Visualizing treatment response dynamics of an in vitro three-dimensional ovarian cancer model

Conor L. Evans, Lnnran Rizvi, Jonathan Celli, Adnan Abu-Yousif, Johannes F. de Boer, Tayyaba Hasan

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Ovarian epithelial cancer (OVCA) is the fifth leading cause of cancer death among women in the US. The majority of patients have advanced-stage disseminated OVCA that coats the many surfaces in the abdomen with widespread nodular disease. These metastatic lesions often become drug resistant following standard chemotherapy regiments, leading to an unacceptably low survival rate of about 30%. In order to more effectively eradicate this metastatic disease, it is imperative to understand of the dynamics of ovarian tumor treatment response at the cellular and nodular levels. A three-dimensional in vitro model of OVCA developed in our group has proven to be a promising system for visualizing and optimizing the therapy of ovarian nodular disease, enabling studies that would otherwise be implausible to carry out in vivo. Ovarian cancer cells plated on Matrigel spontaneously self-assemble to form a heterogeneous mixture of three-dimensional spheroids that replicate many of the molecular and morphological features observed in avascular micrometastatic nodules found in vivo. Using the non-perturbative three-dimensional structural imaging technology known as optical coherence tomography (OCT), we have observed these nodules to grow beyond 500 µm in diameter and display complex structural changes during development. We have used this model system as a platform for multimodal OCT and fluorescence microscopy experiments aimed at understanding the treatment response of ovarian micronodular disease to cytotoxic therapies. High-throughput confocal fluorescence viability imaging alongside time-lapse OCT experiments revealed that treatments with the front-line chemotherapeutics cisplatin and carboplatin do not effectively kill cells in the center of large (>300 µm diameter) nodules. This three-dimensional pattern of cell death suggests a possible treatment resistance mechanism in vivo. To target this seemingly resistant cell population, we have used photodynamic therapy (PDT), an alternative modality that has been found to be effective against platinum-resistant ovarian cancer. PDT utilizes molecules known as a photosensitizers that, when exposed to a particular wavelength of light, generate cytotoxic reactive oxygen and radical species. We found that treatment using the photosensitizer EtNBS results in effective cellular killing of the previously spared nodule cores. Moreover, when combined with carboplatin, we observed a synergistic treatment response compared to the individual monotherapies alone. Ongoing studies using the 3D model aim to examine the underlying mechanisms behind these treatment responses and will be important in optimizing new therapeutic regimens for metastatic ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3261. ©2010 American Association for Cancer Research
Original languageEnglish
JournalCancer Research
Volume70
Issue number8
DOIs
Publication statusPublished - Apr 2010

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