Distinct malignant behaviors of mouse myogenic tumors induced by different oncogenetic lesions

Abstract

Rhabdomyosarcomas (RMS) are heterogeneous cancers with myogenic differentiation features. The cytogenetic and mutational aberrations in RMS are diverse. This study examined differences in the malignant behavior of two genetically distinct and disease-relevant mouse myogenic tumor models. Kras; p1619(null) myogenic tumors, initiated by expression of oncogenic Kras in p16p19(null) mouse satellite cells, were metastatic to the lungs of the majority of tumor-bearing animals and repopulated tumors in seven of nine secondary recipients. In contrast, SmoM2 tumors, initiated by ubiquitous expression of a mutant Smoothened allele, did not metastasize and repopulated tumors in 2 of 18 recipients only. In summary, genetically distinct myogenic tumors in mice exhibit marked differences in malignant behavior.

Keywords: metastasis; myogenic differentiation; rhabdomyosarcoma; transplantation.

Figure 1

Terminal myogenic differentiation in Kras; p16p19^null and SmoM2 mouse tumors. (A) Subsets of Kras; p16p19^null tumors cells express terminal muscle differentiation markers, actin and desmin. (B) The majority of SmoM2 tumor cells express actin and desmin. Images were taken at 20× (scale bars indicate 100 μm).

Figure 2

Kras; p16p19^null mouse myogenic tumors metastasize to the lungs of tumor-bearing animals. Random lung sections from Kras; p16p19^null tumor-bearing mice show metastases. Tumor cells invade lung capillaries (top panel). Similar to primary tumors arising from GFP+ Kras-expressing; p16p19^null satellite cells, lung metastases are GFP+ (bottom right panel). Images were taken at 10× and 20× (scale bars indicate 100 μm)

Figure 3

Kras; p16p19^null tumor cells repopulate tumors in secondary recipients more effectively than SmoM2 mouse tumor cells. Pi⁻Ca⁺GFP⁺ Kras; p16p19^null tumor cells were sorted independently from two primary tumors and injected into the cardiotoxin-pre-injured gastrocnemius muscles of NOD.SCID mice (50 cells per injection). Pi-Ca+ SmoM2 tumor cells were sorted independently from four primary tumors and injected into the cardiotoxin-pre-injured gastrocnemius muscles of NOD.SCID mice (100,000–150,000 cells per injection). Recipient mice were monitored for the occurrence of secondary tumors at the injection site for up to 4 months.