Patient-derived cell line models revealed therapeutic targets and molecular mechanisms underlying disease progression of high grade serous ovarian cancer

Kreuzinger, Caroline; Decken, Isabel von der; Wolf, Andrea; Gamperl, Magdalena; Koller, Júlia; Karacs, Jasmine; Pfaffinger, Stephanie; Bartl, Thomas; Reinthaller, Alexander; Grimm, Christoph; Singer, Christian F.; Braicu, Elena Ioana; Cunnea, Paula; Gourley, Charlie; Smeets, Dominiek; Boeckx, Bram; Lambrechts, Diether; Perco, Paul; Horvat, Reinhard; Berns, Els M.J.J.; Castillo‐Tong, Dan Cacsire

doi:10.1016/j.canlet.2019.05.032

Cited by 16 publications

(21 citation statements)

References 43 publications

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“…For example, in multistep cell models of 34 cancer cell lines derived from 23 HGSOC patients to develop new treatments for therapy, it is demonstrated that loss of TP53 wild type is the main driving force of tumorigenesis and tumor progression in HGSOC. [ 156 ] Cancer cell line models can be applied for clinical therapeutic targets in multistep tumor progression. Over the last decade, to develop groundbreaking therapeutic agents and recapitulate cell heterogeneity in vivo, in many tumor types, such as oral cancer, [ 157 ] breast cancer, [ 158 ] colorectal cancer, [ 159 ] prostate cancer, [ 160 ] pancreatic cancer, [ 161 ] and more recently, ovarian cancer, [ 162 ] 3D primary cell models in vitro have made stride forward in building tumor organoids ( Figure ), a type of precise oncology remodeling, which at largest extent recapitulates the tumorigenesis in vivo.…”

Section: Instructive Cell Constructs In Tissue Engineering and Precismentioning

confidence: 99%

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

Yang

Zhao

2020

Advanced Science

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mouse intestinal stem cells and primary colorectal cancer cells can be propagated in vitro long term, [1] there is an urgent need to develop more physiologically relevant, efficient, and robust precise oncology models that closely recapitulate the genetic and morphological heterogeneous composition and mimic the arrangement pattern of cancer cells in the original tumor. [2] To our knowledge in biomedical research, hydrogel is the best tool to reconstruct precise oncology models in vitro, especially tumor organoid, which not only recapitulates in vivo biology and microenvironmental factors, but also at large extent allows side-by-side comparison to evaluate the translational potential of 3D model systems to the patients. [2a,3] Generally, hydrogels are mainly composed of hydrophilic polymeric scaffolds that absorb large amounts of water, so the hydrogel matrix better mimics elastic and viscoelastic properties in ECM and microscale topographies of cell matrices, which controls proper cell morphology, directs viable cell behaviors, and drives in vivo fundamental cell-cell or cell-ECM interactions. [4] To recapitulate pathophysiological features of human tumors and imitate various aspects of human tumorigenesis in vivo, hydrogels can provide a realistic platform to establish a useful bridge between in vitro assays and in vivo cell microenvironments. In current biomedical applications, there are many kinds of hydrogels to be developed to mimic the biological properties of ECM, such Designer self-assembling peptides form the entangled nanofiber networks in hydrogels by ionic-complementary self-assembly. This type of hydrogel has realistic biological and physiochemical properties to serve as biomimetic extracellular matrix (ECM) for biomedical applications. The advantages and benefits are distinct from natural hydrogels and other synthetic or semisynthetic hydrogels. Designer peptides provide diverse alternatives of main building blocks to form various functional nanostructures. The entangled nanofiber networks permit essential compositional complexity and heterogeneity of engineering cell microenvironments in comparison with other hydrogels, which may reconstruct the tumor microenvironments (TMEs) in 3D cell cultures and tissue-specific modeling in vitro. Either ovarian cancer progression or recurrence and relapse are involved in the multifaceted TMEs in addition to mesothelial cells, fibroblasts, endothelial cells, pericytes, immune cells, adipocytes, and the ECM. Based on the progress in common hydrogel products, this work focuses on the diverse designer self-assembling peptide hydrogels for instructive cell constructs in tissue-specific modeling and the precise oncology remodeling for ovarian cancer, which are issued by several research aspects in a 3D context. The advantages and significance of designer peptide hydrogels are discussed, and some common approaches and coming challenges are also addressed in current complex tumor diseases.

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Section: Instructive Cell Constructs In Tissue Engineering and Precismentioning

confidence: 99%

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

Yang

Zhao

2020

Advanced Science

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“…Serous ovarian cancer (SOC) is the main type of ovarian cancer, which progresses quickly, lacks effective treatment and is prone to bladder metastasis ( 6 ). At present, surgery supplemented by chemotherapy remains the main treatment option for advanced stages of SOC, and treatment outcomes are unsatisfactory ( 7 ). In recent years, targeted therapy has shown advantages for SOC treatment ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of AK4 as a novel therapeutic target for serous ovarian cancer

et al. 2020

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The present study aimed to assess the expression level of adenylate kinase 4 (AK4) in human serous ovarian cancer (SOC) tissues and investigate the possible involvement of AK4 in SOC progression. Bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database and immunohistochemical (IHC) assays were performed to assess the expression level of AK4 in human SOC tissues. Clinical pathological features of patients with SOC were also evaluated. Colony formation, MTT, wound healing and Transwell assays were conducted to investigate the effects of AK4 on the proliferation, migration, and invasion of SOC cells in vitro . Mouse xenograft and lung metastasis models were developed to evaluate the effects of AK4 on tumor growth and metastasis in vivo . High expression levels of AK4 were identified in human SOC tissues compared with in normal tissues according to TCGA database and the results of IHC assays. A contribution of AK4 to tumor growth and metastasis of SOC cells in vivo was also shown. The present study confirmed the involvement of AK4 in the progression of SOC, and the results indicated that AK4 could serve as a novel therapeutic target for SOC treatment.

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“…The lack of additional proliferation in the presence of hormone precursors is most likely a consequence of the fact that all cell lines already reached their respective maximum proliferation capacity from the stimulatory effect of various cyclines (e.g., D1, E1, A1, and B) overexpressed in these cell lines. Genes such as CDKN1A BAX or TIGAR, controlling apoptosis and cell cycle arrest, are furthermore downregulated [26,49]. These data indicate that the loss of wild type p53 function is the major driving force of tumor cell progression [50].…”

Section: Discussionmentioning

confidence: 94%

“…Expression of selected genes (CYP3A4, CYP19A1, TP53, PAX8, AR, ESR1, ESR2, PGR, IL6, EGFR, ERBB2, and ESRRG) in the HGSOC cell lines 13363, 13699, 13914_1, and 15233 was analyzed by next-generation sequencing, as described previously [49]. Expression data for these selected genes in Kuramochi and OVSAHO cells were taken from the GENEVESTIGATOR platform [56].…”

Section: Gene Expression Analyses and Identification Of Gene Mutationsmentioning

confidence: 99%

“…In addition, ddPCR systems for each unique TP53 mutation were established to determine the percentage of the TP53 mutant cells in cell culture. The BRCA1, BRCA2, and KRAS mutations were determined by Sanger sequencing [49]. Data for Kuramochi and OVSAHO cells were obtained from the Cancer Cell Line Encyclopedia (CCLE) [57].…”

Section: Gene Expression Analyses and Identification Of Gene Mutationsmentioning

confidence: 99%

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Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

Poschner

Wackerlig

Castillo‐Tong

et al. 2020

Cancers

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High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.

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Patient-derived cell line models revealed therapeutic targets and molecular mechanisms underlying disease progression of high grade serous ovarian cancer

Abstract: Patient-derived cell line models revealed therapeutic targets and molecular mechanisms underlying disease progression of high grade serous ovarian cancer', Cancer letters.

Cited by 16 publications

References 43 publications

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

Identification of AK4 as a novel therapeutic target for serous ovarian cancer

Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

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