Neuroblastoma – Patofizjologia i mechanizm

Neuroblastoma
Patofizjologia i mechanizm

Neuroblastoma to złośliwy nowotwór wywodzący się z komórek grzebienia nerwowego obwodowego układu współczulnego, stanowiący około 8% nowotworów złośliwych u dzieci. Rokowanie zależy od stopnia zróżnicowania guza, z gorszymi wynikami u pacjentów z prymitywnymi formami. Genetycznie neuroblastoma dzieli się na grupy z niemal diploidalną (45%) i triploidalną (55%) zawartością DNA. Amplifikacja onkogenu MYCN, obecna u 20-25% pacjentów, koreluje z agresywnym przebiegiem choroby. Mutacje aktywujące kinazę ALK oraz mutacje linii zarodkowej genu PHOX2B są kluczowymi czynnikami patogenezy, szczególnie w rodzinnych przypadkach. Najczęstsze aberracje genetyczne to zysk chromosomu 17q (≥80% przypadków), delecje 1p36 (25-35%) i 11q, które wiążą się z gorszym rokowaniem i zaawansowanym stadium choroby. Epigenetyczne zmiany, w tym hipometylacja genów takich jak CCND1, oraz dysregulacja niekodujących RNA (np. miR-137, miR-152, miR-495) odgrywają istotną rolę w patogenezie i różnicowaniu neuroblastoma.

Patofizjologia neuroblastoma

Neuroblastoma jest złośliwym nowotworem rozwijającym się z komórek grzebienia nerwowego obwodowego układu nerwowego współczulnego. Jest to najczęstszy pozaczaszkowy guz lity wieku dziecięcego, stanowiący około 8% wszystkich nowotworów złośliwych u dzieci. Rokowanie długoterminowe zależy przede wszystkim od stopnia zróżnicowania guza, przy czym pacjenci z bardziej prymitywnymi guzami przypominającymi komórki grzebienia nerwowego mają gorsze rokowanie niż pacjenci z bardziej zróżnicowanymi nowotworami¹²³.

Pochodzenie neuroblastoma

Neuroblastoma wywodzi się z komórek prekursorowych układu współczulnego podczas embriogenezy. Powstaje, gdy neuroblasty (pluripotencjalne komórki współczulne) nie dojrzewają prawidłowo, zamiast tego kontynuują niekontrolowany wzrost i podział. Guzy te mogą występować w różnych lokalizacjach, najczęściej w nadnerczach lub zwojach współczulnych jamy brzusznej¹²³.

Kluczowym elementem dojrzewania komórek grzebienia nerwowego jest programowana transformacja nabłonkowo-mezenchymalna (EMT). Zaburzenie tego procesu na różnych etapach dojrzewania prekursorów grzebienia nerwowego może prowadzić do rozwoju neuroblastoma¹². Badania wykazały, że TGF-β1 indukuje EMT w komórkach neuroblastoma, zwiększając ich migrację, przy czym proces ten nie zależy od klasycznej ścieżki sygnałowej Smad, a zamiast tego może angażować czynnik transkrypcyjny Gli³⁴.

Heterogenność molekularna neuroblastoma

Neuroblastoma charakteryzuje się znaczną heterogennością kliniczną i molekularną. Pomimo sekwencjonowania DNA i RNA ponad tysiąca przypadków, nie zidentyfikowano pojedynczej mutacji genetycznej lub epigenetycznej, która byłaby odpowiedzialna za wszystkie przypadki neuroblastoma¹². Ta różnorodność molekularna potwierdza koncepcję, że neuroblastoma reprezentuje spektrum choroby¹.

Pod względem genetycznym, neuroblastoma można podzielić na grupę z niemal diploidalną zawartością DNA jądrowego (około 45% przypadków) oraz grupę z niemal triploidalną zawartością DNA (około 55% przypadków)¹. Ta różnorodność genetyczna koreluje z klinicznym zachowaniem guza i odpowiedzią na leczenie¹.

Główne mechanizmy molekularne w patogenezie neuroblastoma

Amplifikacja i nadekspresja genu MYCN

Onkogen MYCN odgrywa kluczową rolę w patogenezie neuroblastoma i definiuje agresywną podgrupę guzów. Amplifikacja MYCN występuje u około 20-25% pacjentów z neuroblastoma¹²³. Gen ten zlokalizowany jest na chromosomie 2p24 i zazwyczaj występuje w postaci podwójnych minut (fragmenty chromosomów) lub jednorodnie barwiących się regionów¹.

Stopień amplifikacji wykazuje bimodalny rozkład: albo 3-10-krotny, albo 100-300-krotny¹. Obecność tej mutacji silnie koreluje z zaawansowanymi stadiami choroby i gorszym rokowaniem¹²³. Chociaż modele myszy transgenicznych wykazały, że nadekspresja MYCN może być czynnikiem inicjującym nowotwór, wiele innych genów współpracujących i genów supresorowych nowotworów jest nadal badanych i może również odgrywać rolę w rozwoju guza¹.

Mutacje aktywujące ALK

Aktywujące mutacje genu ALK (kinaza chłoniaka anaplastycznego) są również zaangażowane jako onkogenne czynniki napędzające rozwój neuroblastoma¹². ALK to sieroca receptorowa kinaza tyrozynowa, która normalnie ulega ekspresji tylko w rozwijającym się embrionalnym i noworodkowym ośrodkowym układzie nerwowym¹.

Mutacje genu ALK występują częściej niż mutacje genu PHOX2B w rodzinnych przypadkach neuroblastoma¹. Amplifikacja lub mutacja ALK promuje fosforylację ALK, prowadząc do zwiększonej aktywności kinazy, co ostatecznie skutkuje nowotworzeniem¹. Wykazano, że znacząca korelacja między aktywującymi mutacjami w domenie kinazy tyrozynowej ALK a złym wynikiem klinicznym występuje w sporadycznych przypadkach neuroblastoma¹.

Aktywowany ALK współpracuje z MYCN w patogenezie neuroblastoma¹, sygnalizując przez ścieżkę ERK-ETV5-RET, aby napędzać onkogenezę neuroblastoma¹. Przełomowym odkryciem w rozumieniu patogenezy neuroblastoma była identyfikacja aktywujących mutacji punktowych w domenie kinazy tyrozynowej genu ALK jako głównej przyczyny rodzinnych przypadków neuroblastoma oraz ich implikacja w znacznej części sporadycznych guzów neuroblastoma¹.

Mutacje PHOX2B

Mutacje linii zarodkowej genu PHOX2B (Paired-like Homeobox 2B) występują w podgrupie rodzinnych przypadków neuroblastoma i w około 4% przypadków sporadycznych¹. PHOX2B to gen kodujący czynnik transkrypcyjny z homeodomeną, który promuje wyjście z cyklu komórkowego i różnicowanie neuronalne, odgrywając kluczową rolę w rozwoju neuronów autonomicznych pochodzących z grzebienia nerwowego¹.

Warianty PHOX2B stymulują proliferację i dedyferencjację niedojrzałych neuronów współczulnych¹. Obserwacje sugerują, że zaburzenia w ścieżce różnicowania regulowanej przez PHOX2B mogą być wspólnym czynnikiem genetycznym odpowiedzialnym za choroby wywodzące się z grzebienia nerwowego¹.

Aberracje chromosomowe

Najczęstszą aberracją genetyczną występującą u pacjentów z neuroblastoma jest zysk chromosomu 17q, który występuje w co najmniej 80% guzów pierwotnych¹²³. Ta zmiana wiąże się z gorszym rokowaniem¹.

Delecja krótkiego ramienia chromosomu 1 (1p36) jest wykrywana w około 25-35% pierwotnych neuroblastoma¹². Ta zmiana jest częstsza w guzach o wysokim stopniu zaawansowania i zwykle związana z amplifikacją MYCN¹. Delecja 1p36 wiąże się ze zwiększonym ryzykiem nawrotu po resekcji zlokalizowanych neuroblastoma¹.

Delecje chromosomu 11q są często znajdowane w guzach o wysokim stopniu zaawansowania bez amplifikacji MYCN i z nienaruszonym chromosomem 1p¹. Te delecje są związane z złym rokowaniem wśród pacjentów z neuroblastoma¹.

Utrata chromosomu 3p często występuje w powiązaniu z utratą 11q i zwykle występuje w guzach bez amplifikacji MYCN lub delecji 1p¹.

Mechanizmy epigenetyczne w patogenezie neuroblastoma

Modyfikacje epigenetyczne

Badania z immunoprecypitacją chromatyny z sekwencjonowaniem wysokoprzepustowym (ChIPseq) i sekwencjonowaniem RNA wykazały specyficzne wzory epigenetyczne, które różnią neuroektodermę, grzebień nerwowy i bardziej dojrzałe stany neuronalne¹. Modyfikacje epigenetyczne są odwracalnymi zmianami, które odgrywają rolę w regulacji ekspresji genów poprzez regulację dostępności chromatyny dla elementów niezbędnych do transkrypcji¹.

Wyniki badań metylacji DNA opartych na mikromacierzach przeprowadzonych u pacjentów z neuroblastoma wykazały, że hipometylacja specyficzna dla genów (promotorów) występuje częściej niż hipermetylacja genomowa¹². Zaobserwowano również, że utrata metylacji DNA jest bardziej powszechna niż hipermetylacja promotorów w neuroblastoma¹.

Co ciekawe, hipometylacja dotyka genów istotnych dla patogenezy neuroblastoma, takich jak CCND1, a także wpływa na biologiczne funkcje związane z rakiem¹². W przypadku CCND1 różnicowa metylacja dotyczyła głównie ewolucyjnie zachowanego, funkcjonalnie istotnego regionu 3′ UTR, sugerując, że hipometylacja poza regionami promotorów może odgrywać rolę w patogenezie neuroblastoma¹.

Rola niekodujących RNA

Niekodujące RNA (mikroRNA, lncRNAs, piRNAs) są niezbędnymi regulatorami transkrypcyjnymi biologii komórek macierzystych, rozwoju i różnicowania grzebienia nerwowego¹. W neuroblastoma wiele niekodujących RNA ulega dysregulacji, wskazując, że odgrywają ważne role w rozwoju choroby¹.

W neuroblastoma niekodujące RNA są zaangażowane w przedtranskrypcyjną regulację genów, w tym w składanie chromatyny, modyfikację histonów i metylację DNA¹. Zaobserwowano, że nadregulacja miR-137 w apoptozie komórek neuroblastoma indukowanej resveratrolem prowadzi do zaburzenia równowagi poziomów metyltransferazy histonowej EZH2¹.

Utrata EZH2 ułatwia redukcję poziomów H3K27me3 i aktywację genów supresorowych nowotworów w neuroblastoma, takich jak klusteryna (CLU) i receptor czynnika wzrostu nerwów (NGFR)¹. miR-152 celuje w metylotransferazę DNA 1 (DNMT1), aby pośredniczyć w demetylacji DNA, przyczyniając się do procesu różnicowania indukowanego przez kwas all-trans retinowy (ATRA)¹.

Badania wykazały również, że miRNA, które są nadmiernie ekspresjonowane w komórkach neuroblastoma z delecją 1p, mogą potencjalnie zakłócać regulację genów związanych z różnicowaniem neuronalnym, przyczyniając się w ten sposób do patogenezy neuroblastoma¹. W szczególności zaobserwowano, że miR-495 celuje głównie w większość mRNA, które są zaangażowane w różnicowanie neuronalne¹.

Chromotripsja i niestabilność genetyczna

Chromotripsja to katastrofalny proces, który opisuje nowy mechanizm karcynogenezy spowodowany dużą liczbą (dziesiątkami do setek) rearanżacji zachodzących w tej samej komórce w jednym lub kilku chromosomach¹. Chromotripsję obserwowano w co najmniej 2-3% wszystkich nowotworów, przy czym najwyższą częstość wykryto w guzach tkanek miękkich¹.

Zaproponowany model przez profesora Ugo Rovigatti jest oparty na infekcji wirusem indukującym mikroogniska i jego potencjalnej roli onkogennej jako czynnika wyzwalającego: (i) wysoki i trwały stan zapalny; (ii) chromotripsję i niestabilność genetyczną; oraz (iii) transformację komórek in vitro i karcynogenezę in vivo¹.

Mechanizmy progresji i regresji neuroblastoma

Odwracalna plastyczność adaptacyjna

Zdolność neuroblastoma wysokiego ryzyka do przetrwania niekorzystnych warunków wzrostu i terapii wielomodalnej wynika z nowego zjawiska, jakim jest zdolność do odwracalnej plastyczności adaptacyjnej. Ta plastyczność pozwala komórkom na przejście między wysoce proliferacyjnym fenotypem zależnym od zakotwiczenia (AD) a wolno rosnącym, opornym na anoikis fenotypem niezależnym od zakotwiczenia (AI)¹.

Profil różnicowej ekspresji genów tych dwóch fenotypów komórkowych w linii komórkowej myszy Neuro2a wyznaczył ścieżki proliferacji w komórkach AD lub aktywacji kinazy tyrozynowej/hamowania apoptozy w komórkach AI¹. Zidentyfikowano 20-krotną nadekspresję inhibitora różnicowania 2 (Id2) w komórkach AD, podczas gdy w komórkach AI zaobserwowano regulację w górę genów zaangażowanych w oporność na anoikis, takich jak PI3K/Akt, Erk, Bcl2 i integryny¹.

Wymuszenie regulacji w dół Id2 w komórkach AD lub nadekspresja w komórkach AI indukowały komórki do uzyskania cech innego fenotypu¹. Id2 wiąże zarówno TGF-β, jak i Smad2/3 i wydaje się kluczowy dla utrzymania fenotypu proliferacyjnego, przynajmniej częściowo poprzez negatywną regulację ścieżki TGF-β/Smad¹.

Spontaniczna regresja

Spontaniczna regresja neuroblastoma została dobrze udokumentowana u niemowląt z chorobą w stadium 4S¹. Dokładne mechanizmy odpowiedzialne za spontaniczną regresję nie są w pełni znane, ale zaproponowano kilka prawdopodobnych mechanizmów¹.

Jednym z kandydujących kluczowych mechanizmów leżących u podstaw regresji guza jest zależność komórek neuroblastoma od czynnika wzrostu nerwów (NGF)¹. Badania sugerują, że kryzys telomerowy odgrywa rolę w spontanicznej regresji guza¹.

Mechanizmy spontanicznej regresji mogą obejmować hipermetylację podtelomerowego DNA, apoptozę, pozbawienie czynnika wzrostu nerwów (NGF) i odpowiedź immunologiczną¹.

Podstawy molekularne terapii kwasem retinowym

Naukowcy ze Szpitala Dziecięcego St. Jude odkryli mechanizm, za pomocą którego kwas retinowy selektywnie zabija przerzutowe komórki neuroblastoma, przy niewielkim wpływie na guzy pierwotne¹. Kwas retinowy wykorzystuje nowatorski mechanizm do zabijania przerzutowych komórek neuroblastoma, przejmując normalną ścieżkę rozwojową, aby wywołać śmierć komórek nowotworowych¹.

Badacze wykazali, że sygnalizacja BMP czyni komórki neuroblastoma znacznie bardziej podatnymi na działanie kwasu retinowego¹. Ponieważ mikrośrodowisko szpiku kostnego powoduje, że komórki neuroblastoma mają tam wyższą aktywność BMP, elegancko wyjaśnia to, dlaczego kwas retinowy jest bardzo skuteczny w leczeniu tych komórek podczas terapii konsolidacyjnej, ale nie guzów pierwotnych podczas leczenia początkowego¹.

Wykorzystując technologię edycji genów, naukowcy odkryli związek między sygnalizacją BMP a kwasem retinowym¹. Stwierdzili, że w neuroblastoma sygnalizacja BMP działa z sygnalizacją kwasu retinowego w taki sam sposób, jak podczas rozwoju¹. Jeśli na DNA znajduje się dużo czynników transkrypcyjnych ścieżki sygnałowej BMP, wtedy sygnalizacja kwasu retinowego łączy się z nią, aby promować ekspresję genów związanych ze śmiercią komórki¹.

Inne czynniki w patogenezie neuroblastoma

Rola cytokin

Główne cytokiny i czynniki wzrostu zaangażowane w patogenezę neuroblastoma to VEGF i IL-6, produkowane odpowiednio przez komórki neuroblastoma i komórki zrębu¹. VEGF promuje angiogenezę guza, podczas gdy IL-6 jest zaangażowana w jego wzrost i przerzuty¹.

IL-6 pochodząca z komórek zrębu szpiku kostnego promuje wzrost i przeżycie linii komórkowych neuroblastoma poprzez fosforylację sygnalizacji Erk1/2 i STAT-3 oraz pośredniczy w aktywności stymulującej wzrost w eksperymentalnych modelach neuroblastoma in vivo¹. Mechanizm, który rzuca światło na prometastatyczną rolę IL-6 w neuroblastoma, wynika z odkrycia, że komórki neuroblastoma, choć niezdolne do produkcji czynników aktywujących osteoklasty, uwalniają rozpuszczalną galektynę-3, która z kolei stymuluje komórki zrębu szpiku kostnego do produkcji IL-6¹.

Badania na modelach zwierzęcych wykazały, że zarówno CXCL12, jak i CXCR4 są konstytutywnie ekspresjonowane w liniach komórkowych neuroblastoma, a także w pierwotnym przerzutowym neuroblastoma, wskazując na ich udział w autokrynnych/parakrynnych pętlach stymulacji wzrostu guza, a nie w zwiększaniu tworzenia przerzutów¹.

Zaburzenia szlaków sygnałowych

Badania z wykorzystaniem chip-seq i sekwencjonowania RNA wykazały specyficzne wzory epigenetyczne, które odróżniają neuroektodermę, grzebień nerwowy i bardziej dojrzałe stany neuronalne¹. Potwierdzają to również badania genomowe w neuroblastoma, które pokazały różne zmiany genetyczne i epigenetyczne wpływające na kluczowe ścieżki rozwojowe¹.

Ścieżka TGF-β jest regulowana przez środowisko komórkowe i jej integrację z innymi ścieżkami sygnałowymi¹. W nowotworach ścieżka ta jest związana z supresją komórek we wczesnych guzach oraz proliferacją, inwazyjnością, angiogenezą i karcynogenezą zaawansowanych guzów¹.

Inaktywacja czynnika transkrypcyjnego p53 poprzez bezpośrednią mutację lub aberrację genetyczną jest znakiem rozpoznawczym prawie wszystkich guzów¹. miR-380-5p hamuje wysokie poziomy ekspresji p53, co jest związane z złym rokowaniem w neuroblastoma z amplifikacją MYCN¹.

Rola komórek macierzystych neuroblastoma

Neuroblastoma jest nowotworem wysoce heterogennym, a w pojedynczym guzie występuje wiele różnych specyficznych komórek. Zasugerowano, że wszystkie typy komórek nowotworowych, które zapewniają heterogenne właściwości, charakteryzują się różnicowaniem pojedynczej komórki macierzystej neuroblastoma¹.

Komórki macierzyste neuroblastoma zostały po raz pierwszy opisane jako komórki typu I (typ pośredni), złośliwe komórki grzebienia nerwowego, morfologicznie znajdujące się pomiędzy komórkami neuroblastycznymi a komórkami grzebienia nerwowego¹.

Komórki macierzyste neuroblastoma charakteryzują się regulacją w górę białek powierzchniowych PROM1/CD133, KIT/CD117, CSF3R/CD114 oraz genów GPRC5C, NOTCH1, PGF, NTRK2, NGFR, CSF3, STAT3 i RBL2, które odgrywają rolę w różnicowaniu w kierunku złośliwej komórki macierzystej neuroblastoma¹.

Implikacje dla terapii celowanej

Opracowanie skutecznych i specyficznych leków epigenetycznych może wkrótce umożliwić odwrócenie patogennych modyfikacji epigenetycznych, a tym samym promowanie różnicowania neuroblastoma zgodnie z zaprogramowaną ścieżką dojrzewania grzebienia nerwowego¹.

Przełomowe odkrycie aktywujących mutacji punktowych w domenie kinazy tyrozynowej genu ALK jako głównej przyczyny rodzinnego neuroblastoma oraz ich implikacja w znacznej części sporadycznych guzów neuroblastoma sprawia, że selektywne inhibitory ALK, które są głównym celem obecnych wysiłków rozwoju leków, mogą okazać się cenne dla leczenia wybranych pacjentów z neuroblastoma¹.

Wykrycie mutacji ATM, p53, RB1, APC, HNF1A, VHL, NOTCH, NF1 i RAS może być pomocne w zrozumieniu patogenezy neuroblastoma i opracowaniu nowych terapii celowanych¹. Częsta mutacja ERBB2 I655V w neuroblastoma może umożliwić dalsze badanie tej mutacji jako potencjalnego celu terapeutycznego¹².

Jednoczesne celowanie w różnicowe ścieżki molekularne regulujące odwracalną plastyczność adaptacyjną skutkowało 50% wyleczeniem mikroskopowej choroby i opóźnieniem wzrostu guza w ustalonych mysich guzach neuroblastoma¹. Wykorzystanie chemioprewencji, która ma na celu odwrócenie, zapobieganie, opóźnienie lub tłumienie powstawania guzów, wzrostu, progresji i ewolucji, może być obiecującym podejściem do kontroli neuroblastoma¹².

Retinoidy i difluorometylornityna (DFMO) są jednymi z najlepiej przebadanych środków chemoprewencyjnych w neuroblastoma¹². Kwas retinowy pozostaje najbardziej potencjalnym induktorem różnicowania w ludzkim neuroblastoma, podczas gdy DFMO nieodwracalnie hamuje ornitoynodekarobksylazę (ODC), enzym ograniczający szybkość biosyntezy poliamin, i celuje w sygnalizację LIN28/Let7, wpływając tym samym na linię komórek macierzystych raka neuroblastoma¹.

Immunoterapia jest również obiecującym obszarem badań, jednak ze względu na słabo immunogenne cechy neuroblastoma, badane są alternatywne strategie obejmujące leczenie wspomagające w celu indukcji wrażliwości na blokadę punktów kontrolnych układu immunologicznego (ICB)¹.

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Materiały źródłowe

#1 Neuroblastoma: Molecular Pathogenesis and Therapy
https://pmc.ncbi.nlm.nih.gov/articles/PMC4418018/
Neuroblastoma is a developmental malignancy arising within the neuronal ganglia of the peripheral sympathetic nervous system. […] Long-term survival is primarily dependent on the degree of differentiation, with patients exhibiting more primitive crest-like tumors doing worse than patients with more differentiated tumors who have a more favorable outcome. […] The extensive clinical and pathologic heterogeneity of this malignancy reflects the unique developmental biology of the neural crest. […] Placing the pathogenesis of neuroblastoma in the context of neural crest embryogenesis may help to explain the complex molecular heterogeneity of this disease and help identify molecules and pathways for specific biologically-targeted interventions. […] A central component of neural crest maturation is a programmed epithelial-to-mesenchymal transition (EMT).
#1 Neuroblastoma: Molecular Pathogenesis and Therapy
https://pmc.ncbi.nlm.nih.gov/articles/PMC4418018/
The observed clinical and pathological heterogeneity of neuroblastoma may well result from diverse molecular drivers disrupting this carefully orchestrated process at discrete stages of neural crest maturation. […] While the origins of neuroblastoma tumorigenesis arise from the disrupted development of neural crest precursors, no single genetic or epigenetic mutation has been found, after the DNA and RNA sequencing of over one thousand cases, to account for all cases of NB. […] Thus, this extensive molecular heterogeneity supports the concept that neuroblastoma represents a spectrum of disease. […] The MYCN oncogene plays a major role in neuroblastoma tumorigenesis and defines an aggressive subset of tumors. […] Activating mutations of ALK (anaplastic lymphoma kinase) are also implicated as oncogenic drivers of neuroblastoma.
#1 The emerging molecular pathogenesis of neuroblastoma: implications for improved risk assessment and targeted therapy | Genome Medicine | Full Text
https://genomemedicine.biomedcentral.com/articles/10.1186/gm74
In addition, evidence has emerged for the contribution of epigenetic disturbances in neuroblastoma oncogenesis. […] As in other cancer entities, altered microRNA expression is also being recognized as an important player in neuroblastoma. […] The recent successes in unraveling the genetic basis of neuroblastoma are now opening opportunities for development of targeted therapies. […] The clinically heterogeneous nature of NB is also reflected, in part, by its biological and genetic heterogeneity. […] According to their DNA index, NBs can be divided into a group with a near-diploid nuclear DNA content (about 45% of NBs) and those with a near-triploid DNA content (about 55%). […] The MYCN oncogene (located on chromosome 2p24; 'N’ stands for neuroblastoma-derived) was found to be amplified in 20 to 25% of NBs, and is usually present in the form of double-minutes (chromosome fragments) or homogeneously staining regions.
#1 Epidemiology, pathogenesis, and pathology of neuroblastoma – UpToDate
https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-neuroblastoma
The epidemiology, embryogenesis, molecular pathogenesis, and pathology of neuroblastoma will be presented here. […] Neuroblastomas, which account for 97 percent of all neuroblastic tumors, are heterogeneous, varying in location, histopathologic appearance, and biologic characteristics. […] Clinical diversity correlates closely with numerous clinical and biologic factors (including patient age, tumor stage and histology, and genetic and chromosomal abnormalities), although its molecular basis remains largely unknown.
#1 Neuroblastoma – Wikipedia
https://en.wikipedia.org/wiki/Neuroblastoma
Neuroblastoma typically occurs due to a genetic mutation occurring in the first trimester of pregnancy. […] The cause of neuroblastoma is not well understood. The great majority of cases are sporadic and nonfamilial. About 12% of cases run in families and have been linked to specific gene mutations. Familial neuroblastoma in some cases is caused by rare germline mutations in the anaplastic lymphoma kinase (ALK) gene. […] MYCN oncogene amplification within the tumor is a common finding in neuroblastoma. The degree of amplification shows a bimodal distribution: either 3- to 10-fold, or 100- to 300-fold. The presence of this mutation is highly correlated to advanced stages of disease. […] One study strongly indicates that miRNAs that are excessively expressed in 1p-deleted neuroblastoma cells, as opposed to other genetic subgroups of neuroblastoma, could potentially disrupt the regulation of genes associated with neuronal differentiation, thereby contribute to the pathogenesis of neuroblastoma. Furthermore, it was noted that miR-495 primarily targeted the majority of mRNAs that are involved in neuronal differentiation.
#1 Neuroblastoma | Nature Reviews Disease Primers
https://www.nature.com/articles/nrdp201678
Neuroblastoma is the most common extracranial solid tumour occurring in childhood and has a diverse clinical presentation and course depending on the tumour biology. […] The most malignant tumours have amplification of the MYCN oncogene (encoding a transcription factor), which is usually associated with poor survival, even in localized disease. […] Although transgenic mouse models have shown that MYCN overexpression can be a tumour-initiating factor, many other cooperating genes and tumour suppressor genes are still under investigation and might also have a role in tumour development. […] Segmental chromosome alterations are frequent in neuroblastoma and are associated with worse outcome. […] The rare familial neuroblastomas are usually associated with germline mutations in ALK, which is mutated in 10-15% of primary tumours, and provides a potential therapeutic target.
#1 Molecular Basis and Clinical Features of Neuroblastoma | JMA Journal
https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2021-0077
The best-characterized copy number alteration associated with poor prognosis is the amplification of the MYCN oncogene. […] However, because MYCN amplification and 1p LOH are not observed in approximately half of all high-risk neuroblastoma patients, it has been suggested that genetic aberrations other than MYCN amplification and 1p LOH are involved in the development and progression of the disease. […] Notably, although the 11q deletion is predominantly detected in tumors without MYCN amplification and 1p LOH, it remains highly correlated with the dismal prognosis of neuroblastoma patients. […] ALK is an orphan receptor tyrosine kinase normally expressed only in the developing embryonic and neonatal central nervous system. […] Chromothripsis was observed in at least 2%-3% of all cancers, with the highest frequencies detected in soft tissue tumors.
#1 Research progress of neuroblastoma related gene variations | Oncotarget
https://www.oncotarget.com/article/14408/text/
Neuroblastoma, the most common extracranial solid tumor among children, is an embryonal tumor originating from undifferentiated neural crest cell. […] Approximately, 50% of cases are high-risk with overall survival rates less than 40%. […] However, the most lack mutations in genes that are recurrently mutated, which inspires researchers to identify disrupted pathways instead of single mutated genes to unearth biological systems perturbed in neuroblastoma. […] This review primarily focuses on both germline mutations predisposing children to the development of neuroblastoma and somatic events associated with neuroblastoma pathogenesis and clinical phenotypes. […] ALK gene mutations are more common than PHOX2B gene mutations in familial NB. […] Amplification or mutation of ALK promotes phosphorylation of ALK, leading to increased kinase activity and ultimately results in tumorigenesis.
#1 Cytokines in Neuroblastoma: From Pathogenesis to Treatment – Page 4
https://www.medscape.com/viewarticle/754414_4
Studies in animal models have shown that both CXCL12 and CXCR4 are constitutively expressed in NB cell lines, as well as in primary metastatic NB, pointing to their involvement in autocrine/paracrine loops of stimulation of tumor growth rather than in enhancement of metastasis formation. […] Another chemokine axis involved in NB pathogenesis is represented by CCL2/CCR2. […] Recent evidence indicates a pivotal role for the ALK tyrosine kinase (TK) receptor in both familial and sporadic NB pathogenesis. […] A significant correlation between activating mutations in the ALK TK domain and poor clinical outcome has been shown in sporadic NBs. […] Macrophage inhibition factor (MIF) is a cytokine involved in the control of host inflammatory and immune responses that has been recently shown to be endowed with protumorigenic activity.
#1 Neuroblastoma | Nature Reviews Disease Primers
https://www.nature.com/articles/nrdp201678
Advances in therapy for patients with high-risk disease include intensive induction chemotherapy and myeloablative chemotherapy, followed by the treatment of minimal residual disease using differentiation therapy and immunotherapy; these have improved 5-year overall survival to 50%. […] Currently, new approaches targeting the noradrenaline transporter, genetic pathways and the tumour microenvironment hold promise for further improvements in survival and long-term quality of life. […] Human MYCN, recently identified as amplified in neuroblastoma cell lines and shown to be amplified in human tumours, was shown to transform normal rat embryo cells into tumours, suggesting the importance of this gene in the pathogenesis of neuroblastoma. […] The transgenic overexpressing MYCN mouse model for neuroblastoma was shown to have most of the typical features of human neuroblastoma histologically and in molecular characterization, and remains the most widely used spontaneous animal model for investigating the biology and therapy of neuroblastoma. […] Activated ALK collaborates with MYCN in neuroblastoma pathogenesis.
#1 Neuroblastoma Pathogenesis
https://ouci.dntb.gov.ua/en/works/4OZR0Mr7/
Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. […] Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis. […] The ALK receptor in sympathetic neuron development and neuroblastoma. […] Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. […] ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. […] The genetic landscape of high-risk neuroblastoma. […] TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. […] Neuroblastoma is composed of two super-enhancer-associated differentiation states.
#1 The emerging molecular pathogenesis of neuroblastoma: implications for improved risk assessment and targeted therapy | Genome Medicine | Full Text
https://genomemedicine.biomedcentral.com/articles/10.1186/gm74
A recent breakthrough in our understanding of the pathogenesis of NB is the identification of activating point mutations in the tyrosine kinase domain of the ALK gene as the main cause of familial NB, and implication of these mutations in a substantial fraction of sporadic NB tumors. […] Thus, it is expected that selective ALK inhibitors, which are a major focus of current drug development efforts, may prove valuable for the treatment of selected NB patients.
#1 Neuroblastoma: Molecular Pathogenesis and Therapy
https://pmc.ncbi.nlm.nih.gov/articles/PMC4418018/
Germ line mutations of Paired-like Homeobox 2B (PHOX2B) are found in a subset of familial neuroblastoma and in about 4% of sporadic cases. […] Chromatin immunoprecipitation with high throughput sequencing (ChIPseq) and RNA sequencing studies have demonstrated specific epigenetic patterns which distinguish neuroectoderm, neural crest, and more mature neural states. […] Non-coding RNAs (microRNA, lncRNAs, piRNAs) are essential transcriptional regulators of stem cell biology, development and neural crest differentiation. […] The development of effective and specific epigenetic drugs may soon permit a reverse of pathogenic epigenetic modifications and therefore promote neuroblastoma to differentiate along its programmed neural crest maturation pathway.
#1 Molecular Basis and Clinical Features of Neuroblastoma | JMA Journal
https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2021-0077
Genome-wide association studies (GWAS) further disclosed that neuroblastoma is a complex genetic disease related to common polymorphic alleles that can influence neuroblastoma development. […] The discovery of these susceptibility loci demonstrates the utility of analyzing GWAS signals for clues into the underlying biology driving neuroblastoma genesis. […] The first predisposition gene identified in neuroblastoma was PHOX2B, a gene encoding a paired homeodomain transcription factor that promotes cell cycle exit and neuronal differentiation that plays a critical role in the development of neural crest-derived autonomic neurons. […] A more common lesion associated with familial neuroblastoma is found in the ALK locus. […] Thus, these observations suggest that perturbations in the PHOX2B-regulated differentiation pathway may be a common genetic factor responsible for these diseases derived from the neural crest.
#1 Neuroblastoma pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Neuroblastoma_pathophysiology
Neuroblastoma arises from the neural crest cells, which are normally involved in development of sympathetic nervous system and adrenal glands. […] The various genes involved in pathogenesis of neuroblastoma include; NBPF10, KIF1B, ALK, LMO1 and PHOX2A genes. […] Development of neuroblastoma is the result of multiple genetic mutations. […] Genes involved in the pathogenesis of neuroblastoma include: NBPF10 gene located on chromosome 1, KIF1B gene located on chromosome 1, ALK gene located on chromosome 2, LMO1 gene located on chromosome 11, PHOX2A gene located on chromosome 11. […] Gain of chromosome 17q is the most common genetic mutation among neuroblastoma patients. […] MYCN oncogene (chromosome 2p24) amplification predicts a more aggressive nature of neuroblastomas. […] Deletion of chromosome 1p36 is associated with an increased recurrence rate following resection of localized neuroblastomas. […] Deletions of chromosome 11q is associated with poor prognosis among neuroblastoma patients.
#1 The emerging molecular pathogenesis of neuroblastoma: implications for improved risk assessment and targeted therapy | Genome Medicine | Full Text
https://genomemedicine.biomedcentral.com/articles/10.1186/gm74
How MYCN amplification contributes to this aggressive phenotype remains mainly unknown. […] Deletion of the short arm of chromosome 1 has been detected in approximately 25 to 35% of primary NBs. […] This finding suggests the presence of one or more tumor suppressor gene(s) in this chromosome region. […] Deletion of chromosome 1p sequences is more common in high-stage tumors and is usually associated with MYCN amplification. […] Gain of chromosome 17q is the most common genetic aberration, occurring in approximately 80% of NBs. […] Chromosome 11q deletions are often found in high-stage tumors without MYCN amplification and with intact chromosome 1p. […] Chromosome 3p loss is often found in association with 11q loss and typically occurs in tumors without MYCN amplification or 1p deletion.
#1 Molecular Approach to Neuroblastoma | IntechOpen
https://www.intechopen.com/chapters/55723
Epigenetic modifications are reversible changes that play a role in the regulation of gene expression by regulating the chromatin accessibility of the elements necessary for transcription in eukaryotic cells via chromatin remodeling, histone modifications, DNA methylation, and noncoding RNAs. […] Results from microarray-based DNA methylation studies performed in neuroblastoma patients have shown that gene-specific (promoter) hypomethylation occurs more frequently than genomic hypermethylation that cause development of neuroblastoma. […] Since the identification of their roles in the pathogenesis of many solid and hematological malignancies, a large proportion of treatment strategies have been targeting epigenetic mechanisms. […] Neuroblastoma is a heterogeneous cancer and there are many different specific cells in a single tumor. It has been suggested that all types of cancer cells that provide heterogeneous properties are characterized by the differentiation of a single neuroblastoma stem cell.
#1 DNA Hypomethylation Affects Cancer-Related Biological Functions and Genes Relevant in Neuroblastoma Pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048401
Interestingly, we observed that hypoM affected genes relevant to NB pathogenesis such as CCND1. […] Overall, we observed that loss of DNA methylation is more prevalent than promoter hyperM in NB. […] This study provides a genome-wide view of the DNA methylation landscape in NB. […] Our findings suggest that hypoM is a prevalent epigenetic alteration in NB that affects cancer-related biological functions and specific genes relevant for NB pathogenesis, such as CCND1.
#1 DNA Hypomethylation Affects Cancer-Related Biological Functions and Genes Relevant in Neuroblastoma Pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048401
Neuroblastoma (NB) pathogenesis has been reported to be closely associated with numerous genetic alterations. […] Here, we generated microarray-based DNA methylation profiles of primary neuroblastic tumors. […] We observed that gene-specific loss of DNA methylation is more prevalent than promoter hypermethylation. […] Remarkably, such hypomethylation affected cancer-related biological functions and genes relevant to NB pathogenesis such as CCND1, SPRR3, BTC, EGF and FGF6. […] In particular, differential methylation in CCND1 affected mostly an evolutionary conserved functionally relevant 3 untranslated region, suggesting that hypomethylation outside promoter regions may play a role in NB pathogenesis. […] The results derived from this study provide new candidate epigenetic biomarkers associated with NB as well as insights into the molecular pathogenesis of this tumor, which involves a marked gene-specific hypomethylation.
#1 The role of ncRNAs in neuroblastoma: mechanisms, biomarkers and therapeutic targets | Biomarker Research | Full Text
https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-022-00368-2
Neuroblastoma (NB) is a malignant tumor in young children that originates from the neural crest of the sympathetic nervous system. […] Understanding the pathophysiology of NB and developing novel therapeutic approaches are critical. Noncoding RNAs (ncRNAs) are associated with crucial aspects of pathology, metastasis and drug resistance in NB. […] Many ncRNAs are dysregulated in NB, indicating that they play important roles in disease development. […] In NB, ncRNAs are engaged in pretranscriptional gene regulation, including chromatin assembly, histone modification, and DNA methylation. […] It has been reported that the upregulation of miR-137 in resveratrol-induced NB cell apoptosis leads to an imbalance in polycomb protein histone methyltransferase enhancer of zeste homolog 2 (EZH2) levels.
#1 The role of ncRNAs in neuroblastoma: mechanisms, biomarkers and therapeutic targets | Biomarker Research | Full Text
https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-022-00368-2
Loss of EZH2 facilitates reduction of H3K27me3 levels and activation of clusterin (CLU) and nerve growth factor receptor (NGFR), which are tumor suppressive genes in NB. […] MiR-152 targets DNA methyltransferase 1 (DNMT1) to mediate DNA demethylation, contributing to the differentiation process induced by all-trans-retinoic acid (ATRA) and leading to the activation of Nitric oxide synthase (NOS1), which is a key gene in the differentiation of nerve cells. […] The TGF- pathway is regulated by the cellular environment and its integration with other signalling pathways. […] In cancer, this pathway is associated with the cell suppression of early tumors and the proliferation, invasiveness, angiogenesis and carcinogenesis of advanced tumors. […] MiR-380-5p represses the high levels of p53 expression, which is associated with poor prognosis in MYCN-expanded NB.
#1 Molecular Approach to Neuroblastoma | IntechOpen
https://www.intechopen.com/chapters/55723
Familial neuroblastomas rarely occur and constitute approximately 12% of all cases. The tyrosine kinase receptor ALK, which plays an essential role in the development of the normal brain and nervous system, is the major component of hereditary neuroblastomas. […] While MYCN amplification is responsible for a large proportion of sporadic neuroblastomas (20%), a large proportion of adolescent and young adult patients have ATRX mutations (20%) without MYCN amplification. […] The catastrophic process, called chromothripsis, describes a new carcinogenesis mechanism that is caused by a large number (tens to hundreds) of rearrangements occurring in the same cell in one or several chromosomes, unlike the conventional mechanism in which the accumulation of mutations over time causes cancer. […] Large spectrum of genetic-wide association studies has identified many genetic alterations related to predisposition to non-familial (sporadic) neuroblastomas, recently.
#1 Neuroblastoma in childhood and its potential viral involvement: A webinar by the Paediatric Virology Study Group
https://www.spandidos-publications.com/10.3892/wasj.2022.151
Neuroblastoma represents the most common and lethal solid tumour of early childhood. […] however, overall, the pathogenesis of neuroblastoma remains to be resolved. […] The proposed model by Professor Ugo Rovigatti, Professor of Molecular Biology at the University of Florence in Italy, is based upon infection with microfoci inducing virus and its potential tumorigenic role as trigger of i) high and persistent inflammation; ii) chromothripsis and genetic instability; and iii) in vitro cell transformation and in vivo carcinogenesis. […] The variation of clinical outcomes in neuroblastoma cases indicates distinct genetic and environmental factors affecting the development of this malignancy. […] Among genetic factors, MYCNA is certainly the most prominent, since it occurs in approximately one quarter of cases.
#1 A Mechanism Linking Id2-TGFÎ² Crosstalk to Reversible Adaptive Plasticity in Neuroblastoma | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083521
The ability of high-risk neuroblastoma to survive unfavorable growth conditions and multimodal therapy has produced an elusive childhood cancer with remarkably poor prognosis. A novel phenomenon enabling neuroblastoma to survive selection pressure is its capacity for reversible adaptive plasticity. This plasticity allows cells to transition between highly proliferative anchorage dependent (AD) and slow growing, anoikis-resistant anchorage independent (AI) phenotypes. […] The differential gene expression profile of the two cellular phenotypes in the mouse Neuro2a cell line delineated pathways of proliferation in AD cells or tyrosine kinase activation/ apoptosis inhibition in AI cells. […] A 20 fold overexpression of inhibitor of differentiation 2 (Id2) was identified in AD cells while up-regulation of genes involved in anoikis resistance like PI3K/Akt, Erk, Bcl2 and integrins was observed in AI cells.
#1 A Mechanism Linking Id2-TGFÎ² Crosstalk to Reversible Adaptive Plasticity in Neuroblastoma | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083521
Forced down-regulation of Id2 in AD cells or overexpression in AI cells induced the cells to gain characteristics of the other phenotype. […] Id2 binds both TGF and Smad2/3 and appears critical for maintaining the proliferative phenotype at least partially through negative regulation of the TGF/Smad pathway. […] Simultaneously targeting the differential molecular pathways governing reversible adaptive plasticity resulted in 50% cure of microscopic disease and delayed tumor growth in established mouse neuroblastoma tumors. […] We present a mechanism that accounts for reversible adaptive plasticity and a molecular basis for combined targeted therapies in neuroblastoma. […] Id2 mediates mitogenic signals, inhibits differentiation and plays a critical role in cancer development and metastasis.
#1 Molecular Basis and Clinical Features of Neuroblastoma | JMA Journal
https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2021-0077
Spontaneous regression of neuroblastoma has been well documented in infants with stage 4S disease. […] The accurate mechanisms responsible for spontaneous regression are not fully known, but several plausible mechanisms have been proposed to date. […] One of the candidate key mechanisms underlying tumor regression is the nerve growth factor (NGF) dependency of neuroblastoma cells. […] These findings suggest that telomere crisis has a role in spontaneous tumor regression. […] Biological findings facilitate our understanding of neuroblastoma heterogeneity and improve disease management and prognosis. […] This review summarizes our understanding of neuroblastoma pathogenesis and the promising therapeutic strategies.
#1 Neuroblastoma – EyeWiki
https://eyewiki.org/Neuroblastoma
Spontaneous regression mechanisms may include hypermethylation of subtelomeric DNA, apoptosis, deprivation of Nerve Growth Factor (NGF) deprivation and immune response. […] The mechanism by which neuroblastoma cells grow has been a subject of hypothesis and in a review by Tsubota et al, few mechanisms including precursor in sympathoadrenal lineage of neural crest and Schwann cell and initiation including upregulation by N-Myc and downregulation by polycomb repressive complex 2.
#1 St. Jude scientists solve mystery of how the drug retinoic acid works to treat neuroblastoma – St. Jude Childrenâs Research Hospital
https://www.stjude.org/media-resources/news-releases/2025-medicine-science-news/st-jude-scientists-solve-mystery-of-how-the-drug-retinoic-acid-works-to-treat-neuroblastoma.html
Scientists at St. Jude Childrens Research Hospital have uncovered the mechanism by which retinoic acid selectively kills metastatic neuroblastoma cells, with little effect on primary tumors. […] St. Jude Childrens Research Hospital scientists resolved the mystery in a new study, showing retinoic acid uses a novel mechanism to kill metastasized neuroblastoma. The drug hijacks a normal developmental pathway to trigger cancer cell death. […] Retinoic acids activity heavily depends on the cellular microenvironment. […] The researchers showed that BMP signaling makes neuroblastoma cells much more vulnerable to retinoic acid. […] However, since the bone marrow microenvironment causes neuroblastoma cells there to have higher BMP activity, it neatly explained why retinoic acid is very effective at treating those cells during consolidation therapy, but not the primary tumors during up-front treatment.
#1 St. Jude scientists solve mystery of how the drug retinoic acid works to treat neuroblastoma – St. Jude Childrenâs Research Hospital
https://www.stjude.org/media-resources/news-releases/2025-medicine-science-news/st-jude-scientists-solve-mystery-of-how-the-drug-retinoic-acid-works-to-treat-neuroblastoma.html
Using gene editing technology, the scientists uncovered the relationship between BMP signaling and retinoic acid. […] We found that, in neuroblastoma, BMP signaling works with retinoic acid signaling in the same way as during development. […] If there are a lot of BMP-signaling pathway transcription factors already on DNA, then retinoic acid signaling combines with it to promote downstream cell death-related gene expression. […] We are the first to uncover such an example of hijacking a normal embryonic developmental process preserved in cancer that we can exploit therapeutically.
#1 Cytokines in Neuroblastoma: From Pathogenesis to Treatment – Page 4
https://www.medscape.com/viewarticle/754414_4
Numerous papers addressing the in vitro effects of cytokines on human NB cell lines have been published. […] The main cytokines and growth factors involved in neuroblastoma (NB) pathogenesis are VEGF and IL-6 produced by NB and stromal cells, respectively. VEGF promotes tumor angiogenesis, while IL-6 is involved in tumor growth and metastasis. […] A cytokine that appears to play a fundamental role in NB growth is IL-6. IL-6 derived from bone marrow stromal cells was found to promote the growth and survival of NB cell lines through Erk1/2 and STAT-3 signaling phosphorylation and to mediate a growth-stimulatory activity on in vivo experimental NB models. […] A mechanism that sheds light on the prometastatic role of IL-6 in NB is provided by the finding that NB cells, although unable to produced osteoclast-activating factors, release soluble galectin-3 that in turn stimulates bone marrow stromal cells to produce IL-6.
#1 Nervous system: Embryonal tumors: Neuroblastoma
https://atlasgeneticsoncology.org/solid-tumor/5002/nervous-system-embryonal-tumors-neuroblastoma
Neuroblastoma is a clinically heterogenous pediatric cancer of the sympathetic nervous system that originates from neural crest cells. […] Over the past several decades, genomic features such as germline mutations, somatic genetic aberrations, chromosome copy number, transcriptomics, and epigenetics have proven to contribute to the pathogenesis of neuroblastoma. […] The pathogenesis is not fully understood, but it is clear that many cytogenetic and molecular factors drive the development of neuroblastoma. […] Somatic changes in the tumor genome such as gene mutations, loss or gain of alleles, and variations in ploidy have been identified as important factors in the development of neuroblastoma and contribute to its diverse phenotype. […] The major cause of familial neuroblastoma is heritable gain-of-function mutations of ALK. […] Amplification of the MYCN gene is noted in 20% of all primary neuroblastoma tumors. […] Loss-of-function mutations or deletions in ATRX have been observed in neuroblastoma and are often found in older patients. […] Genomic rearrangements in TERT, a target of MYCN, can lead to neuroblastoma.
#1 The role of ncRNAs in neuroblastoma: mechanisms, biomarkers and therapeutic targets | Biomarker Research | Full Text
https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-022-00368-2
Inactivation of the transcription factor p53 through direct mutation or genetic aberration is a hallmark of almost all tumors. […] The ideal biomarker should have the characteristics of good stability, strong specificity and high sensitivity. […] NcRNAs either have significant tissue specificity or can be detected in serum or other body fluids. […] In summary, ncRNA studies have enriched the understanding of NB. However, information on the role and mechanism of ncRNAs in NB is only starting to appear.
#1 Molecular Approach to Neuroblastoma | IntechOpen
https://www.intechopen.com/chapters/55723
Neuroblastoma stem cells were first described as I-type cells (intermediate type), malignant cells of neural crest, morphologically located between neuroblastic cells and neural crest cells. […] Neuroblastoma stem cells are characterized by upregulation of prominin1 (PROM1/CD133), proto-oncogene receptor tyrosine kinase (KIT/CD117), colony stimulating factor 3 receptor (CSF3R/CD114) cell surface proteins and G protein-coupled receptor class C group 5 member C (GPRC5C), NOTCH1, placental growth factor (PGF), neurotrophic receptor tyrosine kinase 2 (NTRK2), nerve growth factor receptor (NGFR), colony stimulating factor 3 (CSF3), signal transducer and activator of transcription 3 (STAT3), and RB transcriptional corepressor-like 2 (RBL2) genes which play a role in differentiation to malignant neuroblastoma stem cell.
#1 Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies
https://www.imrpress.com/journal/FBL/28/8/10.31083/j.fbl2808171/htm
Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies […] The aim of the present study was to document the specific gene mutations related to targeted therapy in relapsed or refractory NB patients by using next generation sequencing (NGS). […] Increased knowledge of NB at the molecular level is needed to better understand its pathogenesis and to develop novel therapeutics that could improve outcomes in high-risk, relapsed, or refractory cases. […] The detection of ATM, p53, RB1, APC, HNF1A, VHL, NOTCH, NF1, and RAS mutations may be helpful for understanding the pathogenesis of NB. […] In the present study we report NGS mutation and fusion data for relapsed and refractory NB patients from our institute. […] The ERBB2 I655V missense mutation was common in this NB cohort.
#1 Chemoprevention of neuroblastoma: progress and promise beyond uncertainties
https://www.oaepublish.com/articles/2394-4722.2022.40
Considering neuroblastoma heterogeneity and drug resistance, achieving a cure after the relapse of high-risk neuroblastoma is challenging. […] It is clear that the rapid reduction in the timeline between successive recurrences is due to the ongoing acquisition of genetic rearrangements in undifferentiated/poorly differentiated cancer. […] Hence, it is critical to identify new and effective chemoprevention strategies to delay or prevent these acquired events and/or lineage transformation in neuroblastoma cells and thereby defy tumor evolution into progressive disease. […] Chemoprevention is purposing/repurposing the natural, synthetic, or biological compounds to reverse, prevent, delay, or suppress tumor genesis, progression, and evolution. […] The modes of action for blocking agents include regulation of metabolic activation, blocking DNA damage, hypermethylation of tumor suppressors, and inhibition of histone deacetylases.
#1 Chemoprevention of neuroblastoma: progress and promise beyond uncertainties
https://www.oaepublish.com/articles/2394-4722.2022.40
Retinoids are one major class of chemopreventive agents investigated in neuroblastoma. […] Importantly, since retinol controls epithelial differentiation, it is regarded as a cancer prevention agent and has demonstrated benefit and efficiency in cancer control. […] In human neuroblastoma, retinoic acid (RA) remains the most potent differentiation inducer. […] ATRA treatment resulted in neuroblastoma cell differentiation by selectively rearranging miRs and consequently altering the pathways of neuronal differentiation and maturation. […] The retinoid 13-cis-RA (13-cis-RA, isotretinoin), an isomer of ATRA, is a cancer chemoprevention drug that causes differentiation, decreased proliferation and inhibition of MYCN expression in progressive neuroblastoma cells. […] The major clinical limitations of retinoids are their toxicity and water insolubility.
#1 Chemoprevention of neuroblastoma: progress and promise beyond uncertainties
https://www.oaepublish.com/articles/2394-4722.2022.40
Thus, studies are focused on identifying retinoids that are well tolerated in humans with favorable outcomes in preneoplastic and neoplastic conditions. […] The chemopreventive agent difluoromethylornithine (DFMO) has been widely studied in neuroblastoma evolution control. […] DFMO irreversibly inhibits ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis. […] High expression of ODC has been shown to drive neoplastic transformation in neuroblastoma. […] Importantly, DFMO targets LIN28/Let7 signaling and thereby affects the neuroblastoma cancer stem cell lineage. […] DFMO has been under continuous clinical investigation for neuroblastoma since the first Phase 1 study that established a safe dose of 1,500 mg/m2 in relapsed patients. […] A Phase II study demonstrated clinically significant improvement in the survival of high-risk neuroblastoma patients with DFMO administration after standard COG therapy when compared with the no-DFMO matched controls.
#1 Neuroblastoma: an ongoing cold front for cancer immunotherapy | Journal for ImmunoTherapy of Cancer
https://jitc.bmj.com/content/11/11/e007798
Due to the poorly immunogenic features of neuroblastomas, alternative strategies involving adjuvant treatments are being investigated to induce sensitivity to ICB. […] The immune contexture of neuroblastomas comprises tumour associated macrophages (TAMs), natural killer (NK) cells, lymphocytes, dendritic cells (DCs), Schwann cells, cancer-associated fibroblasts (CAFs), vascular endothelial cells and mesenchymal cells. […] The presence of TAMs in the TME is associated with poor patient prognosis as secretion of a cocktail of inflammatory cytokines, such as IL-6 and vascular endothelial growth factors (VEGF), promotes angiogenesis and neuroblastoma proliferation, whilst having an immunosuppressive role by inhibiting the function of DCs, NK cells and T cells. […] Because of the poorly immunogenic TME, patients are often resistant to immune checkpoint blockade (ICB) therapy.
#2 Molecular Basis and Clinical Features of Neuroblastoma | JMA Journal
https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2021-0077
Neuroblastoma, a neoplasm of the sympathetic nervous system, originates from neuroblastoma stem cells during embryogenesis. […] Genetic risk factors and epigenetic dysregulation also play a significant role in the development of neuroblastoma. […] As more information is revealed regarding the molecular mechanisms underlying neuroblastoma pathogenesis as well as the genetic events leading to tumor initiation, maturation, and progression, there will be an increased understanding of the various clinical phenotypes, which will ultimately identify new therapeutic targets. […] The dysregulation of the process of neural crest cell development can alter cell specification and deregulation of migration as well as cell differentiation, causing hyper-neoplastic lesions that may eventually result in neuroblastoma initiation and progression.
#2 Neuroblastoma Pathogenesis | SpringerLink
https://link.springer.com/chapter/10.1007/978-3-030-18396-7_3
Neuroblastoma is an embryonal neoplasm of the peripheral sympathetic nervous system and is therefore observed at various locations, occurring either in sympathetic ganglia or in adrenal medulla. […] These tissues are formed from trunk neural crest cells during development, suggesting that neuroblastoma is a cancer of neural crest-derived progenitor cells in the sympathetic nervous system. […] Study of the tumor genetic alterations occurring in these various contexts has revealed the role of key genes in neuroblastoma pathogenesis. […] This chapter will particularly focus on the involvement of the PHOX2B, MYCN, ALK, TERT, ATRX, and LIN28B genes in various forms of the disease. […] It will also address the role of noncoding RNAs in neuroblastoma pathogenesis. […] Very recent studies in the chick and zebrafish model organisms highlighted the LMO1 and SEMA3C genes as potential important genes involved in the metastatic process. […] Finally, this chapter will discuss recent progress into the understanding of neuroblastoma pathogenesis linked to cell identity and plasticity features characterized through the analysis of epigenetic marks.
#2 The mechanism of epithelial-mesenchymal transition induced by TGF-Î²1 in neuroblastoma cells
https://www.spandidos-publications.com/10.3892/ijo.2017.3954
Neuroblastoma is the second most common extracranial malignant solid tumor that occurs in childhood, and metastasis is one of the major causes of death in neuroblastoma patients. […] The epithelial-mesenchymal transition (EMT) is an important mechanism for both the initiation of tumor invasion and subsequent metastasis. […] Therefore, this study investigated the mechanism by which transforming growth factor (TGF)-1 induces EMT in human neuroblastoma cells. […] A scratch test and Transwell migration assay revealed that cell migration significantly and directly correlated with the concentration of TGF-1 indicating that TGF-1 induced EMT in neuroblastoma cells and led to their migration. […] Thus, TGF-1 induced EMT in neuroblastoma cells to increase their migration. […] Specifically, EMT induced by TGF-1 in neuroblastoma cells did not depend on the Smad signaling pathway, and the transcription factor Gli participated in TGF-1-induced EMT independent of Smad signaling.
#2 Epidemiology, pathogenesis, and pathology of neuroblastoma – UpToDate
https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-neuroblastoma
The epidemiology, embryogenesis, molecular pathogenesis, and pathology of neuroblastoma will be presented here. […] Neuroblastomas, which account for 97 percent of all neuroblastic tumors, are heterogeneous, varying in location, histopathologic appearance, and biologic characteristics. […] Clinical diversity correlates closely with numerous clinical and biologic factors (including patient age, tumor stage and histology, and genetic and chromosomal abnormalities), although its molecular basis remains largely unknown.
#2 The emerging molecular pathogenesis of neuroblastoma: implications for improved risk assessment and targeted therapy | Genome Medicine | Full Text
https://genomemedicine.biomedcentral.com/articles/10.1186/gm74
In addition, evidence has emerged for the contribution of epigenetic disturbances in neuroblastoma oncogenesis. […] As in other cancer entities, altered microRNA expression is also being recognized as an important player in neuroblastoma. […] The recent successes in unraveling the genetic basis of neuroblastoma are now opening opportunities for development of targeted therapies. […] The clinically heterogeneous nature of NB is also reflected, in part, by its biological and genetic heterogeneity. […] According to their DNA index, NBs can be divided into a group with a near-diploid nuclear DNA content (about 45% of NBs) and those with a near-triploid DNA content (about 55%). […] The MYCN oncogene (located on chromosome 2p24; 'N’ stands for neuroblastoma-derived) was found to be amplified in 20 to 25% of NBs, and is usually present in the form of double-minutes (chromosome fragments) or homogeneously staining regions.
#2 Pediatric Neuroblastoma: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/988284-overview
Neuroblastoma is the most common extracranial solid tumor of infancy. It is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic cells). […] Over the last 2 decades, many chromosomal and molecular abnormalities have been identified in patients with neuroblastoma. These biologic markers have been evaluated to determine their value in assigning prognosis, and some of these have been incorporated into the strategies used for risk assignment. […] The most important of these biologic markers is MYCN. MYCN is an oncogene that is overexpressed in approximately one quarter of cases of neuroblastoma via the amplification of the distal arm of chromosome 2. This gene is amplified in approximately 25% of de novo cases and is more common in patients with advanced-stage disease.
#2 The emerging molecular pathogenesis of neuroblastoma: implications for improved risk assessment and targeted therapy | Genome Medicine | Full Text
https://genomemedicine.biomedcentral.com/articles/10.1186/gm74
How MYCN amplification contributes to this aggressive phenotype remains mainly unknown. […] Deletion of the short arm of chromosome 1 has been detected in approximately 25 to 35% of primary NBs. […] This finding suggests the presence of one or more tumor suppressor gene(s) in this chromosome region. […] Deletion of chromosome 1p sequences is more common in high-stage tumors and is usually associated with MYCN amplification. […] Gain of chromosome 17q is the most common genetic aberration, occurring in approximately 80% of NBs. […] Chromosome 11q deletions are often found in high-stage tumors without MYCN amplification and with intact chromosome 1p. […] Chromosome 3p loss is often found in association with 11q loss and typically occurs in tumors without MYCN amplification or 1p deletion.
#2 Neuroblastoma pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Neuroblastoma_pathophysiology
Neuroblastoma arises from the neural crest cells, which are normally involved in development of sympathetic nervous system and adrenal glands. […] The various genes involved in pathogenesis of neuroblastoma include; NBPF10, KIF1B, ALK, LMO1 and PHOX2A genes. […] Development of neuroblastoma is the result of multiple genetic mutations. […] Genes involved in the pathogenesis of neuroblastoma include: NBPF10 gene located on chromosome 1, KIF1B gene located on chromosome 1, ALK gene located on chromosome 2, LMO1 gene located on chromosome 11, PHOX2A gene located on chromosome 11. […] Gain of chromosome 17q is the most common genetic mutation among neuroblastoma patients. […] MYCN oncogene (chromosome 2p24) amplification predicts a more aggressive nature of neuroblastomas. […] Deletion of chromosome 1p36 is associated with an increased recurrence rate following resection of localized neuroblastomas. […] Deletions of chromosome 11q is associated with poor prognosis among neuroblastoma patients.
#2 DNA Hypomethylation Affects Cancer-Related Biological Functions and Genes Relevant in Neuroblastoma Pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048401
Neuroblastoma (NB) pathogenesis has been reported to be closely associated with numerous genetic alterations. […] Here, we generated microarray-based DNA methylation profiles of primary neuroblastic tumors. […] We observed that gene-specific loss of DNA methylation is more prevalent than promoter hypermethylation. […] Remarkably, such hypomethylation affected cancer-related biological functions and genes relevant to NB pathogenesis such as CCND1, SPRR3, BTC, EGF and FGF6. […] In particular, differential methylation in CCND1 affected mostly an evolutionary conserved functionally relevant 3 untranslated region, suggesting that hypomethylation outside promoter regions may play a role in NB pathogenesis. […] The results derived from this study provide new candidate epigenetic biomarkers associated with NB as well as insights into the molecular pathogenesis of this tumor, which involves a marked gene-specific hypomethylation.
#2 DNA Hypomethylation Affects Cancer-Related Biological Functions and Genes Relevant in Neuroblastoma Pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048401
Interestingly, we observed that hypoM affected genes relevant to NB pathogenesis such as CCND1. […] Overall, we observed that loss of DNA methylation is more prevalent than promoter hyperM in NB. […] This study provides a genome-wide view of the DNA methylation landscape in NB. […] Our findings suggest that hypoM is a prevalent epigenetic alteration in NB that affects cancer-related biological functions and specific genes relevant for NB pathogenesis, such as CCND1.
#2 Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies
https://www.imrpress.com/journal/FBL/28/8/10.31083/j.fbl2808171
Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies […] The aim of the present study was to document the specific gene mutations related to targeted therapy in relapsed or refractory NB patients by using next generation sequencing (NGS). […] This study presents valuable mutation data for relapsed and refractory NB patients. The high frequency of the ERBB2 I655V mutation may allow further exploration of this mutation as a potential therapeutic target. Rare BRAF mutations may also provide opportunities for targeted therapy. The role of ABL1 mutations in NB should also be explored further.
#2 Chemoprevention of neuroblastoma: progress and promise beyond uncertainties
https://www.oaepublish.com/articles/2394-4722.2022.40
Suppressing agents act by targeting the signaling pathways that drive cancer cell metabolism, cell proliferation, apoptosis, angiogenesis, lineage transformation, differentiation, clonal selection, and cancer stem cell stemness maintenance. […] Apoptosis is arguably the prime cellular event for chemoprevention and has been extensively investigated. […] Although serious efforts are focused on identifying chemopreventive agents for deadly neuroblastoma, the clinical translation of these agents remains limited, principally attributed to the lack of a comprehensive and compiled understanding of the realized outcomes to date. […] Here we review the drugs investigated for chemoprevention of neuroblastoma, their strategies, the mechanism(s) of action, and outcomes. […] This review is focused on the chemopreventive agents that reduce, inhibit, or delay neuroblastoma progression.
#2 Chemoprevention of neuroblastoma: progress and promise beyond uncertainties
https://www.oaepublish.com/articles/2394-4722.2022.40
Thus, studies are focused on identifying retinoids that are well tolerated in humans with favorable outcomes in preneoplastic and neoplastic conditions. […] The chemopreventive agent difluoromethylornithine (DFMO) has been widely studied in neuroblastoma evolution control. […] DFMO irreversibly inhibits ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis. […] High expression of ODC has been shown to drive neoplastic transformation in neuroblastoma. […] Importantly, DFMO targets LIN28/Let7 signaling and thereby affects the neuroblastoma cancer stem cell lineage. […] DFMO has been under continuous clinical investigation for neuroblastoma since the first Phase 1 study that established a safe dose of 1,500 mg/m2 in relapsed patients. […] A Phase II study demonstrated clinically significant improvement in the survival of high-risk neuroblastoma patients with DFMO administration after standard COG therapy when compared with the no-DFMO matched controls.
#3
https://link.springer.com/article/10.1007/s00441-017-2747-0
Neuroblastoma (NB) is an aggressive pediatric cancer that originates from neural crest tissues of the sympathetic nervous system. […] At a cellular level, the heterogeneous behavior of NB likely arises from an arrest and deregulation of normal neural crest development. […] We will critically review recent and past evidence in the literature supporting the concept of CSCs as drivers of neuroblastoma pathogenesis.
#3 Neuroblastoma pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Neuroblastoma_pathophysiology
Neuroblastoma arises from the neural crest cells, which are normally involved in development of sympathetic nervous system and adrenal glands. […] The various genes involved in pathogenesis of neuroblastoma include; NBPF10, KIF1B, ALK, LMO1 and PHOX2A genes. […] Development of neuroblastoma is the result of multiple genetic mutations. […] Genes involved in the pathogenesis of neuroblastoma include: NBPF10 gene located on chromosome 1, KIF1B gene located on chromosome 1, ALK gene located on chromosome 2, LMO1 gene located on chromosome 11, PHOX2A gene located on chromosome 11. […] Gain of chromosome 17q is the most common genetic mutation among neuroblastoma patients. […] MYCN oncogene (chromosome 2p24) amplification predicts a more aggressive nature of neuroblastomas. […] Deletion of chromosome 1p36 is associated with an increased recurrence rate following resection of localized neuroblastomas. […] Deletions of chromosome 11q is associated with poor prognosis among neuroblastoma patients.
#3 The mechanism of epithelial-mesenchymal transition induced by TGF-Î²1 in neuroblastoma cells
https://www.spandidos-publications.com/10.3892/ijo.2017.3954
Neuroblastoma is the second most common extracranial malignant solid tumor that occurs in childhood, and metastasis is one of the major causes of death in neuroblastoma patients. […] The epithelial-mesenchymal transition (EMT) is an important mechanism for both the initiation of tumor invasion and subsequent metastasis. […] Therefore, this study investigated the mechanism by which transforming growth factor (TGF)-1 induces EMT in human neuroblastoma cells. […] A scratch test and Transwell migration assay revealed that cell migration significantly and directly correlated with the concentration of TGF-1 indicating that TGF-1 induced EMT in neuroblastoma cells and led to their migration. […] Thus, TGF-1 induced EMT in neuroblastoma cells to increase their migration. […] Specifically, EMT induced by TGF-1 in neuroblastoma cells did not depend on the Smad signaling pathway, and the transcription factor Gli participated in TGF-1-induced EMT independent of Smad signaling.
#3 Neuroblastoma – Wikipedia
https://en.wikipedia.org/wiki/Neuroblastoma
Neuroblastoma typically occurs due to a genetic mutation occurring in the first trimester of pregnancy. […] The cause of neuroblastoma is not well understood. The great majority of cases are sporadic and nonfamilial. About 12% of cases run in families and have been linked to specific gene mutations. Familial neuroblastoma in some cases is caused by rare germline mutations in the anaplastic lymphoma kinase (ALK) gene. […] MYCN oncogene amplification within the tumor is a common finding in neuroblastoma. The degree of amplification shows a bimodal distribution: either 3- to 10-fold, or 100- to 300-fold. The presence of this mutation is highly correlated to advanced stages of disease. […] One study strongly indicates that miRNAs that are excessively expressed in 1p-deleted neuroblastoma cells, as opposed to other genetic subgroups of neuroblastoma, could potentially disrupt the regulation of genes associated with neuronal differentiation, thereby contribute to the pathogenesis of neuroblastoma. Furthermore, it was noted that miR-495 primarily targeted the majority of mRNAs that are involved in neuronal differentiation.
#3 Neuroblastoma | Nature Reviews Disease Primers
https://www.nature.com/articles/nrdp201678
Neuroblastoma is the most common extracranial solid tumour occurring in childhood and has a diverse clinical presentation and course depending on the tumour biology. […] The most malignant tumours have amplification of the MYCN oncogene (encoding a transcription factor), which is usually associated with poor survival, even in localized disease. […] Although transgenic mouse models have shown that MYCN overexpression can be a tumour-initiating factor, many other cooperating genes and tumour suppressor genes are still under investigation and might also have a role in tumour development. […] Segmental chromosome alterations are frequent in neuroblastoma and are associated with worse outcome. […] The rare familial neuroblastomas are usually associated with germline mutations in ALK, which is mutated in 10-15% of primary tumours, and provides a potential therapeutic target.
#3 Neuroblastoma – Molecular Biology | Cancer Genetics Web
http://www.cancerindex.org/geneweb/X1701.htm
Neuroblastoma tumour cells are characterised by a wide diversity of somatic genetic mutations. Some common genetic features include: Amplification of the MYCN gene is one of the most established genetic prognostic factors. Amplified tumours are mostly (though not exclusively) found in children aged over 1 year at diagnosis with advanced stage disease. Other genes, such as DDX1 are often co-amplified with MYCN. […] Deletion of material from the chromosome 1p36 region is also associated with adverse prognosis. This is thought to be a candidate region for a suppressor gene which has yet to be identified. […] Gain of 17q material is the most frequent genetic abnormality in neuroblastoma. Unbalanced 17q gain is an adverse prognostic factor and is strongly associated with adverse clinical features, 1p deletion, and MYCN amplification.
#4 The mechanism of epithelial-mesenchymal transition induced by TGF-Î²1 in neuroblastoma cells
https://www.spandidos-publications.com/10.3892/ijo.2017.3954
The mechanisms regulating EMT in tumor cells are complex and involve the cell microenvironment and various cytokine signal transduction pathways. […] Transforming growth factor (TGF)- level was indeed elevated in neuroblastoma cases and found to be related to a pathway important for promoting neuroblastoma invasion. […] Although, TGF-1 is known to induce EMT, the mechanism of this induction in neuroblastoma is poorly understood. […] The signaling pathways by which TGF-1 induces EMT in neuroblastoma cells remain unknown. […] Thus, the Smad signaling pathway was not directly involved in TGF-1-induced EMT in neuroblastoma cells, suggesting that this process is mediated by Smad-independent signaling. […] TGF-1 treatment increased Gli2 expression, irrespective of Smad2/Smad3 overexpression or knocked down, indicating that Smad2 or Smad3 was not related to the expression of Gli2.