Organotypic slice cultures of pancreatic ductal adenocarcinoma preserve the tumor microenvironment and provide a platform for drug response

Lim, Chae Yoon; Chang, Jae Hyuck; Lee, Won Sun; Lee, Kangmin; Yoon, Young Chul; Kim, Jeana; Park, Il Young

doi:10.1016/j.pan.2018.09.009

Cited by 31 publications

(31 citation statements)

References 19 publications

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“…Precision-cut tissue slices represent an intermediate experimental approach between in vivo and in vitro models, which retain histological and three-dimensional structure, with inter- and extracellular interactions, cell matrix components, and metabolic capacity [47]. There are several studies that report ex vivo tumor responses to anticancer drugs in tissue slices in breast [48,49,50,51,52], liver [53], head and neck [54,55], colorectal [56], gastric, esophagogastric [57], lung [58], pancreatic [59,60], prostate, and bladder [61] cancers. Since different types of tumors display different growth and culture characteristics, the aforementioned studies served to standardize a number of differing tumor-slice culture systems; for example, recently, we used breast tumor explants prepared from precision-cut breast slices to study the antitumoral effect of a number of natural compounds [62].…”

Section: Resultsmentioning

confidence: 99%

“…In addition to intratumoral heterogeneity, our results exhibit how patient response to treatment varies on a case-by-case basis. Therefore, assays aimed toward predicting whether or not an individual tumor responds to cancer treatments are needed, and we believe that tumor-derived organotypic cultures provide a suitable approach to deal with said requirement [50,54,56,57,60,62], since they comprise various cells that are collectively important for tissue homeostasis, as well as tumor response [66]. As it was proven in the present study, cell cultures are a helpful approach as a first screening option due to their simplicity.…”

Section: Resultsmentioning

confidence: 99%

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Antitumoral Effect of Laurinterol on 3D Culture of Breast Cancer Explants

et al. 2019

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Macroalgae represent an important source of bioactive compounds with a wide range of biotechnological applications. Overall, the discovery of effective cytotoxic compounds with pharmaceutical potential is a significant challenge, mostly because they are scarce in nature or their total synthesis is not efficient, while the bioprospecting models currently used do not predict clinical responses. Given this context, we used three-dimensional (3D) cultures of human breast cancer explants to evaluate the antitumoral effect of laurinterol, the major compound of an ethanolic extract of Laurencia johnstonii. To this end, we evaluated the metabolic and histopathological effects of the crude extract of L. johnstonii and laurinterol on Vero and MCF-7 cells, in addition to breast cancer explants. We observed a dose-dependent inhibition of the metabolic activity, as well as morphologic and nuclear changes characteristic of apoptosis. On the other hand, a reduced metabolic viability and marked necrosis areas were observed in breast cancer explants incubated with the crude extract, while explants treated with laurinterol exhibited a heterogeneous response which was associated with the individual response of each human tumor sample. This study supports the cytotoxic and antitumoral effects of laurinterol in in vitro cell cultures and in ex vivo organotypic cultures of human breast cancer explants.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Antitumoral Effect of Laurinterol on 3D Culture of Breast Cancer Explants

et al. 2019

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“…Although the connection of FOXM1 to the TME is not yet well understood, it is suggested to play a role in T-cell differentiation and to affect the proliferation of macrophages [59,60]. Considering an important influence of immune cells in cancer development and treatment, tissue cultures display a vital immunological compartment [40,61], and thus might help to understand the complex FOXM1 network in context of the TME and the effects of thiostrepton by modulating immune activation. While our findings have set the base for investigations on ovarian carcinoma tissue culture, further work should also take clinical patient data into consideration for correlative comparison and evaluation with ex vivo results.…”

Section: Discussionmentioning

confidence: 99%

FOXM1 Inhibition in Ovarian Cancer Tissue Cultures Affects Individual Treatment Susceptibility Ex Vivo

Brückner

Reinshagen

Hoang

et al. 2021

Cancers

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Diagnosis in an advanced state is a major hallmark of ovarian cancer and recurrence after first line treatment is common. With upcoming novel therapies, tumor markers that support patient stratification are urgently needed to prevent ineffective therapy. Therefore, the transcription factor FOXM1 is a promising target in ovarian cancer as it is frequently overexpressed and associated with poor prognosis. In this study, fresh tissue specimens of 10 ovarian cancers were collected to investigate tissue cultures in their ability to predict individual treatment susceptibility and to identify the benefit of FOXM1 inhibition. FOXM1 inhibition was induced by thiostrepton (3 µM). Carboplatin (0.2, 2 and 20 µM) and olaparib (10 µM) were applied and tumor susceptibility was analyzed by tumor cell proliferation and apoptosis in immunofluorescence microscopy. Resistance mechanisms were investigated by determining the gene expression of FOXM1 and its targets BRCA1/2 and RAD51. Ovarian cancer tissue was successfully maintained for up to 14 days ex vivo, preserving morphological characteristics of the native specimen. Thiostrepton downregulated FOXM1 expression in tissue culture. Individual responses were observed after combined treatment with carboplatin or olaparib. Thus, we successfully implemented a complex tissue culture model to ovarian cancer and showed potential benefit of combined FOXM1 inhibition.

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“…Tumor texture also relates to its ease of slicing as soft, mucinous or fibrous tumor sections could not be sliced into sections <500 μm (Holliday et al, 2013; Gerlach et al, 2014; Naipal et al, 2016). Automated slicing has been used extensively in the preparation of OTS for NSCLC (Vaira et al, 2010; Davies et al, 2015), brain (van der Kuip et al, 2006; Holliday et al, 2013; Merz et al, 2013; Carranza-Torres et al, 2015; Davies et al, 2015; Naipal et al, 2016), colon (Vaira et al, 2010), prostate (Hällström et al, 2007; Vaira et al, 2010; Zhang et al, 2018b), HNSCC (Gerlach et al, 2014), and pancreatic tumor tissues (Lim et al, 2018; Misra et al, 2019).…”

Section: Engineering Patient-specific Tumor Microenvironment Modelsmentioning

confidence: 99%

Addressing Patient Specificity in the Engineering of Tumor Models

Bray

Hutmacher

2019

Front. Bioeng. Biotechnol.

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Cancer treatment is challenged by the heterogeneous nature of cancer, where prognosis depends on tumor type and disease stage, as well as previous treatments. Optimal patient stratification is critical for the development and validation of effective treatments, yet pre-clinical model systems are lacking in the delivery of effective individualized platforms that reflect distinct patient-specific clinical situations. Advances in cancer cell biology, biofabrication, and microengineering technologies have led to the development of more complex in vitro three-dimensional (3D) models to act as drug testing platforms and to elucidate novel cancer mechanisms. Mostly, these strategies have enabled researchers to account for the tumor microenvironment context including tumor-stroma interactions, a key factor of heterogeneity that affects both progression and therapeutic resistance. This is aided by state-of-the-art biomaterials and tissue engineering technologies, coupled with reproducible and high-throughput platforms that enable modeling of relevant physical and chemical factors. Yet, the translation of these models and technologies has been impaired by neglecting to incorporate patient-derived cells or tissues, and largely focusing on immortalized cell lines instead, contributing to drug failure rates. While this is a necessary step to establish and validate new models, a paradigm shift is needed to enable the systematic inclusion of patient-derived materials in the design and use of such models. In this review, we first present an overview of the components responsible for heterogeneity in different tumor microenvironments. Next, we introduce the state-of-the-art of current in vitro 3D cancer models employing patient-derived materials in traditional scaffold-free approaches, followed by novel bioengineered scaffold-based approaches, and further supported by dynamic systems such as bioreactors, microfluidics, and tumor-on-a-chip devices. We critically discuss the challenges and clinical prospects of models that have succeeded in providing clinical relevance and impact, and present emerging concepts of novel cancer model systems that are addressing patient specificity, the next frontier to be tackled by the field.

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Organotypic slice cultures of pancreatic ductal adenocarcinoma preserve the tumor microenvironment and provide a platform for drug response

Cited by 31 publications

References 19 publications

Antitumoral Effect of Laurinterol on 3D Culture of Breast Cancer Explants

Antitumoral Effect of Laurinterol on 3D Culture of Breast Cancer Explants

FOXM1 Inhibition in Ovarian Cancer Tissue Cultures Affects Individual Treatment Susceptibility Ex Vivo

Addressing Patient Specificity in the Engineering of Tumor Models

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