Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents

Abstract

Abstract. Undifferentiated pleomorphic sarcoma not otherwise specified belongs to the heterogeneous group of soft tissue tumors. It is preferentially located in the upper and lower extremities of the body, and surgical resection remains the only curative treatment. Preclinical animal models are crucial to improve the development of novel chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma. However, this approach has been hampered by the lack of reproducible animal models. The present study established two xenograft animal models generated from stable non-clonal cell cultures, and investigated the difference in chemotherapeutic effects on tumor growth between undifferentiated pleomorphic sarcoma in vivo and in vitro. The cell cultures were generated from freshly isolated tumor tissues of two patients with undifferentiated pleomorphic sarcoma. For the in vivo analysis, these cells were injected subcutaneously into immunodeficient mice. The mice were monitored for tumor appearance and treated with the most common or innovative chemotherapeutic agents available to date. Furthermore, the same drugs were administered to in vitro cell cultures. The most effective tumor growth inhibition in vitro was observed with doxorubicin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as vorinostat. In the in vivo xenograft mouse model, the combination of doxorubicin and the tyrosine kinase inhibitor pazopanib induced a significant tumor reduction. By contrast, treatment with vorinostat did not reduce the tumor growth. Taken together, the results obtained from drug testing in vitro differed significantly from the in vivo results. Therefore, the novel and reproducible xenograft animal model established in the present study demonstrated that in vivo models are required to test potential chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma prior to clinical use, since animal models are more similar to humans, compared with in vitro cell cultures.

Therapeutic applications of histone deacetylase inhibitors in sarcoma

“…The most effective tumor growth inhibition in vitro was observed with doxorubicin and the HDI vorinostat. In the in vivo xenograft mouse model, the combination treatment of doxorubicin and vorinostat did not reduce the tumor growth 94 . In this study, xenograft animal models were established by subcutaneously injecting the stable oligoclonal cell cultures from freshly tumor species of two patients into immuno-deficient mice.…”

Mandibular undifferentiated pleomorphic sarcoma: Molecular analysis of a primary cell population

“…This is important considering UPS is a common subtype of soft tissue sarcoma with currently no clinical biomarkers available. Cellular and mouse models of UPS from various sites of the body have been developed (Becker et al, 2016; De Vita, Recine, Mercatali, et al, 2017; Kiyuna et al, 2017; Oyama et al, 2018; Salawu et al, 2016). The lower limbs, in particular the quadriceps muscle, was the most common tumor location.…”

“…JPH2 may serve as a marker for UPS, as it was previously reported to be overexpressed in leiomyosarcomas compared to an endometrial stromal sarcoma (Davidson et al, 2013). (Becker et al, 2016;De Vita, Recine, Mercatali, et al, 2017;Kiyuna et al, 2017;Oyama et al, 2018;Salawu et al, 2016 Note: Genes bolded were chosen from additional analysis. transport gene) message compared to healthy tissue from the same patient.…”

CORR Insights®: Are Biopsy Tracts a Concern for Seeding and Local Recurrence in Sarcomas?

“…For instance, a xenograft model of implanted sarcoma subtypes could be used to determine which types of tumor are most likely to survive in and seed a biopsy tract. Given the many xenograft options [2,5,6] and the ability to replicate the experiments and evaluate in a blinded fashion, this approach may inform clinical decision-making. In addition, various dye or fluorescent techniques could be assessed in animals to determine the feasibility of visually marking the biopsy tract.…”