Dataset Information

Cancer-Associated Fibroblasts Positively Correlate with Dedifferentiation and Aggressiveness of Thyroid Cancer.

ABSTRACT:

Background and objectives

Targeting cancer-associated fibroblast (CAF) is being explored as an approach to improve cancer therapies. The roles of CAF remain unclarified in malignant transformation of papillary thyroid cancer (PTC) into dedifferentiated thyroid cancer (DDTC). This study aimed to investigate correlations of CAF with dedifferentiation and clinicopathological characteristics of thyroid cancer.

Materials and methods

We applied three different mRNA-based CAF gene signatures to quantify CAF in our cohort, the Gene Expression Omnibus (GEO) cohort and The Cancer Genome Atlas (TCGA) cohort, and analyzed expression of ?-SMA by immunohistochemistry in thyroid cancer. The CAF score was analyzed for its associations with clinicopathological characteristics, genetic mutations, tumor-associated signaling pathways and immune landscape.

Results

The CAF score increased significantly in DDTCs compared with normal thyroid tissues and PTCs, and the ?-SMA-positive CAFs were found enriched in DDTCs. The high CAF score showed a significant correlation with the anaplastic phenotype in DDTC and low thyroid differentiation score in PTC. Patients with a high CAF score remarkably increased the risk of aggressive outcomes in both DDTC and PTC. Furthermore, the CAF score was positively correlated with genetic mutations, oncogenic signaling pathways, the immune score and increased expression of tumor microenvironment (TME) target markers.

Conclusion

Our findings suggest CAFs positively correlate with dedifferentiation and aggressive outcomes of thyroid cancer, and targeting CAFs as a therapeutic approach may benefit DDTC patients.

SUBMITTER: Wen S

PROVIDER: S-EPMC7910116 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Cancer-Associated Fibroblasts Positively Correlate with Dedifferentiation and Aggressiveness of Thyroid Cancer.

Wen Shishuai S Qu Ning N Ma Ben B Wang Xiao X Luo Yi Y Xu Weibo W Jiang Hongyi H Zhang Yan Y Wang Yu Y Ji Qinghai Q

OncoTargets and therapy 20210222

<h4>Background and objectives</h4>Targeting cancer-associated fibroblast (CAF) is being explored as an approach to improve cancer therapies. The roles of CAF remain unclarified in malignant transformation of papillary thyroid cancer (PTC) into dedifferentiated thyroid cancer (DDTC). This study aimed to investigate correlations of CAF with dedifferentiation and clinicopathological characteristics of thyroid cancer.<h4>Materials and methods</h4>We applied three different mRNA-based CAF gene signat ...[more]

PMID: 33654411

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Project description:Papillary thyroid carcinoma (PTC) is the fastest-growing disease caused by numerous molecular alterations in addition to previously reported DNA mutations. There is a compelling need to identify novel transcriptomic alterations that are associated with the pathogenesis of PTC with potential diagnostic and prognostic implications. Methods: We gathered and compared 242 expression profiles between paired PTC and adjacent normal tissues and identified and validated the coding and long non-coding RNAs (lncRNAs) associated with the extrathyroidal extension (ETE) of 655 PTC patients in two independent cohorts, followed by predicting their interactions with drugs. Co-expression, RNA interaction, Kaplan-Meier survival and multivariate Cox proportional regression analyses were performed to identify dysregulated lncRNAs and genes that correlated with clinical outcomes of PTC. Alternative splicing (AS), RNA circularization, and editing were also compared between transcriptomes to expand the repertoire of molecular alterations in PTC. Results: Numerous genes related to cellular microenvironment and steroid hormone response were associated with the ETE of PTC. Drug susceptibility predictions of the expression signature revealed two highly ranked compounds, 6-bromoindirubin-3'-oxime and lovastatin. Co-expression and RNA interaction analysis revealed the essential role of lncRNAs in PTC pathogenesis by modulating extracellular matrix and cell adhesion. Eight genes and two novel lncRNAs were identified that correlated with the aggressive nature and disease-free survival of PTC. Furthermore, this study provided the transcriptome-wide landscape of circRNAs in PTC and uncovered dissimilar expression profiles among circRNAs originating from the same host gene, suggesting the functional complexity of circRNAs in PTC carcinogenesis. The newly identified AS events in the SERPINA1 and FN1 genes may improve the sensitivity and specificity of these diagnostic biomarkers. Conclusions: Our study uncovered a comprehensive transcriptomic signature associated with the carcinogenesis and aggressive behavior of PTC, as well as presents a catalog of 10 potential biomarkers, which would facilitate PTC prognosis and development of new therapeutic strategies for this cancer.

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Project description:BACKGROUND:Prostate-specific membrane antigen (PSMA) is overexpressed on the endothelial cells of tumor neo-vessels of several solid malignancies, including differentiated thyroid cancer (DTC). We aimed to test the potential role of PSMA as a biomarker for DTC aggressiveness and outcome prediction. We retrospectively screened all patients who underwent thyroidectomy between 1 January 2010 and 31 December 2017 in our institution. Applying the inclusion (histological diagnosis of thyroid cancer and tissue availability) and exclusion criteria (no clinical or follow-up data or diagnosis of medullary thyroid cancer), a cohort of 59 patients was selected. The monoclonal mouse anti-human PSMA antibody was used to stain tissue sections. A 3-point scale was used to score PSMA positivity: 0-5% expression was considered as negative (score 0), 6-50% as moderately positive (score 1), and 51-100% as highly positive (score 2). A cumulative score (0-10%, 11-79%, and 80-100%) was also explored. Univariate and multivariate logistic regression analyses were performed to predict the presence of distant metastases, chosen as endpoint of aggressiveness. The area under the curve (AUC) was calculated. Cox models were built to predict patient outcome in terms of recurrence, iodine refractoriness, and status at last follow-up, which were calculated using the Kaplan-Meier failure function. RESULTS:At immunostaining, 12, 25, and 22 patients had scores of 0, 1, and 2, respectively. According to the cumulative score, PSMA expression was ??10% in 17 cases, 11-79% in 31 cases, and ??80% in 11 cases. At multivariate analysis, age, sex, histotype, vascular invasion, T and N parameters, and PSMA positivity were significant predictors of distant metastases. The AUC was 0.92. Recurrence or progression occurred in 19/59 patients. Twelve patients developed radioiodine (RAI) refractoriness, after a median time of 17?months (range 2-32). One patient died of DTC; 46 of the 58 patients alive at last follow-up were disease free. Median DFS was 23?months (range 3-82). The final multivariate model to predict RAI refractoriness included as covariates the stage, high PSMA expression (??80%), and the interaction between moderate PSMA expression (11-79%) and stage. CONCLUSIONS:PSMA, a marker of neovasculature formation expressed by DTC, contributes in the prediction of tumor aggressiveness and patient outcome.

Dataset Information

Cancer-Associated Fibroblasts Positively Correlate with Dedifferentiation and Aggressiveness of Thyroid Cancer.

Background and objectives

Materials and methods

Results

Conclusion

Publications

Cancer-Associated Fibroblasts Positively Correlate with Dedifferentiation and Aggressiveness of Thyroid Cancer.

Similar Datasets

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