Purpose or Case Report: Neuroblastoma (NB) is the most common non-cranial solid tumor in childhood. The MYCN oncogene plays a crucial role in tumorigenesis and angiogenesis in NB and is a strong indicator of poor prognosis. The tyrosine hydroxylase (TH)-MYCN transgenic mouse model of NB is extensively utilized; however, little is known about disease progression in this model. In this work, we use multi-modal imaging to study tumor progression and vascular architecture in TH-MYCN transgenic, allograft, and syngeneic mouse models of NB.
Methods & Materials: Longitudinal in vivo studies were performed in TH-MYCN transgenic, allograft, and syngeneic mice (n=9 each). Tumors harvested from TH-MYCN transgenic mice were surgically implanted in the left renal capsule in nude mice (NCr) and wild-type littermates of TH-MYCN mice to generate allograft and syngeneic tumors, respectively. Disease progression was studied using T2w-MRI in transgenic (2-7 weeks of age) and allograft and syngeneic mice (weeks 2- 5 post tumor implantation). High resolution CT angiograms (CTA) were captured to image tumor vascular architecture and estimate tumor fractional blood volume (FBV). Histopathology was performed to compare tumor morphology and microvessel density among NB models.
Results: Tumors in TH-MYCN mice became evident in the dorsal retroperitoneal region at week 4 (~ 1.5 mm diameter) and grew rapidly between weeks 4-7 [10 mm³ – 1160 mm³]. TH-MYCN mice also demonstrated a delayed paraspinal growth along thoracic vertebrae visible at week 5. In contrast, allograft and syngeneic mice demonstrated tumor growth restricted to the peritoneal cavity [allograft: 40 mm³ -2420 mm³ ; syngeneic: 20 mm³ – 1730 mm³]. CTA demonstrated TH-MYCN tumors developed a microvascular network with large, superficial blood vessels and tumor FBV of 0.12 ± 0.04. Tumors in allograft and syngeneic mice exhibited similar vasculature patterns to transgenic mice [allograft FBV: 0.14 ± 0.02; syngeneic FBV: 0.12 ± 0.03]. Histological analysis demonstrated similarity in tumor architecture and microvessel density between TH-MYCN and implanted tumors.
Conclusions: The TH-MYCN transgenic NB model demonstrated aggressive disease progression originating in the retroperitoneal cavity and a delayed growth along the paraspinal thoracic tract. In comparison, allograft and syngeneic renally-implanted models demonstrated single-mass tumor growth in the peritoneal cavity. Other than the secondary findings, TH-MYCN and implanted models demonstrated similar vasculature and tumor morphology.