Introduction: Epithelial ovarian cancer (EOC) is a heterogenous disease that is represented by multiple histological subtypes. Of these subtypes, low-grade serous (LGSC), clear cell (CCC), and endometrioid (EC) ovarian cancer encompass only 15% of all cases. Currently, there are very few valid pre-clinical animal models for these histological subtypes. Hence, in this study, human tumor cell line-derived xenograft (CLDX) mice were developed to recapitulate human tumor characteristics seen in each rare histological subtype.

Methods: Cell lines were provided by OvCAN; LGSC (VOA6406 & VOA7681), CCC (TOV21G & XVOA295), and EC (TOV112D & VOA4395). Female NRG (NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ) mice were sourced from the Jackson Lab. The mice were injected with five million cells intraperitoneally under light anaesthesia. Thereafter, they were monitored weekly, body weights were recorded, and the body condition score (BCS) was used as a determination of a humane endpoint. Upon reaching a BCS of less than 2, by having difficulty breathing or moving, the mice were euthanized. Each animal underwent a gross examination and necropsy with multiple tissue samples collected for histopathology.

Results: Amongst the subtypes, both CCC and EC CLDXs took ~35 days to reach a humane endpoint, whereas LGSC CLDXs on average took ~200 days. Moreover, the pathobiology of each subtype varied highly whilst remaining consistent between cell lines. EC CLDX mice presented with very large bulky abdominal tumours, while CCC mice showed micro tumours, diaphragmatic involvement, and a significant amount of bloody ascites. Finally, LGSC CLDX mice had cystic tumors filled with yellow turbid liquid, tumours embedded in the lower spine, all without gross involvement on the upper cavity.

Conclusion: The development of these CLDX mice for the rare histological subtypes of EOC provides noticeable tumor burden characteristics, creating opportunities for studies on disease progression and novel therapeutics.