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Three-dimensional organoid culture reveals involvement of Wnt/?-catenin pathway in proliferation of bladder cancer cells.

ABSTRACT: There has been increasing awareness of the importance of three-dimensional culture of cancer cells. Tumor cells growing as multicellular spheroids in three-dimensional culture, alternatively called organoids, are widely believed to more closely mimic solid tumors in situ. Previous studies concluded that the Wnt/?-catenin pathway is required for regeneration of the normal urothelium after injury and that ?-catenin is upregulated in human bladder cancers, but no clear evidence has been advanced to support the idea that the Wnt/?-catenin pathway is directly involved in deregulated proliferation and the other malignant characteristics of bladder cancer cells. Here we report that the Wnt/?-catenin pathway activator, CHIR99021, promoted proliferation of established human bladder cancer cell lines when they were grown in organoid culture but not when they were grown in conventional adherent cultures. CHIR99021 activated Wnt/?-catenin pathway in bladder cancer cell lines in organoid culture. CHIR99021 also stimulated proliferation and the Wnt/b-catenin pathway in primary human bladder cancer organoids. RNAi-mediated knockdown of ?-catenin blocked growth of organoids. The effects of CHIR99021 were associated with decreased expression of the urothelial terminal differentiation marker, cytokeratin 20. Our data suggest that the Wnt/?-catenin pathway is required for the proliferation of bladder cancer cells in three-dimensional organoid culture and provide a concrete example of why organoid culture is important for cancer research.

SUBMITTER: Yoshida T

PROVIDER: S-EPMC5834271 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Three-dimensional organoid culture reveals involvement of Wnt/β-catenin pathway in proliferation of bladder cancer cells.

Yoshida Takahiro T Sopko Nikolai A NA Kates Max M Liu Xiaopu X Joice Gregory G McConkey David J DJ Bivalacqua Trinity J TJ

Oncotarget 20180124 13

There has been increasing awareness of the importance of three-dimensional culture of cancer cells. Tumor cells growing as multicellular spheroids in three-dimensional culture, alternatively called organoids, are widely believed to more closely mimic solid tumors <i>in situ</i>. Previous studies concluded that the Wnt/β-catenin pathway is required for regeneration of the normal urothelium after injury and that β-catenin is upregulated in human bladder cancers, but no clear evidence has been adva ...[more]

PMID: 29541396

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Project description:BackgroundGlioblastoma (GBM) is the most common primary brain tumor with a dismal prognosis. The inherent cellular diversity and interactions within tumor microenvironments represent significant challenges to effective treatment. Traditional culture methods such as adherent or sphere cultures may mask such complexities whereas three-dimensional (3D) organoid culture systems derived from patient cancer stem cells (CSCs) can preserve cellular complexity and microenvironments. The objective of this study was to determine if GBM organoids may offer a platform, complimentary to traditional sphere culture methods, to recapitulate patterns of clinical drug resistance arising from 3D growth.MethodsAdult and pediatric surgical specimens were collected and established as organoids. We created organoid microarrays and visualized bulk and spatial differences in cell proliferation using immunohistochemistry (IHC) staining, and cell cycle analysis by flow cytometry paired with 3D regional labeling. We tested the response of CSCs grown in each culture method to temozolomide, ibrutinib, lomustine, ruxolitinib, and radiotherapy.ResultsGBM organoids showed diverse and spatially distinct proliferative cell niches and include heterogeneous populations of CSCs/non-CSCs (marked by SOX2) and cycling/senescent cells. Organoid cultures display a comparatively blunted response to current standard-of-care therapy (combination temozolomide and radiotherapy) that reflects what is seen in practice. Treatment of organoids with clinically relevant drugs showed general therapeutic resistance with drug- and patient-specific antiproliferative, apoptotic, and senescent effects, differing from those of matched sphere cultures.ConclusionsTherapeutic resistance in organoids appears to be driven by altered biological mechanisms rather than physical limitations of therapeutic access. GBM organoids may therefore offer a key technological approach to discover and understand resistance mechanisms of human cancer cells.

Dataset Information

Three-dimensional organoid culture reveals involvement of Wnt/?-catenin pathway in proliferation of bladder cancer cells.

Publications

Three-dimensional organoid culture reveals involvement of Wnt/β-catenin pathway in proliferation of bladder cancer cells.

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