Los ntawm lub raum raug mob mus rau raum mob cancer

Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com

Anna Julie Peired1,2, Elena Lazzeri1,2, Francesco Guzzi2, Hans-Joachim Anders3 thiab Paola Romagnani1,2,4

Cancerogenesis yog txheej txheem nyuaj uas cuam tshuam nrog cov kab mob germline thiab / lossis kev hloov pauv somatic uas ua rau muaj kev tswj tsis tau nthuav dav ntawm cov hlwb hloov pauv. Feem ntau, qhov no tshwm sim nyob rau hauv ib tug series ntawm cov kauj ruam nyob rau hauv uas heev heev ua ke ntawm kev hloov pauv tsuas yog maj mam dhau qhov chaw pib rau unrestricted cell loj hlob.1 cov ntaub so ntswg raug mob yog ib tug paub ua rau mob cancerogenesis rau 2 yog vim li cas: (i) nws muaj peev xwm induce DNA puas thiab somatic mutations , tshwj xeeb tshaj yog nyob rau hauv cov ntaub so ntswg-nyob ntev-nyob qia hlwb2; thiab (ii) nws lub peev xwm los txhawb txoj kev nthuav dav ntawm cov hlwb hloov pauv thaum lub sijhawm kho cov ntaub so ntswg.3 Piv txwv li, 2 cov txheej txheem no ua rau muaj kev mob plab hnyuv mob ntsig txog mob qog noj ntshav 4 thiab raumob ntsws cancerMuaj feem cuam tshuam rau cov pa luam yeeb thiab plua plav, 5 atrophic gastritis-txog kab mob plab hnyuv, 6 thiab cirrhosis-txog hepatocellular carcinoma.7 Ntau yam kev tshawb fawb txog kab mob kis tau tshaj tawm txog kev koom tes ntawm cov kab mob raum ntev (CKD) thiab mob raum (Table 18-15). Txawm hais tias ob qho tib si tshwm sim zoo dua nyob rau hauv ib nrab ntawm lub neej, nws tseem tsis tau paub meej tias thiab seb cov koom haum no tau txuas li cas los ntawm qhov ua rau. Piv txwv li, kev ua txhaum cai yuav yog ib txoj hauv kev vim tias kev kho mob qog nqaij hlav, suav nrog kev phais, thiab cov tshuaj antiangiogenic lossis lub hom phiaj ntawm rapamycin (mTOR) thiab cov tshuaj tiv thaiv kab mob tiv thaiv kab mob cuam tshuam nrog kev pheej hmoo ntawm kev mob hnyav.mob raum(AKI) thiab CKD.16,17 Ib yam li ntawd, sebmob raumua rau mob qog noj ntshav tsis paub meej, txawm tias qee qhov kev tshawb fawb qhia tiasraummob qog noj ntshav tshwm sim tom qab AKI rov los yog tom qab xyoo ntawm CKD nyob rau theem ntawmraumtsis ua hauj lwm (Table 218–25). Hauv kev tshuaj xyuas no, peb tham txog lub luag haujlwm ntawmmob raumraws li tus neeg tsav tsheb ntawm lub raum mob cancer.

cistanche tuaj yeem kho mob raum thiab tiv thaiv kab mob raum

Pib nrog cov pov thawj epidemiological thiab noob caj noob ces, peb tham txog kev hloov pauv kev sim txhawb raumob raumraws li qhov ua rau DNA puas tsuaj thiab clonal proliferation ntawm mutated raum hlwb nyob rau hauv lub raum sib txawv compartments, txiav txim lub qog histotype. Peb tham txog cov kev pom tsis ntev los no ntawm cov kab mob putative ntawm keeb kwm rau benign thiab malignantraumqog nqaij hlav thiab piav qhia txog yuav ua li cas raug mob-kho kev hloov pauv hauv kev ua kom muaj kev sib txawv ntawm cov kev taw qhia sib txawv ua rau muaj qhov sib txawv ntawm cov qog nqaij hlav hauv lub raum. Peb txuas ntxiv tshawb nrhiav seb cov txheej txheem hauv nruab nrab ntawm lub raum kho tau ua haujlwm li cas ntawm AKI ntu thiab qhov ua haujlwm tsis tu ncua hauv CKD txhawb cov qog loj hlob thiab qog rov ua haujlwm. Thaum kawg, peb xav tias kev tiv thaiv ntawm AKI thiab CKD yog txoj hauv kev zoo tshaj plaws los tiv thaiv lub raum cell carcinoma (RCC) kev loj hlob thiab zam nws qhov tshwm sim. Lub tswv yim ntawm bidirectional causal Correspondence: Paola Romagnani, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy. Tau txais 21 Lub Kaum Hli 2020; hloov kho 4 Lub Ob Hlis 2021; txais 17 Lub Ob Hlis 2021; luam tawm online 29 Lub Peb Hlis 2021 www.kidney-international.org tshuaj xyuas Kidney International (2021) 100, 55–66 55Kev sib raug zoo ntawm cov kab mob raum thiab cov qog nqaij hlav hauv lub raum hu rau lub luag haujlwm tseem ceeb ntawm nephrologist hauv kev tiv thaiv thiab kho cov neeg mob nrogmob qog noj ntshav.

Cov yam uas pheej hmoo rau mob qog noj ntshav yog yam muaj feem cuam tshuam rau cov kab mob raum

Kev tshawb fawb txog kab mob kis tau txheeb xyuas cov koom haum, tab sis tsis tau lees paub qhov laj thawj, cov koom haum no feem ntau ua rau kev txhais lus tsis raug. Piv txwv li, nyob rau hauv kev tshawb fawb ntawm qhov tsis paub ua raumob qog noj ntshav, kev tshawb fawb txog kab mob kis tau txheeb xyuas ntau yam "kev pheej hmoo" uas qhov cuam tshuam ncaj qha rau kev mob qog noj ntshav tsis yog ib txwm pom tseeb (Table 326-43). Kev rog rog, ntshav qab zib, ntshav siab, haus luam yeeb, tshuaj nephrotoxic, thiab hlau hnyav tag nrho txhawb nqamob raum, yog AKI lossis CKD, thiab tej zaum yuav txuas ncaj qha rau kev raug mob ntawm lub raum mob qog noj ntshav.44–46 Tseeb tiag, cov tshuaj nephrotoxic thiab cov hlau hnyav ua rau muaj cov tshuaj lom AKI cuam tshuam nrog neuroinflammation thiab oxidative stress.45 Kev rog, ntshav qab zib, thiab kev haus luam yeeb yog qhov zoo. tsim kom muaj kev pheej hmoo rau glomerular hyperfiltration thiab glomerulosclerosis-txog CKD, imposing nephron poob thiab txiav txim siab hloov cellular hloov nyob rau hauv cov seem nephrons kom haum rau cov kev xav tau ntawm metabolic.46 Thaum kawg, kub siab, tsis yog ib qho ua rau, feem ntau yog qhov tshwm sim ntawm kab mob raum thiab rhiab heev. qhov taw qhia ntawm ntxov CKD.44

Qhov chaw tshwj xeeb raum raug mob ua rau cov kab mob qog nqaij hlav raum tshwj xeeb

Cov ntaub ntawv pov thawj qhia tau hais tias qhov sib txawv subtypes ntawm lub raum qog los ntawm cov hlwb nyob ntawm qhov chaw ntawm qhov pib raug mob. Tsis tas li ntawd, qhov sib txawv ntawm qhov sib txawvmob qog noj ntshavhistotypes correlates nrog cov prevalence ntawm tej yam tshwm sim ntawmmob raum.

Feem ntau nquag: ntshiab cell carcinoma tshwm sim los ntawm metabolic overload ntawm cov seem nephron's proximal tubule hauv CKD (S1 / S2 ntu).

Cov kev tshawb fawb yav tom ntej qhia tias CKD ncaj qha ua raumob qog noj ntshav, tshwj xeeb tshaj yog ntawm cov cell ntshiab RCC (ccRCC) histotype uas sawv cev rau 70 feem pua ​​-80 feem puamob qog noj ntshav. Kev tshawb nrhiav tom qab ntawm 33,346 cov ntsiab lus, hnub nyoog 26 txog 61 xyoo ntawm lub hauv paus nrog kev soj ntsuam nruab nrab ntawm 28 xyoo, pom tias qhov nruab nrab CKD ntawm qhov pib ua rau muaj kev pheej hmoo tom qab.raummob qog noj ntshav.19 Kev rog rog thiab ntshav qab zib, uas txhawb nqa CKD, kuj ua rau kev txhim kho RCC. Qhov kev sib txuas ntawm 2 cov xwm txheej no yog sawv cev los ntawm cov kab mob metabolic overload ntawm cov hlwb ntawm cov tubule ze ze hauv cov nephrons seem uas tau ntsib ib qho kev nce siab hauv ib leeg-nephron hyperfiltration (thiab tubular hyper reabsorption).47 Qhov no ua rau mob cortical puas thiab CKD hauv cov neeg mob rog thiab Ntshav qab zib mellitus, nrog rau kev txhim kho tom qab ntawm ccRCC, uas feem ntau tshwm sim los ntawm cov hlwb ntawm cortical proximal tubule (S1 / S2 ntu) 47 (Daim duab 125,44–46,48–57).

Tseem nquag: papillary carcinoma tshwm sim los ntawm ischemic necrosis ntawm proximal tubules (S3 ntu). Cov ntaub ntawv tau txais los ntawm Italian thiab Danish cov kev tshawb fawb qhia tau hais tias cov neeg mob uas muaj AKI lub sijhawm dhau los qhia tias muaj kev pheej hmoo ntau ntxiv ntawm kev tsim papillary RCC (pRCC). Qhov kev pheej hmoo siab dua ntawm cov qog rov ua dua piv rau cov uas tsis tau ntsib tom qab kev phais AKI, qhia tias kev raug mob ischemic txhawb nqa cov qog loj hlob.25 Lub koom haum no tau lees paub ntxiv hauv cov qauv kev sim ntawm AKI, qhov twg cov kws sau ntawv pom tias postischemic AKI txhawb nqa lub sijhawm ntev. txoj kev loj hlob ntawm papillary qog nyob rau hauv nas los ntawm activating qog loj hlob-txhim txoj kev.mob qog noj ntshavlos ntawm kev sim qhia qhov pib ntawm papillary adenomas 3 mus rau 6 lub hlis tom qab ischemia, uas qee zaum tom qab hloov mus rau pRCC hauv classic adenoma-carcinoma sequence.25 Papillary adenomas thiab carcinomas feem ntau yog nyob rau hauv cov kab txaij ntawm sab nrauv medulla, qhov twg. ischemic necrosis cuam tshuam cov hlwb ntawm S3 ntu ntawm proximal tubules25 (Daim duab 1).

Tsis tshua muaj tab sis tshwj xeeb: lithium yog tshuaj lom rau kev sau cov ducts thiab ua rau cov kab mob sib txuas ntawm cov qog.

Kev kho lithium yog txuam nrog kev sau cov kab mob toxicity, ua rau nephrogenic mob ntshav qab zib insipidus txog li 40 feem pua ​​​​ntawm cov neeg mob.58 Kev tshawb fawb qhia tias lithium ua rau poob ntawm cov dej molecular channel aquaporin-2. Lithium kuj hloov txoj hauv kev Notch, uas koom nrog ntau yam ntawm kev mob qog noj ntshav59 thiab muaj lub luag haujlwm tseem ceeb hauv kev tswj xyuas kev saib xyuas ntawm lub raum epithelial cell states.60 Lub sij hawm ntev raug rau lithium ua rau tubulointerstitial nephritis thiab lub raum hlwv, pib los ntawm distal. tubules thiab sau ducts.58 Txawm hais tias kev siv lithium mus sij hawm ntev tsis cuam tshuam nrog kev pheej hmoo ntau ntxiv ntawmmob qog noj ntshav, 61 cov neeg mob lithium-kho tau pom tias muaj kev pheej hmoo siab ntawm kev tsim cov kab mob oncocytomas/chromophobe RCC (uas tshwm sim los ntawm cov kab mob progenitor lesion62 thiab yog histologically thiab morphologically zoo sib xws63) thiab khaws cov kab mob carcinomas49 (Daim duab 1). Tag nrho cov qog no tshwm sim los ntawm cov kab sib sau thiab tau tshaj tawm tias tsis tshua muaj.48,49,64 Txawm li cas los xij, Pharmacovigilance Risk Assessment Committee ntawm European Medicine Agency tau pom zoo tias cov pov thawj txaus los txiav txim siab tias kev siv lithium mus ntev yuav ua rau cov kab mob microcysts. , oncocytomas, thiab khaws cov ductlub raum mob cancer(http://www.ema.europa.eu/docs/en_GB/document_library/PRAC_recommendation_on_signal /2015/01/WC500181043.pdf). Raws li txoj cai, cov tsiaj kho nrog lithium nthuav tawm kev loj hlob ntawm cov hlwb tseem ceeb, nrog rau ntau cov cell intercalated, tejzaum nws tshwm sim los ntawm kev loj hlob thiab kev sib txawv ntawm cov hlwb progenitor lossis hloov pauv ntawm cov hlwb tseem ceeb rau hauv cov hlwb intercalated.50 Yog li, lithium therapy-related. oncocytomas thiab carcinomas ntawm cov ducts sib sau ua ke sawv cev rau lwm qhov piv txwv ntawm kev raug mob ntawm qhov chaw tshwj xeeb mob qog noj ntshav hauvraum.

Tsis tshua muaj tab sis tshwj xeeb: sickle cell anemia induces ischemic medulla raug mob thiab medullary carcinoma.

Sickle cell anemia (SCA) yog ib yam kab mob monogenic hemoglobin uas cuam tshuam nrog kev rov ua dua ntawm lub cev hypoperfusion, cov ntaub so ntswg ischemia, thiab necrosis.65 Sickle cell nephropathy yog ib qho teeb meem loj ntawm SCA nrog rau kev nce mus rau CKD thiabraum tsis ua haujlwm.66,67 Hauv kev tshawb fawb hla ntu ntawm cov menyuam yaus nrog SCA, nce ntshav siab thiab CKD tau txheeb xyuas hauv 16.7 feem pua ​​​​thiab 8.3 feem pua ​​​​ntawm cov neeg mob, raws li .67 Ischemia thaum mob mob tuaj yeem ua rau tsis zoo rau cov hlab ntsha ntawm lub raum medulla,52 qee zaum ua raws li kev loj hlob ntawm medullary carcinoma, 52,53 ib qho kev txhoj puab heev ntawmmob qog noj ntshavYuav luag tshwj xeeb cuam tshuam nrog SCA.51 Tseeb tiag, qhov xwm txheej hnyav ntawm hypoxia thiab hypertonicity ntawm lub raum medulla, ua ke nrog lub cheeb tsam ischemia tshwm sim los ntawm cov qe ntshav liab mob, qhib DNA kho cov txheej txheem los tsav kev tshem tawm thiab hloov pauv hauv kev hloov / sucrose nonfermentable-txog, matrix -kev koom tes, actin-dependent regulator ntawm chromatin, subfamily b, tus tswv cuab 1 (SMARCB1), ib tug qog suppressor gene, uas yog nyob rau hauv ib cheeb tsam tsis yooj yim ntawm chromosome 2268 (Daim duab 1).

Lub koom haum no qhia tias ua rau muaj kev raug mob rau mob qog noj ntshav vim tias mob qog noj ntshav tsis tuaj yeem ua rau SCA, hemoglobin hloov pauv tsis tuaj yeem ua rau mob qog noj ntshav ncaj qha, thiab SCA ntsig txog medullary cancer tsis tshwm sim yam tsis muajmob raum.52,53 Yog li ntawd, nyob rau hauv sib piv rau monogenic cov ntaub ntawv ntawm lub raum mob cancer uas ncaj qha cuam tshuam kev hloov nyob rau hauv lub raum hlwb, SCA-txogmob qog noj ntshavmuab cov ntaub ntawv muaj zog rau lub luag haujlwm ntawm kev raug mob hauvmob qog noj ntshav, raws li cov noob caj noob ces tsis tuaj hauv lub raum hlwb thiab tsuas yog tso nyiaj raumob raumraws li ib qho kev tshwm sim ntawm lub raum cancerogenesis. Tsis tas li ntawd, lub luag haujlwm ntawm kev ua xua thiab lwm yam muaj peev xwm thib peb tsis zoo li hauv cov ntsiab lus no, vim tias qhov chaw medullary ntawm qhov raug mob thiab cov kab mob qog noj ntshav sib cav tawm tsam qhov ua rau muaj kuab lom tab sis txhawb nqa lub luag haujlwm ntawm SCA-mediated ischemic raug mob hauv qhov chaw no. Yog li, SCA-txog raum mob qog noj ntshav muab lwm cov pov thawj ntawm lub tswv yim uasmob raumtuaj yeem yog qhov ua raumob qog noj ntshav.

Monogenic raum mob qog noj ntshav tshem tawm qhov tseem ceeb tshaj tawm txoj hauv kev hauv lub raum mob qog noj ntshav thiab kho lub raum

Muaj ntau hom monogenic ntawmmob qog noj ntshavqhia tias tseem ceeb oncogenes thiab txoj hauv kev koom nrograumcancerogenesis tseem koom nrog hauv cov lus teb raumob raumthiab kho.

Von Hippel-Lindau Syndrome.Kev hloov pauv hauv von Hippel-Lindau (VHL) cov qog qog nqaij hlav tuaj yeem ua rau mob qog noj ntshav autosomal dominant mob qog noj ntshav nrog visceral cysts hauv lub raum70 thiab mob qog noj ntshav raum ntawm hom cell ntshiab (ccRCCs) hauv 24 feem pua ​​​​rau 45 feem pua ​​​​ntawm cov neeg mob.71 Vice versa, 90 feem pua ​​​​ntawm cov neeg mob uas muaj qhov sib txawv ntawm ccRCC nqa cov kev hloov pauv ua rau VHL tsis ua haujlwm.72 VHL yog tus tswj hwm tseem ceeb ntawm cov protein koom nrog hauv kev nkag siab oxygen los ntawm txoj hauv kev hypoxia-inducible factor (HIF). VHL kev hloov pauv qhov chaw cuam tshuam cov hlwb hauv lub xeev ntawm pseudohypoxia, txhawb lub xeev angiogenic tshwj xeeb thiab txuas ntxiv mitogenic signaling.71 Interestingly, VHL mutations muaj ntau heev nyob rau hauv cov kab mob cystic raum thiab ccRCCs ntawm cov neeg mob nyob rau theem kawg ntawm lub raum kab mob, hais tias.mob raumTej zaum yuav ua rau muaj kev xaiv siab rau cov hlwb uas nqa cov kev hloov pauv ntawm VHL thiab HIF activation.73 Tsis tas li ntawd, cov metabolic kev ntxhov siab nyob rau hauv cov seem nephrons ntawm CKD ob lub raum hloov mus rau pseudohypoxia ntawm cov cellular theem uas mus tas li ua rau HIF activation, uas tsav ib tug mob mitogenic teb los hloov tubular epithelial. Cov hlwb succumbing rau metabolic stress.74 Cov kev soj ntsuam no tuaj yeem muab qhov laj thawj tom qab kev koom tes ntawm ccRCC thiab CKD ua ntej thiab piav qhia vim li cas ccRCC muab tau los ntawm cov tubules sib thooj, qhov twg metabolic overload feem ntau tshwm sim. Tsis tas li ntawd, qhov no tuaj yeem piav qhia vim li cas ccRCC, cuam tshuam nrog CKD uas muaj ntau heev hauv cov pejxeem, yog qhov nquag tshaj plaws.mob qog noj ntshav. Thaum kawg, hypoxia yog qhov tshwm sim loj ntawm AKI, thiab txoj hauv kev HIF tau ua kom muaj zog tom qab AKI ntu los tsav cov lus teb mitogenic xav tau los hloov cov necrotic tubular epithelial hlwb.75

Autosomal dominant polycystic raum kab mob.Kev hloov pauv hauv cov kab mob hauv lub raum polycystic (PKD) 1 (encoding polycystin-1) lossis PKD2 (encoding polycystin-2)76 ua rau muaj kev loj hlob zuj zus ntawm ntau lub raum raum, uas ua rauraumtsis ua hauj lwm nyob rau hauv 50 feem pua ​​​​ntawm cov neeg mob autosomal dominant polycystic raum kab mob (ADPKD) cov neeg mob thaum muaj hnub nyoog 60 xyoo.76 Cystic thiab cov qog nqaij hlav hauv lub raum muaj ntau qhov sib xws ntawm kev tswj tsis tau hyperplasia ntawm lub raum epithelial hlwb77 vim muaj ntau yam kev sib xws ntawm ADPKD thiab mob qog noj ntshav. Muaj cov ntaub ntawv rau kev mob qog noj ntshav hauv cov neeg mob nrog ADPKD ntawm kev lim ntshav, 78 lossis tom qab hloov pauv, 22,79 tau pom tias muaj kev pheej hmoo ntau ntxiv.raumThaum piv nrog cov pej xeem, tab sis tsis yog rau lwm tus neeg mob ntawm kev kho lub raum hloov tsis muaj ADPKD.80 Tsis ntev los no, hauv kev tshawb fawb loj hauv Taiwan, Yu et al. tau tshaj tawm tias muaj kev cuam tshuam ntau ntxiv raumob qog noj ntshavHauv cov neeg mob ADPKD ua ntej tau txais kev kho lub raum, thaum piv nrog cov neeg mob uas tsis muaj tus kab mob tab sis muaj qhov zoo sib xws (lossis tsis muaj) qib ntawm lub raum tsis zoo, 81 txawm tias tom qab hloov kho rau txhua yam uas muaj feem cuam tshuam. Qhov no txhawb nqa qhov kev xav tias qhov hloov pauv hauv lub raum cystic hauv cov neeg mob ADPKD, thiab tshwj xeeb tshaj yog pawg zoo li papillary hyperplasia, tuaj yeem sawv cev rau cov kab mob precancerous uas tuaj yeem hloov zuj zus hauv RCC, feem ntau ntawm papillary histotype.82,83 Lwm qhov kev piav qhia yog overactivation hauv cyst- cov kab mob epithelial 84 ntawm txoj kev koom nrogmob raum85, 86 as well as in the pathogenesis ofmob qog noj ntshav(ie, aberrant activation of Notch and HIF-1a).87,88

Tuberous sclerosis complex.Tuberous sclerosis complex (TSC) yog tus kab mob autosomal dominant kab mob89 vim germline inactivating mutations ntawm tog twg los TSC1 (encoding hamartin) los yog TSC2 (encoding tuberin) noob, tsim ib tug complex uas tsis zoo tswj mTOR complex 1, tus tswv regulator ntawm cell proliferation thiab sib txawv. 90 Kev tshwm sim muaj xws li multifocal angiomyolipomas, epithelial cysts, thiab RCC txog li 5 feem pua ​​​​ntawm cov neeg mob, suav nrog ccRCC, 90 pRCC, 90 chromophobe RCC, 91, thiab neuroendocrine qog.89 Thib ob hits tuaj yeem txheeb xyuas cov seem ntawm TSC1 lossis TSC2 hauv feem ntau sporadic angiomyolipomas92 thiab TSC-txog RCCs.93 Kev hloov pauv hauv TSC2 tau pom nyob rau hauv 60 feem pua ​​​​ntawm kev kis tau cysticraumCov neeg mob cov kab mob, 94 qhia txog lub luag haujlwm hauv kev txhim kho cov kab mob sib kis / RCC. Kev sib raug zoo ntawm lub hnub nyoog, angiomyolipoma loj, thiab CKD tau tshaj tawm; Cov neeg mob uas muaj theem CKD zuj zus tuaj yeem ua rau laus dua thiab muaj ntau dua angiomyolipoma.95 CKD tuaj yeem txhim kho raws li qhov tshwm sim ntawm kev phais tshem tawm ntawm lub raum parenchyma vim kev loj hlob ntawm angiomyolipoma lossis hlwv, lossis mob hnyav los ntawm angiomyolipomas thiab / lossis RCCs.96,97 Cov. Qhov tseeb tias mTOR overactivation yog lub luag haujlwm rau lub raum mob hauv cov neeg mob TSC tau pom los ntawm kev ua tau zoo ntawm kev kho mob nrog mTOR inhibitors.90,98 Ntxiv rau, mTOR inhibitors txhim kho glomerular hypertrophy thiab hyperfiltration hauv cov neeg mob ntshav qab zib CKD, qhia tias txoj hauv kev no plays a lub luag haujlwm tseem ceeb hauvmob raumthiab kho.87,99

Keeb kwm pRCC. Cov qog nqaij hlav papillary raum tau pom nyob rau hauv ntau yam kab mob tsis tshua muaj caj ces.72,100 Tshwj xeeb, hereditary pRCC ntawm hom 1 yog txuam nrog nquag nce ntawm chromosome 7 uas cuam tshuam rau kev hloov pauv ntawm MET.72 Ib yam li ntawd, kev hloov pauv ntawm somatic lossis germline hloov pauv lossis lwm yam kev hloov pauv caj ces cuam tshuam nrog MET. tau pom nyob rau hauv 81.3 feem pua ​​​​ntawm hom 1 pRCCs.101 MET gene codes rau tyrosine kinase receptor uas khi hepatocyte loj hlob yam uas tiv thaiv tubular cell tuag102 thiab koom nrog AKI.

Kev raug mob raum ua rau mob qog noj ntshav los ntawm cov kab mob progenitor ntev ntev uas proliferate thaum kho lub raum

Lub cev loj hlob ntawm cov pov thawj qhia tau hais tias lub raum progenitors sawv cev rau kev sib txuas tseem ceeb ntawm ntau homraummob qog noj ntshav, 103–105 AKI, 25 thiab CKD.106–109 Lub raum progenitors yog cov tsis paub qab hau precursors ntawm epithelial hlwb nyob rau hauv lub glomerulus thiab nyob rau hauv tag nrho cov segments ntawm lub nephron thiab nyob rau hauv lub collecting duct.108–115 Nyob rau hauv sib piv rau cov heev proliferative phenotypes. Cov neeg nyob hauv cov ntaub so ntswg nyob rau hauv siab tig-tshaj plab, xws li daim tawv nqaij los yog lub plab, lub raum progenitors feem ntau quiescent thiab qhia ib tug txwv spontaneous proliferative muaj peev xwm los hloov physiological poob ntawm podocytes thiab tubular epithelial hlwb.108,109,111raumKev kho mob qhia tau hais tias feem ntau cov tubular epithelial hlwb muaj peev xwm ntawm proliferation, undergoing dedifferentiation ntawm qhov raug mob.116,117 Txawm li cas los xij, cov ntaub ntawv tsis ntev los no tshaj tawm hais tias cov neeg uas muaj preexisting ntawm lub raum progenitors undergo clonal proliferation los hloov txawv epithelial hlwb poob los ntawm detachment (xws li, podocytes). los yog necrosis (piv txwv li, tubular epithelial cells).

Xyoo 2011, Lindgren et al. Ua kom pom qhov zoo sib xws ntawm transcriptional thiab protein ntau ntawm lub raum progenitors thiab pRCCs nrog rau papillary adenomas.112 Ib txoj kev tshawb fawb ntxiv tau pom tias cov vascular cell adhesion molecule -1-ib tug zoo subset ntawm lub raum progenitors yog endowed nrog siab tiv thaiv kom tuag. , proliferative capacity, and multipotent differentiation capacity.108 Nyob rau hauv 2017, Cho et al. thiab Goncalves et al. qhia txog keeb kwm ntawm angiomyolipomas los ntawm multipotentraumCov hlwb epithelial nyob hauv cov tubule uas tab tom muaj kev nthuav dav clonal nyob rau hauv teb rau TSC gene deletion.103,104 Ob txoj kev tshawb fawb pom tias cov hlwb no tuaj yeem yog lub raum progenitors103,104 uas tau txais txiaj ntsig nrog ntau hom kab sib txawv muaj peev xwm113 thiab tias hauv qee yam mob tsim muaj ntau yam kab mob coexisting nyob rau hauv angiomyolipomas sporadic angiomyolipomas. txuam nrog TSC103,104 (Daim duab 225,103–105,112). Xyoo 2018, Young et al. siv ib leeg-cell RNA sequencing thev naus laus zis los txheeb xyuas lub xovtooj ntawm keeb kwm ntawm ccRCC thiab pRCC.105 Lawv txheeb xyuas cov pawg ze ze ntawm tubule 1, tsim los ntawm ib qho tshwj xeeb ntawm cov kab mob sib kis ntawm cov kab mob vascular adhesion molecule-1-cov hlwb zoo nyob rau hauv convoluted proximal tubule uas phim cov canonical cancer transcriptome ntawm pRCC thiab ccRCC.105 Ib tug tsis ntev los no reanalysis ntawm cov Hluas li al. Ib leeg-cell RNA sequencing database qhia tau hais tias proximal tubule 1 sib koom zoo sib xws nrog tib neeg lub raum progenitor cells25 (Daim duab 2). Thaum kawg, los ntawm kev siv cov kab ke taug qab raws li tus neeg sau xov xwm Confetti, 25 Paired li al. ncaj qha ua pov thawj tias pRCC yog muab los ntawm clonal expansion ntawm lub raum progenitors los ntawm cov kab mob adenoma-carcinoma nyob rau hauv cov lus teb rau AKI.25 Renal progenitors sawv cev rau cov pej xeem uas muaj peev xwm loj hlob thiab tiv thaiv kev tuag thiab tsim clones uas tsim tag nrho cov tubule ntu tom qab AKI. 111 Overactivation ntawm txoj kev Notch1, uas yog qhov tseem ceeb hauv kev teb rau AKI los ntawm kev txhawb nqa lub raum progenitor proliferation, 120 kuj tuaj yeem tsim cov papillary adenomas thiab pRCC tsim nyob rau hauv transgenic tsiaj qauv25 (Daim duab 2). Hauv kev khaws cov ducts, lub raum progenitors tau npaj siab ua lub hauv paus ntawm kev khaws cov duct-derived oncocytoma thiab carcinoma RCC.50,62 Vim li cas lub raum progenitors tuaj yeem muaj ntau yam.raumqog nqaij hlav? thiab yuav ua li cas yog qhov no txuas rau lubraumkho txheej txheem?

Ntau qhov kev tshawb fawb tau tsim kev sib txuas ncaj qha ntawm cov neeg nyob hauv cov qia hlwb thiab cov kab mob qog noj ntshav hauv ntau lub cev ntawm lub cev.1-3 Pivotal piv txwv yog cov tawv nqaij, lossis ntawm lub plab, qhov chaw sib sau ntawm DNA puas thiab kev hloov pauv hauv cov neeg nyob hauv. stem cell pib cov txheej txheem oncogenic.1–3 Qhov tseem ceeb ntawm cov txheej txheem yog cov neeg nyob hauv qia hlwb yog cov hlwb nyob ntev uas tiv taus kev tuag thiab muaj ntau lub voj voog ntawm cell faib thaum lub neej los cuam tshuam nrog lub cev hloov pauv lossis cov lus teb rau kev raug mob. .2 Qhov no ua rau muaj kev cuam tshuam ntawm DNA puas yam tsis muaj kev tshem tawm ntawm tes, txhawb kev mob qog noj ntshav.1 Cov pov thawj tshwm sim qhia tias muaj tshwm sim zoo sib xws kuj tshwm sim hauvraum. Zoo ib yam li cov neeg nyob hauv cov qia hlwb ntawm lwm cov kabmob, lub raum progenitors yog cov hlwb nyob ntev 100,111 nrog kev tiv thaiv siab rau kev tuag108,111,121 uas tau dhau mus qeeb qeeb thaum lub sijhawmraumlifespan109,111 thiab clonally amplify, muaj ntau ntau faib nyob rau hauv teb rau kev raug mob.122 Kev tshuaj ntsuam ntawm somatic mutations123 nyob rau hauv lub subset ntawm lub raum progenitors txuam lub proximal tubule 1 phenotype pom los ntawm Young et al.105 qhia ib tug enrichment inrichment chromatin, tswj cheeb tsam, thiab transcrisis. , uas tau nce zuj zus xyoo dhau los, ua rau muaj kev pheej hmoo ntawm cov qog hloov pauv.123 Ischemic raug mob, raug rau cov tshuaj nephrotoxic, xws li kws khomob, yog txuam nrog ib leeg-stranded so, ob-stranded so, covalently khi tshuaj DNA adducts, oxidative -induced lesions, thiab DNA DNA los yog DNA-protein cross-links.124 Kev ua kom cov ntaub so ntswg raug mob-txog txoj hauv kev uas thawb kev loj hlob sai tuaj yeem muab qhov thib ob ntaus rau cov progenitors, nyiam cov khoom txuam ntxiv ntawm DNA puas thiab sai carcinogenesis.

Kev mob qog nqaij hlav hauv lub raum tom qab raug mob raug ntxias los ntawm kev ua kom muaj txoj hauv kev tshwj xeeb

Txhua hom kev raug mob, tshwm sim hauv qhov chaw sib txawv, nyiam ua kom muaj txoj hauv kev sib txawv koom nrog cov ntaub so ntswg raug mob thiab kho. Raws li txoj cai, ntau cov kev tshawb fawb tsis ntev los no qhia tias cov txheej txheem ua rau kev hloov pauv ntawm lub raum progenitors mus rau hauv cov qog-initiating cell kuj tseem txuas rau kev ua kom muaj kev taw qhia, 25 xws li HIF, Notch, mTOR, thiab Hippo (Daim duab 2). Cov ntaub ntawv pov thawj ntawm qhov kev sib cuam tshuam no tsis yog los ntawm cov kab mob monogenic nkaus xwb tab sis kuj los ntawm cov kev pheej hmoo sib koom nrog rau cov qauv tsiaj.

VHL-HIF txoj kev.

Cov lus teb hypoxia los ntawm txoj kev HIF ua lub luag haujlwm tseem ceeb hauvmob raumthiab kho cov neeg mob cuam tshuam los ntawm AKI thiab CKD75 thiab ccRCC.

Ib yam li ntawd, nyob rau hauv cov neeg mob ntshav siab, hypoxia thiab HIF txoj hauv kev, uas tshwm sim los ntawm kev txwv ntawm cov hlab ntsha vim renin-angiotensin system, prostaglandins, thiab endothelin, 127,128 yog ib txoj hauv kev ua rau mob qog noj ntshav thiab CKD. Nyob rau hauv cov qauv tsiaj, tsis tu ncua transgenic qhia ntawm HIF-2ib tug nyob rau hauv tubular hlwb ua rau lub raum fibrosis thiab insufficiency, ib sab ntawm ntau lub raum cysts.129 Transgenic nas nrog raum epithelial-tshwj xeeb VHL deletion ua tsis tau tejyam los tsim ccRCC, hais tias thib ob- ntaus poob-ntawm-kev ua haujlwm hloov pauv tau xav tau.130 Cov qauv sib txuas VHL tshem tawm nrog PTEN, KIF3a, TRP53, lossis BAP1 poob, lossis nrog kev ua kom lub cev ntawm intracellular ntawm Notch1, ua rau tsim cov kab mob yooj yim thiab atypical cystic, zes ntawm dysplastic hlwb. nrog cov cytoplasm ntshiab, lossis txawm tias cov qog me me, ua rau ccRCC cov kab mob ua ntej 130 (Daim duab 2). Thaum kawg, qhov kev tshem tawm ntawm VHL ua ke nrog TRP53 thiab RB1 tau ua rau muaj cov kab mob zoo ib yam li tib neeg ccRCC.130 Qhov zoo siab, txhua txoj hauv kev qhib los ntawm Pten, Kif3a, Trp53, Bap1, Rb1, thiab Notch1 tau koom nrog hauv cov txheej txheem.raumkho los ntawm kev raug mob, underlining interconnection ntawm lub raum kab mob thiab lub raum mob cancer thiab qhia hais tias qhov thib ob hit tej zaum yuav feem ntau los ntawmmob raum.25 Raws li cov pov thawj ntxiv, cov nas laus uas muaj lub raum tshwj xeeb tsis ua haujlwm ntawm KIF3a tau tsim cov hlwv sai, zoo ib yam li hauv VHL KIF3a ob-knockout nas, 131 tsuas yog thaum raug rau AKI rov.

mTOR txoj kev.

Hauv cov ntshav qab zib mellitus, cov protein kinase B / mTOR txoj hauv kev, ua ke nrog hyperglycemia- thiab hyperinsulinemia ua rau kev ua haujlwm ntawm molecular pathways, pab txhawb kev txhim kho RCC thiab mob ntshav qab zib raum.133,134 Kev hloov pauv ntawm phosphoinositide 3-kinase-protein kinase B- mTOR txoj hauv kev genes (xws li PTEN, MTOR, thiab PIK3CA) tau nquag tshaj tawm hauv RCC.135 Ntxiv rau, kev hloov pauv hauv TSC1 / TSC2 ua rau ua kom mTOR signaling los ntawm Ras homolog enriched hauv hlwb (RHEB)–Notch RHEB regulatory voj, 90,103,104 ua rau kev txhim kho angiomyollipoma (Daim duab 2).

ANTI-CANCER CISTANCHE EXTRACT

Nthuav txoj kev.

Aberrant Notch signaling tuaj yeem ua rau ntau yam pathologies, suav nrog mob qog noj ntshav, hauv ntau yam kabmob, los ntawm kev khaws cia ntawm tus kheej rov ua dua tshiab thiab nthuav dav ntawm cov kab mob qog nqaij hlav cancer.136 Kev ua kom lub Notch txoj hauv kev ua lub luag haujlwm tseem ceeb hauvmob raumthiab kho120 tab sis kuj tuaj yeem ua rau muaj kev hloov pauv ntawm lub raum progenitors thiab kev loj hlob ntawm papillary adenomas thiab RCC hauv tib neeg thiab nas25 (Daim duab 2). Kev sim ua nyob rau hauv cov nas transgenic overexpressing Notch1 intracellular domain nyob rau hauv tubular hlwb pom kev loj hlob ntawm CKD raws li zoo raws li pRCC thiab acceleration ntawm cancerogenesis induced los ntawm AKI lub sijhawm, ntxiv kev lees paub qhov sib txuas ntawm AKI, CKD, thiab pRCC.25 Notch muaj lub luag haujlwm tseem ceeb hauv Kev tswj ntawm polarity thiab orientation ntawm mitotic spindle nyob rau hauv ntau hom cell.25,137-139 Tseeb, aberrant Notch activation cuam tshuam cov cell polarity signaling, ua rau ib tug tseem ceeb tus naj npawb ntawm txawv txav mitoses nyob rau hauv lub raum progenitors, los ntawm deregulation ntawm txoj kev koom tes nyob rau hauv lub cell voj voog checkpoints. thiab/los yog mitotic spindle tswj tau hais txog cov protein 1/transcriptional coactivator nrog PDZ-binding motif [YAP/TAZ] downstream phiaj) yog pom nyob rau hauv ntau hom cysticmob raum,140,141 nyob rau hauv teb rau AKI,142 thiab nyob rau hauv ntau yam mob qog noj ntshav, qhia txog txoj kev no kuj yog ib qho kev sib txuas ntawm cell proliferation hauv cyst tsim thiab RCC.143,144 Downregulation ntawm Salvador homolog-1 (SAV1 ), ib qho kev tivthaiv ntawm Hippo txoj kev, vim yog cov ntawv luam ntawm cov lej poob yog koom nrog hauv cov kab mob ntawm qib siab ccRCC los ntawm kev tswj cov kev loj hlob ntawm RCC hlwb los ntawm Hippo-YAP1 signaling.145 Tsis tas li ntawd, poob ntawm chromosome 22, uas muaj cov qog. suppressor noob NF2 (encoding a Hippo pathway regulator, SAV1)72 and SMARCB1 (encoding a protein of the chromatin-modifying switch/sucrose nonfermentable complex), yog txuam nrog sporadic pRCC.146 Thaum kawg, Cancer Genome Atlas tsom xam ntawm pRCC qhia qhov siab. Tus naj npawb ntawm kev hloov pauv hauv ob hom 1 thiab hom 2 cov qog uas cuam tshuam nrog Hippo signaling pathway (2.8 feem pua ​​​​thiab 10.0 feem pua ​​​​, feem). hway.147 Ntxiv mus, SAV1-knockout (SAV1flfl/flfl ) nas pom tau hais tias morphologic abnormalities nyob rau hauv lub raum tubules, xws li loj irregular nuclei, augmented cellularity, ib tug multi-layered epithelium, thiab tsim ntawm lub raum cysts.

c-Met-hepatocyte txoj kev loj hlob zoo.

Iron overload tau txuam nrog carcinogenesis hauv tib neeg.41 Hauv cov nas, rov ua haujlwm ntawm cov hlau ua rau lub cev tso tawm ntawm cov pa oxygen reactive (piv txwv li, Fenton cov tshuaj tiv thaiv) hauv lub raum proximal tubules, uas thaum kawg ua rau muaj qhov tshwm sim ntawm RCC.148 Cov tsiaj txhu. nthuav tawm ntau qhov kev hloov pauv genomic, thiab 2 ntawm qhov feem ntau hloov pauv loci sib raug rau MET amplification thiab CDKN2a / 2b deletion.148 Qhov zoo siab, qhov loj me ntawm cov qog tau cuam tshuam nrog Met qhia thiab / lossis kev nthuav dav, raws li tau lees paub los ntawm kev txheeb xyuas pawg.

Kev hloov kho chromatin.

Aberrations nyob rau hauv chromatin remodeling proteins yog txuam nrog tib neeg cov kab mob, xws li mob cancer.149,150 Chromatin remodeling txoj kev yog qhib tom qab DNA puas, teb rau raug mob, thiab teb rau carcinogens, nrog rau kev haus luam yeeb.124 Hauv ccRCC, txoj kev koom tes yog chromosome caj npab 3p noob polybromo 1 (PBRM1), SET domain-muaj protein ntau 2 (SETD2), thiab BRCA-associated protein-1 (BAP1) lossis hauv SMARCB1. 151,152 Kev poob ntawm CDKN2A vim kev hloov pauv, tshem tawm, lossis txhawb nqa hypermethylation thiab hloov pauv ntawm TP53 kuj tau tshaj tawm hauv ccRCC.

Kev hu rau lub luag haujlwm tshiab rau nephrologists hauv kev kho mob raum mob cancer

Kev raug mob cuam tshuam nrog DNA kev puas tsuaj yog ib qho kev paub tsav tsheb ntawm kev hloov pauv tsis zoo ntawm cov cell proliferating.3 Lub tswv yim no muab los ntawm irradiation-related leukemia thiab txhais mus rau cov qog nqaij hlav uas tshwm sim los ntawm cov nqaij mos nyob ntev-cov neeg nyob hauv progenitor/stem cells.2 Cov pov thawj ntxiv tam sim no qhia tau zoo ib yam. rau cov ntawv uas tsis yog Mendelianmob qog noj ntshav.153 Sickle cell-related diseasemob qog noj ntshavyog ib qho piv txwv paradigmatic ntawm yuav ua li cas rov ua dua ischemicmob raumtuaj yeem ua rau mob qog noj ntshav nyob rau hauv qhov chaw raug mob ntawm covraum.52–54 Epidemiologic thiab kev sim kev tshawb fawb tam sim no qhia tib yam rau ntau yam ntawm cov qog nqaij hlav hauv lub raum, thiab qhia tias muaj cov kab mob premalignant, tsuas yog txog lub sij hawm cov tswv yim tshiab rau kev kuaj mob raum tau sib cav.154 Tab sis vim li cas peb thiaj li soj ntsuam qhov qis RCC. Cov neeg mob CKD/AKI feem ntau muaj ntau npaum li cas? Ua ntej, benign/thaum ntxov cov qog nqaij hlav hauv lub raum mus tsis tu ncua raws li lawv tshwm sim nyob rau hauv cov neeg mob laus thiab siv sij hawm los tsim rau hauv cov ntaub ntawv malignant. Raws li ib qho piv txwv tseem ceeb, cov kev tshawb fawb txog kev puas siab puas ntsws qhia tias papillary adenomas yog ib txwm muaj, nrog rau qhov ntau ntawm 5 feem pua ​​​​mus rau 10 feem pua ​​​​ua ntej hnub nyoog 40 xyoo thiab nce mus txog yuav luag 40 feem pua ​​​​ntawm cov hnub nyoog 70 xyoo.155 Tsis tas li ntawd, kev hloov pauv ntawm benign rau malignant qog sawv cev rau ntau tus txheej txheem uas yuav tsum tau ntxiv ib puag ncig los yog noob caj noob ces ntxiv rau CKD/AKI kom txhim kho tag nrho.25 Thaum kawg, AKI thiab CKD cov neeg mob muaj lub neej luv dua, 156, tshwj xeeb tshaj yog thaum muaj kev rog thiab ntshav qab zib. Kev kho mob ntawm CKD nrog renin-angiotensin system blockers tsis tsuas yog ncua sijhawm CKD tab sis kuj txo qis qhov tshwm sim ntawm RCC, 157 muab cov pov thawj ntawm lub tswv yim tias kev kho mob raum raug mob yuav yog ib txoj hauv kev zoo los tiv thaiv kev loj hlob ntawm lub raum hlav.

Tam sim no, kev koom tes ntawm nephrologists hauv kev tswj cov neeg mob nrogmob qog noj ntshavfeem ntau txwv rau kev kho CKD tom qab kev phais thiab, ib zaug xav tau, kho raum hloov. Txawm li cas los xij, lub tswv yim raug mob ntawm lub raum mob qog noj ntshav qhia txog cov hauv kev tshiab rau nephrologists los tiv thaivmob qog noj ntshavthiab txhim kho cov txiaj ntsig ntawm cov neeg mob raum mob cancer.

Ua ke nrog cov kws kho mob thawj zaug, nephrologists tuaj yeem nce ntxivpaub txog kab mob raumnyob rau hauv lub zej zog, ameliorate ntshav siab tswj, txhawb kev noj qab nyob zoo txoj kev ua neej nyob rau hauv lub neej, thiab pab txhawb kev zam los yog raug siv tshuaj nephrotoxic (kev tiv thaiv thawj zaug).

Nephrologists tuaj yeem koom nrog hauv kev txheeb xyuas cov neeg mob uas muaj kev pheej hmoo uas yuav tau txais txiaj ntsig zoo tshaj plaws los ntawm cov phiaj xwmmob qog noj ntshavkev tshuaj ntsuam xyuas.

Nephrologists tuaj yeem pab txo qismob raumthiab, thaum nws tshwm sim, muab kev kho mob ncaj nraim (xws li, los ntawm kev txheeb xyuas cov tshuaj uas ua rau muaj kev phom sij thiab txwv tsis pub raug mob los yog kuaj pom thiab kho subacute thiab mob ntev.mob raumkom ntxov li sai tau). Qhov no yuav xav tau kev paub ntau ntxiv hauv cov neeg txiav txim siab, txhawm rau txhawm rau xa cov neeg mob mus rau nephrologists thaum ntxov raws li theem ntawm cov zis txawv txav thiab tsis yog ib zaug CKD theem 3 lossis 4 tau mus txog, uas lig dhau lawm los txwv qhov cuam tshuam ntawmmob raumntawm cancerogenesis.

Nephrologists tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv theem nrabmob raumtxhawm rau txwv cov qog loj hlob los ntawm kev muab kev saib xyuas zoo CKD, los ntawm kev txo cov kev pheej hmoo ntawm CKD, los ntawm kev txwv cov kev ntxhov siab hauv metabolic rau cov nephrons seem, thiab thaum kawg los ntawm kev txiav txim siab kuaj qog nqaij hlav nrog kev kuaj xyuas ultrasound hauv cov neeg mob uas muaj kev pheej hmoo ntau dua.

Nephrologists tuaj yeem ua haujlwm nrog urologists thiab oncologists kom txo tau qhov cuam tshuam ntawm kev phais thiab kev kho mob ntawmmob raum, yog li txo qhov kev pheej hmoo ntawm qog rov ua dua." Los ntawmmob raumrau mob qog noj ntshav" raws li lub tswv yim tshiab tuaj yeem txhais tau tias mob qog noj ntshav hauv lub raum yog qhov txiaj ntsig ntev ntev ntawm AKIand CKD, ua kom muaj kev saib xyuas ntxiv rau kev tiv thaiv.mob raumhauv cov neeg mob nrogmob qog noj ntshav, thiab tsim lub luag haujlwm tshiab rau nephrologists hauv kev tswj cov neeg mob nrogmob qog noj ntshav.

CISTANCHE IMPROVE KIDNEY FUNCTION

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