Characterization of the Tumor-Microenvironment in Patient-Derived Cervix Xenografts (OCICx)

Naz Chaudary,Joerg Schwock,Blaise Clarke,Melania Pintilie,Anthony Fyles,Neesha Dhani,Richard P Hill,Michael Milosevic

doi:10.3390/cancers4030821

Abstract

Rationale: The tumor microenvironment (TME) is heterogeneous including both malignant and host cell components as well as regions of hypoxia, elevated interstitial fluid pressure (IFP) and poor nutrient supply. The quantitative extent to which the microenvironmental properties of primary tumors are recapitulated in xenograft models is not well characterized. Methods: Xenografts were generated by implanting tumor biopsies directly into the cervix of mice to create a panel of orthotopically-passaged xenografts (OCICx). Tumors were grown to ~1 cm (diameter) and IFP measurements recorded prior to sacrifice. Enlarged para-aortic lymph nodes (>1–2 mm) were excised for histologic confirmation of metastatic disease. Quantitative histological analysis was used to evaluate hypoxia, proliferation, lymphatic and blood vessels in the epithelial and stromal regions of the xenografts and original patient tumour. Results: IFP and nodal disease were not correlated with tumor engraftment. IFP measurements in the xenografts were generally lower than those in the patient’s tumor. Lymphatic metastasis increased with passage number as did levels of hypoxia in the epithelial component of the xenografts. The blood vessel density in the stromal component of the xenografts increased in parallel. When all the markers were compared between the biopsy and the respective 3rd generation xenograft 10 of 11 tumors showed a good correlation. Conclusions: This ongoing study provides characterization about tumoral and stromal heterogeneity in a unique orthotopic xenograft model.

Highlights

We studied a range of microenvironmental parameters separately in the epithelial and stromal compartments in serial passages of orthotopically maintained primary cervix xenografts, relating these measurements to those made in the primary patient tumors and/or biopsies from which the xenografts were derived
Most of the patients had measurements of both interstitial fluid pressure (IFP) and hypoxia in their tumors initially we examined these parameters in the xenograft models
We report the establishment of a unique set of serially transplantable, orthotopic, patient-derived cervical cancer xenograft models that, at least within the range of passage numbers examined, show a relatively stable retention of the original tumor characteristics, but demonstrate a range of features faithfully reflecting the tumor heterogeneity encountered in patients

Summary

Introduction

The mortality rates of this disease have remained relatively stable in economically developed countries with adequate screening practices, morbidity and mortality remain high in countries with more limited infrastructure, where the implementation of screening and treatment strategies for early stage disease is challenging [2,5,6]. Epidemiologic studies have demonstrated a critical role of human papillomavirus (HPV) in the pathogenesis of neoplastic cervical lesions, with the “high risk” genotypes HPV 16/18 being associated with 99.7% of invasive cervical carcinomas [5,7,8]. Developed vaccines targeting oncogenic strains of HPV have demonstrated efficacy at reducing the incidence of HPV-related disease including both in situ and invasive cervix cancer. Given the latency of HPV-driven cervix disease it is unlikely that these strategies will have a significant impact on the burden of cervix cancer for some time. It is imperative to continue developing appropriate animal models of human cervix cancer, to facilitate an improved understanding of relevant tumor biology and for the identification and evaluation of novel therapies

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