Non-target genetic manipulation induces rhabdomyosarcoma in KrasPten-driven mouse model of ovarian cancer

Abstract

Background: Genetically engineered mice are ideal models to advance our understanding the tumorigenesis of ovarian cancer. Our original objective was to establish an ovarian cancer model induced by Kras activation and Pten deletion. However, proficiently establishing the model remains a technical problem, which limits its application.Methods: We established the Kras activation/Pten deletion-induced mouse model of ovarian cancer by injecting Cre recombinase-expressing adenovirus in the ovarian bursa. PCR analysis, Western blotting, and immunohistochemistry staining were performed to verify the alteration of conditional genes. We detected expression of canonical molecular markers in order to examine the origin of the tumors.Results: Subcutaneous lumps developed accidentally in mice with ovarian cancer, as early as 2 weeks post in vivo genetic manipulation, far before the destructive growth of ovarian cancer. PCR analysis confirmed the efficient Cre-mediated recombination of Kras and Pten in tumor tissues, which are consistent with the activation of the MAPK and PI3K/Akt/mTOR pathways. Histomorphological and histological analysis showed that the lumps were actually rhabdomyosarcoma (RMS). We confirmed that the leakage of adenovirus transformed healthy adjacent tissues into RMS.Conclusions: Avoiding accidental exposure of non-target tissues to adenovirus is crucial to successfully establish the ovarian cancer mouse model. Moreover, non-specific genetic manipulations can induce the development of RMS.

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

“…Orthotopic CDX models and GEMM which scored highly accounted for 24.6% (n = 29). Two GEMM models were downclassified to the 'low' category, with one study reporting the accidental development of RMS in an ovarian cancer mouse model due to non-specific genetic manipulation (19), and the other study reporting IGF-2 overexpressing pelvic RMS with concomitant salivary carcinoma (20). Ectopic or orthotopic PDX models accounted for 15.3% (n = 18) of trials.…”

“…Moreover, ectopic mouse models did not recapitulate any of the human anatomical tumor sites, thus having very limited translational value. While orthotopic mouse models recapitulated the limb RMS phenotype, a variety of additional tumor locations were observed merely in GEMM systems within our study cohort, including the abdomen, back, head/neck, rib cage, pelvis, body wall, and tongue (19,20,27,(64)(65)(66)(67)(68)(69)(70).…”

Response to the combination use of pazopanib with olaratumab in a patient with lung-metastatic embryonal rhabdomyosarcoma: a case report

“…Embryonal rhabdomyosarcoma (ERMS) is a rare category of soft tissue sarcoma (STS) that originates in the mesenchymal tissue. There are three major histologic subtypes of rhabdomyosarcoma (1,2) and the head and neck region represent the most affected site. Surgery is the best method for removing early-stage tumors (3); however, a high risk of recurrence or distant metastasis remains afterward.…”