A patient derived xenograft model of cervical cancer and cervical dysplasia

Abstract

AimTo develop a patient derived xenograft (PDX) model of cervical cancer and cervical dysplasia using the subrenal capsule.MethodsCervical cancer (12 Squamous Cell Carcinoma, 1 Adenocarcinoma, 1 Adenosquamous Carcinoma), 7 cervical dysplasia biopsy and normal cervical tissues were transplanted beneath the renal capsule of immunocompromised NOD/SCID/gamma mice. Resulting tumours were harvested and portions serially transplanted into new recipient mice for up to three in vivo passages. Parent and xenograft tumours were examined by immunohistochemistry for p16INK41, HPV, and CD-45. Single cell suspensions of mixed mouse and human, or human only cell populations were also transplanted.ResultsThe overall engraftment rate for the primary cervical cancer PDX model was 71.4 ±12.5% (n = 14). Tumours maintained morphological, histoarchitecture and immunohistochemical features of the parent tumour, and demonstrated invasiveness into local tissues. Single cell suspensions did not produce tumour growth in this model. Mean length of time (32.4 +/- 3.5 weeks) for the transplanted tissue to generate a tumour in the animal was similar between successive transplantations. Three of four xenografted cervical dysplasia tissues generated microscopic cystic structures resembling dysplastic cervical tissue. Normal cervical tissue (4 of 5 xenografted) also developed microscopic cervical tissue grafts.ConclusionThe subrenal capsule can be used for a PDX model of human cervical cancer with a good engraftment rate and the ability to model in vivo characteristics of cervical cancer. For the first time we have demonstrated that cervical dysplasia and normal cervical tissue generated microscopic tissues in a PDX model.

The Application of Patient-Derived Xenograft Models in Gynecologic Cancers

“…Additionally, the engraftment success rate of HGS-OC PDXs with subcutaneous and intra-ovarian bursal implantation into NSG mice was 83% [40], higher than 52.9% in ER-positive relapsed HGS-OC patients with intraperitoneal implantation into female SCID beige mice [39]. Consistently, the engraftment success rate of cervical cancer PDX models was identified as 71.4 ±12.5% in NSG mice [18], which was more successful compared with 66.7% in BALB/c nude mice with subrenal capsule implantation [19]. However, an additional recent study addressed that animal species, the initiation site of tumor, cancer malignancy degree, cancer stage, cancer type were not related to the tumor formation rate of ovarian carcinoma [16].…”

“…Some papers have confirmed a high resemblance in histology, phenotypic features and molecular markers between gynecologic cancer PDX models and donor tumors including ovarian cancer, cervical cancer, endometrial cancer and leiomyosarcomas [18,19,32,34,37]. For instance, established orthotopic HGS-OC PDX models in NSG mice from three donors have been found to maintain their original morphology and molecular marker profile [46].…”

“…For example, the establishment time in high-risk endometrial cancer PDXs was between 2 and 11 weeks [28]. It was shorter than the length of tumor establishment in cervical cancer PDX models, whose mean length of time was 32.4 +/-3.5 weeks and similar to the time in its successive transplantations [18].…”

“…The engraftment rate is various according to different gynecologic cancers and different tumor types. The engraftment success rate of cervical cancer PDX models was reported from 66.7% to 71.4% [18,19], while the PDXs engraftment rate of endometrial cancer was between 60% and 86% [32,33]. As to ovarian cancer PDX models, engraftment success ranged from 45.5% to 100% [34][35][36].…”

“…Currently, more and more evidence has witnessed the application of PDX models in numerous gynecologic cancers including ovarian cancer [16,17], and cervical cancer [18,19], improving our understanding of cancer biology and mechanisms of therapeutic response in gynecologic cancers. Hence, this review is designed to assess the application and current preclinical utilization of PDX models in the field of gynecologic cancer, for providing more opportunities to optimize these models to develop clinical guidelines to manage gynecologic cancer treatment.…”