Neuroblastoma (NB) is the most common extracranial solid tumor in children, accounting for approximately 8%-10% of pediatric malignancies. Due to its extremely heterogeneous clinical manifestations, it is known as the "king of childhood tumors."
 

Based on molecular characteristics, it can be classified into three major prognostic subtypes: the favorable prognosis Subtype 1 (often accompanied by triploid karyotype), the intermediate-risk Subtype 2A (with segmental chromosomal abnormalities), and the high-risk Subtype 2B (characterized by MYCN gene amplification). The low-risk group (e.g., Subtype 1) often exhibits a unique tendency for spontaneous regression, while the high-risk group (e.g., Subtype 2B) is characterized by strong invasiveness and a propensity for bone and bone marrow metastasis. About 1%-2% of cases are familial, with ALK and PHOX2B gene mutations being the main genetic factors, together accounting for about 80% of hereditary cases, and ALK activating mutations are the primary causative genetic factor among these.

 

Figure source: Mechanisms of neuroblastoma regression
 

Pathogenesis
 

The core pathogenesis of neuroblastoma involves the arrest of the differentiation program in neural crest-derived progenitor cells. At the genomic level, the core driving event in high-risk Subtype 2B is MYCN gene amplification, which powerfully drives tumor progression by dysregulating cell cycle and apoptosis pathways; ALK gene activating mutations (such as R1275Q) serve as important synergistic or independent genetic events, persistently activating pro-survival signaling pathways such as PI3K/AKT and MAPK; and loss of heterozygosity on chromosomes 1p and 11q may lead to the loss of function of key tumor suppressor genes. At the epigenetic level, abnormalities in DNA methylation and histone modifications, by altering chromatin conformation, repress the expression of genes related to neuronal differentiation, further maintaining the undifferentiated state. Additionally, tumor cells recruit immunosuppressive cells like TAMs and MDSCs to construct an immunosuppressive microenvironment and secrete factors such as VEGF to promote angiogenesis, collectively sustaining the malignant phenotype of the tumor.
 

The spontaneous regression of neuroblastoma is one of the most characteristic biological behaviors in its clinical course, primarily referring to the phenomenon where malignant tumors in infant patients spontaneously shrink or disappear without receiving targeted treatment or only minimal supportive care. Its mechanism is not the result of a single pathway activation but an active biological process precisely regulated by various molecular mechanisms.
 

I) Apoptosis Pathway Induced by Neurotrophin Deprivation: Signal Balance of Tropomyosin Receptor Kinase A (TrkA)
 

When tumor cells with high TrkA expression are in the primary microenvironment rich in Nerve Growth Factor (NGF), the NGF-TrkA pathway activation promotes cell survival and differentiation. However, when cells disseminate to metastatic sites (e.g., liver, skin) lacking NGF, unliganded TrkA acts as a dependence receptor, triggering the intrinsic caspase cascade and mitochondrial apoptosis pathway.
 

II) Immune Mechanisms
 

Anti-tumor antibodies (such as IgG targeting disialoganglioside GD2) produced in patients clear tumor cells through Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Complement-Dependent Cytotoxicity (CDC). Simultaneously, Natural Killer (NK) cells, via surface activation receptors (e.g., NKG2D), recognize stress antigens and directly penetrate tumor cell membranes to release perforin/granzyme.
 

III) Replicative Senescence Due to Telomere Dynamics Abnormalities
 

Low-risk neuroblastomas typically exhibit low or absent telomerase activity. Insufficient telomerase activity leads to progressive shortening of telomeres at chromosome ends with cell division. When telomeres shorten to a critical length (Hayflick limit), the DNA damage response signaling pathway is activated, subsequently inducing an irreversible cell cycle arrest through the p53-p21/Rb pathway, ultimately leading to replicative senescence or programmed cell death, thereby limiting the unlimited proliferation potential of the tumor from within.
 

IV) Epigenetic Regulation
 

Studies have found that regressing tumors exhibit a pattern coexisting with genome-wide hypomethylation and hypermethylation in the promoter regions of specific tumor suppressor genes. Meanwhile, changes in histone modifier enzyme activity can cause chromatin conformational changes, thereby reregulating the expression of transcription factors related to neural crest development. This reprogramming may lift the suppression of differentiation and apoptosis programs, making tumor cells more responsive to differentiation signals in the microenvironment, or directly undergoing programmed cell death.

Figure source: Mechanisms of neuroblastoma regression
 

Gene Therapy
 

MYCN-Targeted Gene Silencing Therapy:​ Utilizes lentivirus, adeno-associated virus, or lipid nanoparticles (LNP) to deliver shRNA targeting the MYCN gene or gene editing systems. By specifically degrading MYCN mRNA or directly editing the MYCN gene promoter region, it inhibits MYCN protein expression, thereby blocking its downstream oncogenic signaling pathways. This is suitable for high-risk neuroblastoma with MYCN amplification.
 

ALK Gene Correction Therapy:​ For ALK activating mutations (such as F1178S, R1275Q), homologous directed repair technology is used, or AAV vectors are used to deliver dominant-negative mutants to correct the oncogenic mutation or competitively inhibit the abnormally activated ALK kinase activity.
 

Mouse Models
 

Dbh-ALKF1178S Mice:​ Introduce the ALK activating mutation (F1178S). Embryonically, they exhibit sympathetic ganglion hypertrophy and neuronal developmental abnormalities. Primarily used to validate the in vivo efficacy of ALK-targeted drugs and to study the driving role of the ALK signaling pathway in the development and progression of neuroblastoma.
 

TH-MYCN Mice:​ Utilize the tyrosine hydroxylase (TH) promoter to drive specific overexpression of the MYCN oncogene. Mice spontaneously develop tumors located in the abdominal sympathetic ganglia within weeks after birth. This is a classic model for studying the biological behavior of MYCN-amplified neuroblastoma and evaluating new therapies.
 

References:
 

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