Apoptosis-Based Evaluation of Chemosensitivity in Ovarian Cancer Patients

Flick, Maryann B.; O’Malley, David M.; Rutherford, Thomas J.; Rodov, Sofya; Kamsteeg, Marijka; Hao, Xiaoying; Schwartz, Peter E.; Kacinski, Barry M.; Mor, Gil

doi:10.1016/j.jsgi.2003.11.003

Cited by 28 publications

(25 citation statements)

References 30 publications

(1 reference statement)

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“…Sensitivity to carboplatin and paclitaxel in ascites-derived cells treated in vitro mimicked the clinical chemosensitive or chemoresistant phenotype in each patient. 71 Therefore, MCTS formation methods that can grow MCTS from patient derived ascites can be useful clinical tools.…”

Section: Discussionmentioning

confidence: 99%

Comparative Study of Multicellular Tumor Spheroid Formation Methods and Implications for Drug Screening

Gencoglu

Barney

Hall

et al. 2017

ACS Biomater. Sci. Eng.

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Improved in vitro models are needed to better understand cancer progression and bridge the gap between in vitro proof-of-concept studies, in vivo validation, and clinical application. Multicellular tumor spheroids (MCTS) are a popular method for three-dimensional (3D) cell culture, because they capture some aspects of the dimensionality, cell–cell contact, and cell–matrix interactions seen in vivo. Many approaches exist to create MCTS from cell lines, and they have been used to study tumor cell invasion, growth, and how cells respond to drugs in physiologically relevant 3D microenvironments. However, there are several discrepancies in the observations made of cell behaviors when comparing between MCTS formation methods. To resolve these inconsistencies, we created and compared the behavior of breast, prostate, and ovarian cancer cells across three MCTS formation methods: in polyNIPAAM gels, in microwells, or in suspension culture. These methods formed MCTS via proliferation from single cells or passive aggregation, and therefore showed differential reliance on genes important for cell–cell or cell–matrix interactions. We also found that the MCTS formation method dictated drug sensitivity, where MCTS formed over longer periods of time via clonal growth were more resistant to treatment. Toward clinical application, we compared an ovarian cancer cell line MCTS formed in polyNIPAAM with cells from patient-derived malignant ascites. The method that relied on clonal growth (PolyNIPAAM gel) was more time and cost intensive, but yielded MCTS that were uniformly spherical, and exhibited the most reproducible drug responses. Conversely, MCTS methods that relied on aggregation were faster, but yielded MCTS with grapelike, lobular structures. These three MCTS formation methods differed in culture time requirements and complexity, and had distinct drug response profiles, suggesting the choice of MCTS formation method should be carefully chosen based on the application required.

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Section: Discussionmentioning

confidence: 99%

Comparative Study of Multicellular Tumor Spheroid Formation Methods and Implications for Drug Screening

Gencoglu

Barney

Hall

et al. 2017

ACS Biomater. Sci. Eng.

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“…Primary EOC cells were isolated from malignant ovarian ascites and cultured as previously described (17). EOC cells were isolated from tumors as previously described (17,18). The normal ovarian surface epithelial cell line immortalized with telomerase was cultured as previously described (19).…”

Section: Methodsmentioning

confidence: 99%

TLR-4 Signaling Promotes Tumor Growth and Paclitaxel Chemoresistance in Ovarian Cancer

et al. 2006

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Evidence suggests that an inflammatory profile of cytokines and chemokines persisting at a particular site would lead to the development of a chronic disease. Recent studies implicate bacterial infection as one possible link between inflammation and carcinogenesis; however, the crucial molecular pathways involved remain unknown. We hypothesized that one possible upstream signaling pathway leading to inflammation in carcinogenesis may be mediated by Toll-like receptors (TLR). We describe for the first time an adaptive mechanism acquired by ovarian cancer cells that allows them to promote a proinflammatory environment and develop chemoresistance. We propose that the TLR-4-MyD88 signaling pathway may be a risk factor for developing cancer and may represent a novel target for the development of biomodulators. Our work explains how bacterial products, such as lipopolysaccharide, can promote, directly from the tumor, the production of proinflammatory cytokines and the enhancement of tumor survival. In addition, we provide new evidence that links TLR-4 signaling, inflammation, and chemoresistance in ovarian cancer cells. (Cancer Res 2006; 66(7): 3859-68)

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“…Cells used in these studies were isolated from either ascites or cancer tissue from ovarian cancer patients and grown as previously described. 41,56,57 The experiments described here were performed using three clones of CD44+/MyD88+ EOC stem cells and three clones of CD44-/ MyD88-EOC cells. 16,27 CD44-/MyD88-EOC cells correspond to the CD44-component of the cells derived from CD44+ EOC stem cells following in vitro and in vivo differentiation.…”

Section: Methodsmentioning

confidence: 99%

TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence

et al. 2013

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Primary ovarian cancer is responsive to treatment, but chemoresistant recurrent disease ensues in majority of patients. Recent compelling evidence demonstrates that a specific population of cancer cells, the cancer stem cells, initiates and sustains tumors. It is therefore possible that this cell population is also responsible for recurrence. We have shown previously that CD44+/MyD88+ epithelial ovarian cancer stem cells (CD44+/MyD88+ EOC stem cells) are responsible for tumor initiation. In this study, we demonstrate that this population drives tumor repair following surgery- and chemotherapy-induced tumor injury. Using in vivo and in vitro models, we also demonstrate that during the process of tumor repair, CD44+/MyD88+ EOC stem cells undergo self-renewal as evidenced by upregulation of stemness-associated genes. More importantly, we show that a pro-inflammatory microenvironment created by the TLR2-MyD88-NFκB pathway supports EOC stem cell-driven repair and self-renewal. Overall, our findings point to a specific cancer cell population, the CD44+/MyD88+ EOC stem cells and a specific pro-inflammatory pathway, the TLR2-MyD88-NFκB pathway, as two of the required players promoting tumor repair, which is associated with enhanced cancer stem cell load. Identification of these key players is the first step in elucidating the steps necessary to prevent recurrence in EOC patients.

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Apoptosis-Based Evaluation of Chemosensitivity in Ovarian Cancer Patients

Abstract: Quantifiable markers of apoptosis such as caspase-3 activation have the potential to predict the clinical response to chemotherapy. Application of this assay in clinical laboratories could optimize the potential for efficient treatment and avoid the toxicities of ineffective drugs.

Cited by 28 publications

References 30 publications

Comparative Study of Multicellular Tumor Spheroid Formation Methods and Implications for Drug Screening

Comparative Study of Multicellular Tumor Spheroid Formation Methods and Implications for Drug Screening

TLR-4 Signaling Promotes Tumor Growth and Paclitaxel Chemoresistance in Ovarian Cancer

TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence

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