Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues
BackgroundPartial epithelial-mesenchymal transition (p-EMT) is a distinct clinicopathological feature prevalent in oral cavity tumors of The Cancer Genome Atlas. Located at the invasion front, p-EMT cells require additional support from the tumor stroma for collective cell migration, including track...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:c5c66b95121f48e0859d1730794ad5c42021-11-16T07:48:06ZIdentification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues2234-943X10.3389/fonc.2021.769665https://doaj.org/article/c5c66b95121f48e0859d1730794ad5c42021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.769665/fullhttps://doaj.org/toc/2234-943XBackgroundPartial epithelial-mesenchymal transition (p-EMT) is a distinct clinicopathological feature prevalent in oral cavity tumors of The Cancer Genome Atlas. Located at the invasion front, p-EMT cells require additional support from the tumor stroma for collective cell migration, including track clearing, extracellular matrix remodeling and immune evasion. The pathological roles of otherwise nonmalignant cancer-associated fibroblasts (CAFs) in cancer progression are emerging.MethodsGene set enrichment analysis was used to reveal differentially enriched genes and molecular pathways in OC3 and TW2.6 xenograft tissues, representing mesenchymal and p-EMT tumors, respectively. R packages of genomic data science were executed for statistical evaluations and data visualization. Immunohistochemistry and Alcian blue staining were conducted to validate the bioinformatic results. Univariate and multivariate Cox proportional hazards models were performed to identify covariates significantly associated with overall survival in clinical datasets. Kaplan–Meier curves of estimated overall survival were compared for statistical difference using the log-rank test.ResultsCompared to mesenchymal OC3 cells, tumor stroma derived from p-EMT TW2.6 cells was significantly enriched in microvessel density, tumor-excluded macrophages, inflammatory CAFs, and extracellular hyaluronan deposition. By translating these results to clinical transcriptomic datasets of oral cancer specimens, including the Puram single-cell RNA-seq cohort comprising ~6000 cells, we identified the expression of stromal TGFBI and HYAL1 as independent poor and protective biomarkers, respectively, for 40 Taiwanese oral cancer tissues that were all derived from betel quid users. In The Cancer Genome Atlas, TGFBI was a poor marker not only for head and neck cancer but also for additional six cancer types and HYAL1 was a good indicator for four tumor cohorts, suggesting common stromal effects existing in different cancer types.ConclusionsAs the tumor stroma coevolves with cancer progression, the cellular origins of molecular markers identified from conventional whole tissue mRNA-based analyses should be cautiously interpreted. By incorporating disease-matched xenograft tissue and single-cell RNA-seq results, we suggested that TGFBI and HYAL1, primarily expressed by stromal CAFs and endothelial cells, respectively, could serve as robust prognostic biomarkers for oral cancer control.Yi-Hong LiuYi-Hong LiuYu-Lian ChenTing-Yu LaiTing-Yu LaiYing-Chieh KoYu-Fu ChouPeir-Rong ChenJenn-Ren HsiaoJang-Yang ChangJang-Yang ChangShine-Gwo ShiahJeng-Woei LeeJia-Ling YangSu-Fang LinFrontiers Media S.A.articleprognostic biomarkersoral cancerpartial epithelial-mesenchymal transition (p-EMT)tumor stromamyofibroblastic CAF (myCAF)inflammatory CAF (iCAF)Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021) |
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| collection |
DOAJ |
| language |
EN |
| topic |
prognostic biomarkers oral cancer partial epithelial-mesenchymal transition (p-EMT) tumor stroma myofibroblastic CAF (myCAF) inflammatory CAF (iCAF) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
prognostic biomarkers oral cancer partial epithelial-mesenchymal transition (p-EMT) tumor stroma myofibroblastic CAF (myCAF) inflammatory CAF (iCAF) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yi-Hong Liu Yi-Hong Liu Yu-Lian Chen Ting-Yu Lai Ting-Yu Lai Ying-Chieh Ko Yu-Fu Chou Peir-Rong Chen Jenn-Ren Hsiao Jang-Yang Chang Jang-Yang Chang Shine-Gwo Shiah Jeng-Woei Lee Jia-Ling Yang Su-Fang Lin Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues |
| description |
BackgroundPartial epithelial-mesenchymal transition (p-EMT) is a distinct clinicopathological feature prevalent in oral cavity tumors of The Cancer Genome Atlas. Located at the invasion front, p-EMT cells require additional support from the tumor stroma for collective cell migration, including track clearing, extracellular matrix remodeling and immune evasion. The pathological roles of otherwise nonmalignant cancer-associated fibroblasts (CAFs) in cancer progression are emerging.MethodsGene set enrichment analysis was used to reveal differentially enriched genes and molecular pathways in OC3 and TW2.6 xenograft tissues, representing mesenchymal and p-EMT tumors, respectively. R packages of genomic data science were executed for statistical evaluations and data visualization. Immunohistochemistry and Alcian blue staining were conducted to validate the bioinformatic results. Univariate and multivariate Cox proportional hazards models were performed to identify covariates significantly associated with overall survival in clinical datasets. Kaplan–Meier curves of estimated overall survival were compared for statistical difference using the log-rank test.ResultsCompared to mesenchymal OC3 cells, tumor stroma derived from p-EMT TW2.6 cells was significantly enriched in microvessel density, tumor-excluded macrophages, inflammatory CAFs, and extracellular hyaluronan deposition. By translating these results to clinical transcriptomic datasets of oral cancer specimens, including the Puram single-cell RNA-seq cohort comprising ~6000 cells, we identified the expression of stromal TGFBI and HYAL1 as independent poor and protective biomarkers, respectively, for 40 Taiwanese oral cancer tissues that were all derived from betel quid users. In The Cancer Genome Atlas, TGFBI was a poor marker not only for head and neck cancer but also for additional six cancer types and HYAL1 was a good indicator for four tumor cohorts, suggesting common stromal effects existing in different cancer types.ConclusionsAs the tumor stroma coevolves with cancer progression, the cellular origins of molecular markers identified from conventional whole tissue mRNA-based analyses should be cautiously interpreted. By incorporating disease-matched xenograft tissue and single-cell RNA-seq results, we suggested that TGFBI and HYAL1, primarily expressed by stromal CAFs and endothelial cells, respectively, could serve as robust prognostic biomarkers for oral cancer control. |
| format |
article |
| author |
Yi-Hong Liu Yi-Hong Liu Yu-Lian Chen Ting-Yu Lai Ting-Yu Lai Ying-Chieh Ko Yu-Fu Chou Peir-Rong Chen Jenn-Ren Hsiao Jang-Yang Chang Jang-Yang Chang Shine-Gwo Shiah Jeng-Woei Lee Jia-Ling Yang Su-Fang Lin |
| author_facet |
Yi-Hong Liu Yi-Hong Liu Yu-Lian Chen Ting-Yu Lai Ting-Yu Lai Ying-Chieh Ko Yu-Fu Chou Peir-Rong Chen Jenn-Ren Hsiao Jang-Yang Chang Jang-Yang Chang Shine-Gwo Shiah Jeng-Woei Lee Jia-Ling Yang Su-Fang Lin |
| author_sort |
Yi-Hong Liu |
| title |
Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues |
| title_short |
Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues |
| title_full |
Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues |
| title_fullStr |
Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues |
| title_full_unstemmed |
Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues |
| title_sort |
identification of prognostic biomarkers originating from the tumor stroma of betel quid-associated oral cancer tissues |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/c5c66b95121f48e0859d1730794ad5c4 |
| work_keys_str_mv |
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