rau kev mob qog noj ntshav, kev tiv thaiv kab mob, thiab dhau mus, kev nkag siab zoo dua ntawm lub luag haujlwm ua los ntawm cov paj hlwb raws li lub suab paj nruag ntawm cov cellular thiab cov nqaij mos loj hlob thiab kev sib txawv yuav tsum qhia txog txoj hauv kev tshiab rau kev tswj hwm tib neeg kev noj qab haus huv thiab kab mob.
Kev kho mob txhais lus ntawm mob qog noj ntshav neuroscience twb tshwm sim nrog lub hom phiaj ntawm adrenergic thiab cholinergic neuron signaling hauv TME, ua pov thawj tias muaj txiaj ntsig zoo hauv kev txo cov qog nqaij hlav hauv vivo, 31, 38, 43, 44 tab sis cov kev sim thiab cov pov thawj tam sim no yuav tsum tau ua. kuaj hauv kev sim tshuaj. Qee qhov kev sim tshuaj tau ua tiav lawm, thiab ntau ntxiv yog nyob ntawm txoj kev siv beta-blockers los tsom adrenergic signaling hauv qog noj ntshav.
Hauv kev mob qog noj ntshav mis, -blockers txo cov biomarkers ntawm metastasis nyob rau theem II randomized trial68 thiab inhibited mob qog noj ntshav nrog txo cov neeg mob tuag.69 Nws tseem yuav tsum tau muab sau tseg tias, nyob rau theem no, cov kev qhia neuro signaling ua haujlwm hauv qog noj ntshav feem ntau yog adrenergic thiab cholinergic, tab sis lub luag hauj lwm muaj peev xwm ntawm lwm yam neuro signaling pathways yuav tsum tsis txhob underestimated. Piv txwv li, dopamine receptor D2 muaj feem cuam tshuam nrog kev mob qog noj ntshav gastric prognosis70, thiab repositioning dopamine D2 receptor agonists tuaj yeem txhim kho chemotherapy thiab kho cov pob txha metastatic hlav; Yog li ntawd, dopamine thiab nws cov teeb liab kuj tshwm sim raws li lub hom phiaj siv tau hauv kev mob qog noj ntshav. Ib cag los ntawm kev cuam tshuam cov teeb liab neuron, lwm txoj hauv kev cog lus yog txhawm rau tsom cov teeb meem kev loj hlob neurotrophic los tiv thaiv qog innervation.72 Thaiv cov tshuaj tiv thaiv kab mob tiv thaiv NGF24 thiab lwm yam kev loj hlob neurotrophic, 25 lossis pharmacological inhibitors ntawm lawv cov tyrosine kinase receptors Trk39,43,44 tau pom tias inhibit. Kev loj hlob ntawm qog nqaij hlav, thiab cov txiaj ntsig ntawm kev tiv thaiv kev loj hlob ntawm cov tshuaj tiv thaiv neurotrophic kuj tseem txuas ntxiv mus rau inhibition of cancer-induced mob.73 Mob yog ib qho teeb meem loj hauv oncology, thiab qhov kev xav ntawm kev tsom mus rau kev mob qog noj ntshav ib txhij thiab mob qog noj ntshav los ntawm kev tsom mus rau kev loj hlob ntawm neurotrophic thiab lawv cov kev taw qhia txoj kev yog qhov txaus nyiam tshwj xeeb.
Ib cag ntawm kev kho mob, lwm qhov chaw cog lus rau mob qog noj ntshav neuroscience yog qog prognosis. Kev txiav txim siab qhov tshwm sim ntawm cov qog nqaij hlav thaum lub sijhawm kuaj mob yog qhov tseem ceeb ntxiv rau kev xaiv kev kho mob thiab cov neeg mob segmentation, thiab raws li cov hlab ntsha infiltration hauv TME yog txuam nrog cov qog aggressiveness, 31,46,74,75 qhov kev ntsuam xyuas ntawm cov paj hlwb yuav dhau los ua ib feem ntawm niaj hnub clincopathological tsom xam nyob rau hauv oncology, raws li zoo raws li ib tug nce nqi hluav taws xob los ntawm kev yees duab, tshwj xeeb tshaj yog nyob rau hauv prostate cancer.37 Ib yam li ntawd, neurotrophic loj hlob yam thiab lawv receptors yog overexpressed nyob rau hauv tib neeg qog nqaij hlav, 76-79 thiab lawv kuj yuav muaj nuj nqis nyob rau hauv mob cancer clinicopathology. . Ntawm qhov kev ceeb toom, kev qhia txog kev loj hlob ntawm neurotrophic yog txuam nrog kev mob qog noj ntshav hauv dev thiab yog li ntawd tus nqi ntawm kev txheeb xyuas qhov kev loj hlob ntawm neurotrophic hauv clinicopathology kuj tseem siv tau rau veterinary oncology.80
Hauv kev xaus, kev txhais lus kho mob tam sim no tshwm sim hauv kev kho mob qog noj ntshav neuroscience thiab exonerate biology yuav ua rau txoj hauv kev rau kev kho mob ntxiv hauv kev tiv thaiv kab mob, mob, mob qog noj ntshav, thiab tshuaj kho dua tshiab. Tsis tas li ntawd, lub paj hlwb, tshwj xeeb tshaj yog lub hlwb, yog qhov chaw sib koom ua ke ntawm kev paub, kev xav, thiab kev sib raug zoo. Kev txiav txim siab ntawm cov txheej txheem puas siab puas ntsws koom nrog kev noj qab haus huv ntawm lub cev twb tau pib ua ntej, 81 thiab nws tuaj yeem cia siab tias qhov kev txhim kho tsis ntev los no ntawm neuroscience uas peb tau piav qhia ntawm no kuj tseem tuaj yeem ua rau kev nkag siab zoo dua ntawm kev koom tes ntawm neurophysiological, kev txawj ntse, thiab kev sib raug zoo. hauv tib neeg kev noj qab haus huv thiab kab mob.
TXOJ CAI
Peb ua tsaug lees paub cov kev sib tham muaj zog nrog Grazia Piizzi ua rau cov ntsiab lus qhia hauv daim duab 2.
Kev tsis sib haum xeeb ntawm kev txaus siab
Pearl S. Huang thiab John A. Wagner yog cov neeg ua haujlwm ntawm Cygnal Therapeutics thiab tej zaum yuav muaj cov khoom lag luam thiab / lossis cov khoom lag luam. Hubert Hondermarck yog ib tug tswv cuab ntawm Pawg Thawj Saib Xyuas Kev Tshawb Fawb Txog Kev Kho Mob Cygnal.
AUTHOR CONTRIBUTIONS
Txhua tus kws sau ntawv tau koom tes hauv daim ntawv thiab muab cov kev hloov kho tseem ceeb thiab kev pom zoo ntawm qhov kawg version.
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