Esophageal adenocarcinoma microenvironment: Peritumoral adipose tissue effects associated with chemoresistance

Carraro, Amedeo; Trevellin, Elisabetta; Fassan, Matteo; Kotsafti, Andromachi; Lunardi, Francesca; Porzionato, Andrea; Dall’Olmo, Luigi; Cagol, Matteo; Alfieri, Rita; Macchi, Veronica; Tedeschi, Umberto; Calabrese, Fiorella; Castoro, Carlo; Vettor, Roberto; Scarpa, Marco

doi:10.1111/cas.13415

Cited by 13 publications

(22 citation statements)

References 35 publications

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“…6 Carraro et al also demonstrated that the peritumoral microenvironment played an important role in tumor resistance to neoadjuvant therapy. 7 To further improve therapeutic strategy precision, however, a range of peritumoral regions impacting on different tasks is required.…”

Section: Introductionmentioning

confidence: 99%

“…For example, Evans et al reported that the peritumoral microenvironment was significantly associated with progression and metastasis in head and neck squamous cell carcinoma 6 . Carraro et al also demonstrated that the peritumoral microenvironment played an important role in tumor resistance to neoadjuvant therapy 7 . To further improve therapeutic strategy precision, however, a range of peritumoral regions impacting on different tasks is required.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the predictive value of additional peritumoral regions based on deep learning and radiomics: A multicenter study

Dong

Zhang

et al. 2021

Medical Physics

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The present study assessed the predictive value of peritumoral regions on three tumor tasks, and further explored the influence of peritumors with different sizes. Methods: We retrospectively collected 333 samples of gastrointestinal stromal tumors from the Second Affiliated Hospital of Zhejiang University School of Medicine, and 183 samples of gastrointestinal stromal tumors from Tianjin Medical University Cancer Hospital. We also collected 211 samples of laryngeal carcinoma and 233 samples of nasopharyngeal carcinoma from the First Affiliated Hospital of Jinan University. The tasks of three tumor datasets were risk assessment (gastrointestinal stromal tumor), T3/T4 staging prediction (laryngeal carcinoma), and distant metastasis prediction (nasopharyngeal carcinoma), respectively. First, deep learning and radiomics were respectively used to construct peritumoral models, to study whether the peritumor had predictive value on three tumor datasets. Furthermore, we defined different sizes peritumors including fixed size (not considering tumor size) and adaptive size (according to average tumor radius) to explore the influence of peritumor of different sizes and types of tumors. Finally, we visualized the deep learning and radiomic models to observe the influence of the peritumor in three datasets. Results: The performance of intra-peritumors are better than intratumors alone in three datasets. Specifically, the comparisons of area under receiver operating characteristic curve in the testing set between intra-peritumoral and intratumoral models are: 0.908 vs 0.873 (P value: 0.037) in gastrointestinal stromal tumor datasets, 0.796 vs 0.756 (P value: 0.188) in laryngeal carcinoma datasets and 0.660 vs 0.579 (P value: 0.431) in nasopharyngeal carcinoma datasets. Furthermore, for gastrointestinal stromal tumor datasets, deep learning is more stable to learn peritumors with both fixed and adaptive size than radiomics. For laryngeal carcinoma datasets, the intraperitumoral radiomic model could make model performance more balanced. For nasopharyngeal carcinoma datasets, radiomics is also more suitable for modeling peritumors than deep learning. The size of the peritumor is critical in this task, and only the performance of 1.5 mm-4.5 mm peritumors is stable. Conclusions: Our results indicate that peritumors have additional predictive value in three tumor datasets through deep learning or radiomics. The definitions of the peritumoral region and artificial intelligence method also have great influence on the performance of the peritumor.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the predictive value of additional peritumoral regions based on deep learning and radiomics: A multicenter study

Dong

Zhang

et al. 2021

Medical Physics

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“…Finally, to investigate the association between SCCA1 and the peritumoral microenvironment, we evaluated SCCA1 expression, stem cell markers, and paracrine adipose tissue mediators in peritumoral adipose tissue that had been proven to play a significant role in the nodal metastatic process and in chemoresistance . In our series, SCCA1 expression within the tumor was inversely correlated with CD34 levels, both within the tumor and in the peritumoral adipose tissue.…”

Section: Discussionmentioning

confidence: 98%

“…In addition, these results agree with the recent report of a direct association between SCCA1 and the expression of immune checkpoint regulators PD‐L1/PD‐L2 in head and neck squamous cell carcinoma . Interestingly, in a very recent multicohort, phase IB study, pembrolizumab, an anti‐PD‐L1 Ab, showed manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD‐L1‐positive advanced esophageal carcinoma . The increased levels of PD‐L1 expression in EAC, induced by SCCA1, might contribute to the observed intratumoral immune impairment.…”

Section: Discussionmentioning

confidence: 99%

“…35 Interestingly, in a very recent multicohort, phase IB study, pembrolizumab, an anti-PD-L1 Ab, showed manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1-positive advanced esophageal carcinoma. 36 The increased levels of PD-L1 expression in EAC, induced by SCCA1, might contribute to the observed F I G U R E 6 Squamous cell carcinoma antigen-1 (SCCA1) and peritumoral microenvironment parameters in patients with esophageal adenocarcinoma. A, Spearman rank correlation analysis of tumor SCCA1 mRNA and peritumoral Leptin mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

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Squamous cell carcinoma antigen 1 is associated to poor prognosis in esophageal cancer through immune surveillance impairment and reduced chemosensitivity

et al. 2019

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Squamous cell carcinoma antigen‐1 ( SCCA 1) overexpression is associated with poor prognosis and chemoresistance in several tumor types, however, the underlying mechanisms remain elusive. Here, we report SCCA 1 in relation to the immune and peritumoral adipose tissue microenvironment in early and advanced esophageal adenocarcinoma ( EAC ). In our series of patients with EAC, free SCCA 1 serum levels were associated with significantly worse overall survival, and SCCA 1‐IgM serum levels showed a trend to a worse overall survival. Serum SCCA 1 and intratumoral SCCA 1 were inversely correlated with immune activation markers. In agreement with these findings, SCCA 1 induced the expression of the immune checkpoint molecule programmed death ligand‐1 on monocytes and a direct correlation of these 2 molecules was observed in sequential tumor sections. Furthermore, SCCA 1 mRNA expression within the tumor was inversely correlated with stem cell marker expression both within the tumor and in the peritumoral adipose tissue. In vitro, in EAC cell lines treated with different chemotherapeutic drugs, cell viability was significantly modified by SCCA 1 presence, as cells overexpressing SCCA 1 were significantly more resistant to cell death. In conclusion, poor prognosis in EAC overexpressing SCCA 1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule .

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Globular adiponectin induces esophageal adenocarcinoma cell pyroptosis via the miR‐378a‐3p/UHRF1 axis

Wang,

Cheng,

Xiaoran

et al. 2024

Environmental Toxicology

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BackgroundAntiapoptosis is a major factor in the resistance of tumor cells to chemotherapy and radiotherapy. Thus, activation of cell pyroptosis may be an effective option to deal with antiapoptotic cancers such as esophageal adenocarcinoma (EAC).MethodsDifferential expression of ubiquitin‐like versus PHD and ring finger structural domain 1 (UHRF1) in EAC and near normal tissues was analyzed, as well as the prognostic impact on survival in EAC. Also, the same study was done for globular adiponectin (gAD). Simultaneously, the mRNA expression of UHRF1 was observed in different EAC cell lines. Real time cellular analysis (RTCA) was used to detect cell proliferation, and flow cytometry and inverted fluorescence microscopy were used to detect pyroptosis. Biocredit analysis was conducted to observe the correlation between UHRF1 and key pyroptosis proteins. OD values and CCK8 assay were used to determine the effect of miR‐378a‐3p on EAC cells. Quantitative real‐time polymerase chain reaction and Western blot were used to detect the correlation between UHRF1, gAD, and miR‐378a‐3p in EAC cells. Moreover, in vivo and in vitro experiments were performed to detect the relevant effects on tumor migration and invasion after inhibiting UHRF1 expression.ResultsUHRF1 was negatively correlated with the survival of patients with EAC, while miR‐378a‐3p showed the opposite effect. Additionally, gAD promoted EAC cell pyroptosis, upregulated miR‐378a‐3p, and significantly inhibited the proliferation of EAC cells. gAD directly reduced UHRF1 expression in EAC cells by upregulating miR‐378a‐3p. In cell migration and invasion assays, inhibition of UHRF1 expression significantly suppressed EAC cell metastasis. In animal experiments, we again demonstrated that gAD induced pyroptosis in EAC cells by inhibiting the expression of UHRF1.ConclusiongAD‐induced upregulation of miR‐378a‐3p significantly inhibited the proliferation of EAC by targeting UHRF1. Therefore, gAD may serve as an alternative therapy for chemotherapy‐ and radiation‐refractory EAC or other cancers with the same mechanism of pyroptosis action.

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Esophageal adenocarcinoma microenvironment: Peritumoral adipose tissue effects associated with chemoresistance

Cited by 13 publications

References 35 publications

Exploring the predictive value of additional peritumoral regions based on deep learning and radiomics: A multicenter study

Exploring the predictive value of additional peritumoral regions based on deep learning and radiomics: A multicenter study

Squamous cell carcinoma antigen 1 is associated to poor prognosis in esophageal cancer through immune surveillance impairment and reduced chemosensitivity

Globular adiponectin induces esophageal adenocarcinoma cell pyroptosis via the miR‐378a‐3p/UHRF1 axis

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