Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Periostin is a mesenchyme-specific gene product, which acts as an adhesion molecule during bone formation and supports osteoblastic cell line attachment and spreading. However, periostin expression is activated in a large variety of epithelial human tumors and correlates with their aggressiveness. Knowledge of expression of periostin in thyroid tumors is still scanty. The aim of the present work was to investigate periostin expression in differentiated neoplasms of the thyroid and to correlate it with several clinical and molecular features of these tumors. Periostin expression was evaluated by quantitative PCR and immunohistochemistry in normal thyroid tissues, papillary thyroid carcinomas (PTCs), follicular thyroid carcinomas (FTCs), and follicular adenomas (FAs). Periostin mRNA levels were also evaluated in several thyroid tumor cell lines. PTCs show mean periostin mRNA levels significantly higher than corresponding normal tissues. In five PTCs, periostin mRNA values were at least 30-fold higher than corresponding normal tissues. Conversely, mean periostin mRNA levels of FTCs and FAs were similar to those of normal tissues. Consistent with mRNA studies, periostin was detectable by immunohistochemistry in cancerous epithelial cells only in several cases of PTCs but not in normal tissue, FTCs, and FAs. In PTCs, periostin mRNA levels positively correlate with extrathyroidal invasion, distant metastasis, and higher grade staging. A negative correlation between periostin and expression of some markers of the thyroid-differentiated phenotype (thyroglobulin, thyrotropin receptor) was also present in the PTCs. These results indicate that an increase in periostin gene expression is present in several PTCs, in which it appears as a marker of aggressiveness. Experiments in thyroid tumor cell lines indicate that high levels of periostin mRNA are due, at least in part, to the increase in periostin promoter activity.

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Generation of a HuTCR mouse platform-derived MAGE-A1-directed high-affinity TCR with superior potency versus human-derived TCRs.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14515 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14515-e14515

Author(s):

Ioannis Gavvovidis ◽

Matthias Leisegang ◽

Jenifer Oduro ◽

Matthias Obenaus ◽

Eugen Leo ◽

...

Keyword(s):

T Cells ◽

Tumor Cell ◽

Cell Lines ◽

Target Cells ◽

Tumor Cell Lines ◽

Functional Avidity ◽

High Affinity ◽

Selective Expression ◽

Tumor Types ◽

Cancer Testis

e14515 Background: As cancer-testis antigens are self-antigens, T cells expressing high-affinity TCRs against such antigens are suppressed via negative thymic selection. Therefore, patient- or donor-derived TCRs are typically of low affinity and result in a reduced antitumor effect. Using our proprietary HuTCR platform, which consists of mouse lines carrying the full human TCR α/β loci in combination with common human HLA alleles, we have isolated high-affinity TCRs specific for the cancer-testis antigen MAGE-A1 and compared them to human-derived MAGE-A1-specific TCRs that are currently reported to be in clinical development. Furthermore, we validated MAGE-A1 as a potential cancer therapy target by using immunohistochemistry to evaluate expression in several major tumor types and healthy tissue. Methods: Using scRNAseq, TCRs were isolated from HuTCR mice. Human-derived MAGE-A1-specific TCR sequences were obtained from publicly available databases. All TCRs were expressed in primary human T cells as verified using peptide-MHC-multimer staining. Functional avidity of the TCRs was analyzed by coculture with T2 target cells loaded with titrated amounts of epitope peptides and measuring cytokine concentration by ELISA. Reactivity of TCRs to endogenously processed MAGE-A1 protein was assessed by co-culture with a panel of tumor cell lines varying in MAGE-A1 and/or MHC-class-I expression. MAGE-A1 expression on protein level was evaluated by immunohistochemistry. Results: Immunization of HuTCR mice with the antigen resulted in robust CD8+ T cell responses and several TCR clonotypes were identified by scRNAseq, with the majority of clonotypes being specific to the MAGE-A1-derived peptide KVLEYVIKV and TCR affinities ranging from 0.3 nM to 3 nM. By comparison, human-derived TCRs exhibited generally lower functional avidity from 3 nM to 60 nM. In addition, HuTCR-mouse-derived TCRs were more sensitive in recognition of tumor cell lines expressing low MAGE-A1 and/or HLA-A2. Immunohistochemical analysis of MAGE-A1 expression in healthy tissues demonstrated highly selective expression of MAGE-A1 in testis, only. Screening for expression confirmed that a significant proportion of several major cancer types expresses MAGE-A1 as reported by various other groups [reviewed in Curr Opin Cell Biol. 2015 December; 37: 1–8]. Conclusions: The HuTCR mouse platform allows for the generation of high-affinity MAGE-A1-specific TCRs with increased anti-tumor efficacy as compared to human-derived TCRs against the same cancer antigen. In addition, it was confirmed that MAGE-A1 has a highly selective expression pattern in healthy tissues (testis, only), but shows distinct expression in several major human tumor types.

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Expression Atlas of FGF and FGFR Genes in Pancancer Uncovered Predictive Biomarkers for Clinical Trials of Selective FGFR Inhibitors

BioMed Research International ◽

10.1155/2020/5658904 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuan Li ◽

Long Wu ◽

Weiping Tao ◽

Dawei Wu ◽

Fei Ma ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trials ◽

Tumor Cell ◽

Cell Lines ◽

Expression Profiles ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Tumor Cell Lines ◽

Expression Atlas ◽

Tumor Types

Background. Clinical trials based on FGFR mutation or amplification as a druggable target of FGFR inhibitors have produced disappointing clinical outcomes. Therefore, the identification of predictive biomarkers for FGFR-targeted agents has remained a crucial issue. Methods. Expression profiles of FGFs and FGFRs in 8,111 patients with 24 types of solid tumors and 879 tumor cell lines along with drug sensitivity data were obtained and followed by integrative bioinformatics analysis. Results. FGFs and FGFRs were frequently dysregulated in pancancer. Most of the expression of FGFs and FGFRs were significantly associated with overall survival in at least two cancer types. Moreover, tumor cell lines with high FGFR1/3 expression were more sensitive to FGFR inhibitor PD173074, especially in breast, liver, lung and ovarian cancer. The predicted positive ratios of FGFR1-4 were generally over 10% in most tumor types, especially in squamous cell carcinoma. High positive FGFR1 or 3 expression ratios were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), and ovarian cancer (34%). Conclusions. FGFR expression was a promising predictive biomarker for FGFR inhibition response in clinical trials, and different combinations of FGFR genes should be used in screening for patients in certain tumor types.

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Comparative analysis of two thyroid tumor cell lines by fluorescence in situ hybridization and comparative genomic hybridization

Cancer Genetics and Cytogenetics ◽

10.1016/s0165-4608(02)00562-9 ◽

2002 ◽

Vol 137 (2) ◽

pp. 108-118 ◽

Cited By ~ 7

Author(s):

Chiara Corso ◽

Hacan Ulucan ◽

Elizabeth M. Parry ◽

James M. Parry

Keyword(s):

In Situ Hybridization ◽

Comparative Analysis ◽

Tumor Cell ◽

Fluorescence In Situ Hybridization ◽

Comparative Genomic Hybridization ◽

Cell Lines ◽

Thyroid Tumor ◽

Comparative Genomic ◽

Tumor Cell Lines

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Absence of functional EpoR expression in human tumor cell lines

Blood ◽

10.1182/blood-2009-10-248674 ◽

2010 ◽

Vol 115 (21) ◽

pp. 4254-4263 ◽

Cited By ~ 69

Author(s):

Susan Swift ◽

Aaron R. Ellison ◽

Paul Kassner ◽

Ian McCaffery ◽

John Rossi ◽

...

Keyword(s):

Tumor Cell ◽

Cell Lines ◽

Human Tumor ◽

Mrna Levels ◽

Tumor Cell Lines ◽

Human Tumor Cell Lines ◽

Protein Levels ◽

And Function ◽

Tumor Types ◽

Positive Controls

Certain oncology trials showed worse clinical outcomes in the erythropoiesis-stimulating agent (ESA) arm. A potential explanation was that ESA-activated erythropoietin (Epo) receptors (EpoRs) promoted tumor cell growth. Although there were supportive data from preclinical studies, those findings often used invalidated reagents and methodologies and were in conflict with other studies. Here, we further investigate the expression and function of EpoR in tumor cell lines. EpoR mRNA levels in 209 human cell lines representing 16 tumor types were low compared with ESA-responsive positive controls. EpoR protein production was evaluated in a subset of 66 cell lines using a novel anti-EpoR antibody. EpoR+ control cells had an estimated 10 000 to 100 000 EpoR dimers/cell. In contrast, 54 of 61 lines had EpoR protein levels lower than 100 dimers/cell. Cell lines with the highest EpoR protein levels (400-3200 dimers/cell) were studied further, and, although one line, NCI-H661, bound detectable levels of [125I]–recombinant human Epo (rHuEpo), none showed evidence of ESA-induced EpoR activation. There was no increased phosphorylation of STAT5, AKT, ERK, or S6RP with rHuEpo. In addition, EpoR knockdown with siRNAs did not affect viability in 2 cell lines previously reported to express functional EpoR (A2780 and SK-OV-3). These results conflict with the hypothesis that EpoR is functionally expressed in tumors.

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