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Current and Future Treatment Strategies for Esophageal Adenocarcinoma

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 33527

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Prof. Dr. Alexander Quaas

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Guest Editor

Faculty of Medicine, Institute of Pathology, University of Cologne, Germany
Interests: esophageal adenocarcinoma; gastric carcinoma; biomarkers; personalized oncology; tumor cell–stroma interaction; gender aspects in oncology.

Special Issue Information

Dear Colleagues,

In the vast majority of cases, adenocarcinoma of the esophagus (EAC) has a lethal clinical course within the first five years after diagnosis. The overall prognosis could be slightly improved by the introduction of a neoadjuvant therapy; however, in contrast to squamous cell carcinomas, adenocarcinomas often show a lower response to this therapy. The main risk factor is the Barrett’s mucosa, which, depending on the study, is largely gender-neutral. However, the risk of developing EAC is higher in males (7–9:1). Our understanding of the molecular basis of the disease has increased significantly over the past six years. Studies have shown relevant differences (and few similarities) to gastric adenocarcinomas, so that it is justified and reasonable to consider EAC separately. Potential personalized therapy options can be derived on this basis, but have not yet arrived in clinical practice. The proportion of patients benefiting from immunocheckpoint inhibition against PD-1/PD-L1 is significantly lower compared with non-small cell lung cancer. Hence, a profound understanding of the specific immunomodulatory factors involved in EAC is necessary. Due to the pronounced genetic heterogeneity, knowledge of tumor cell–environment interactions (matrix, carcinoma-associated fibroblasts, vascular modulation) will be crucial to the selection of suitable (combinations of) therapeutics in the future. In 15 contributions from different disciplines, this Special Issue will present the current state of treatment of EAC (with a curative or a palliative intention), emphasize that a multidisciplinary approach is necessary for successful treatment, and venture to look into successful treatments of the future and the analyses and resources required for them.

Prof. Dr. Alexander Quaas
Guest Editor

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Keywords

esophageal adenocarcinoma
multidisciplinary treatment approach
molecular analyses
tumor cell–microenvironment interaction
immune oncology

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

2 pages, 141 KiB

Open AccessEditorial

Current and Future Treatment Strategies for Esophageal Adenocarcinoma

by Alexander Quaas

Cancers 2020, 12(10), 2930; https://doi.org/10.3390/cancers12102930 - 12 Oct 2020

Cited by 1 | Viewed by 1480

Abstract

The incidence of adenocarcinoma of the esophagus (EAC) is increasing worldwide [...] Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

Research

Jump to: Editorial, Review

18 pages, 3283 KiB

Open AccessArticle

Gene Expression in Barrett’s Esophagus Cell Lines Resemble Esophageal Squamous Cell Carcinoma Instead of Esophageal Adenocarcinoma

by Anshuman Panda, Gyan Bhanot, Shridar Ganesan and Manisha Bajpai

Cancers 2021, 13(23), 5971; https://doi.org/10.3390/cancers13235971 - 27 Nov 2021

Cited by 3 | Viewed by 2282

Abstract

Esophageal adenocarcinoma (EAC) is strongly associated with Barrett’s esophagus (BE), a pre-malignant condition resulting from gastric reflux. Esophageal squamous cell carcinoma (ESCC), the other major subtype of esophageal cancer, shows strong association with smoking and alcohol intake and no association with gastric reflux. In this study, we constructed and validated gene expression signatures of EAC vs. ESCC tumors using publicly available datasets, and subsequently assessed the enrichment levels of these signatures in commonly used EAC and ESCC cell lines, normal esophageal tissues and normal esophageal cell lines, and primary BE tissues and BE cell lines. We found that unlike ESCC cell lines which were quite similar to primary ESCC tumors, EAC cell lines were considerably different from primary EAC tumors but still more similar to EAC tumors than ESCC tumors, as the genes up in EAC vs. ESCC (EAC^hi) had considerably lower expression in EAC cell lines than EAC tumors. However, more surprisingly, unlike various normal cell lines (EPC2, Het-1A) which were very similar to various tissues from normal esophagus, BE cell lines (BAR-T, CP-A) were extremely different from primary BE tissues, as BE cell lines had substantially lower levels of EAC^hi and substantially higher levels of ESCC^hi gene expression. This ESCC-like profile of the BAR-T remained unaltered even after prolonged exposure to an acidic bile mixture in vitro resulting in malignant transformation of this cell line. However, primary BE tissues had EAC-like gene expression profiles as expected. Only one EAC case from the Cancer Genome Atlas resembled BE cell lines, and while it had the clinical profile and some mutational features of EAC, it had some mutational features, the copy number alteration profile, and the gene expression profile of ESCC instead. These incomprehensible changes in gene expression patterns may result in ambiguous changes in the phenotype and warrants careful evaluation to inform selection of appropriate in vitro tools for future studies on esophageal adenocarcinoma. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

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23 pages, 6784 KiB

Open AccessArticle

Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures

by Hardika Dhir, Monica Choudhury, Ketki Patil, Candice Cheung, Adriana Bodlak, Danny Pardo, Asana Adams, Stefano Travaglino, Jose Araque Rojas and S. Balakrishna Pai

Cancers 2021, 13(22), 5811; https://doi.org/10.3390/cancers13225811 - 19 Nov 2021

Cited by 9 | Viewed by 2447

Abstract

Deregulation of signaling pathways due to mutations sets the cell on a path to neoplasia. Therefore, recent reports of increased mutations observed in esophageal tissue reflects the enhanced risk of tumor formation. In fact, adenocarcinoma of the esophagus has been on the rise lately. Increase in mortality due to a paucity of efficacious drugs for this cancer prompted us to discover molecular signatures to combat this malady. To this end, we chose resveratrol—a polyphenol with anticancer property—and studied its impact on three esophageal adenocarcinoma cell lines (OE33, OE19 and FLO-1) by multilevel profiling. Here, we show the impact of resveratrol on the viability of the three adenocarcinoma esophageal cell systems studied, at the cellular level. Furthermore, an analysis at the molecular level revealed that the action was through the programmed cell death pathway, resulting in an increase in apoptotic and caspase-positive cells. The impact on reactive oxygen species (ROS) and a decrease in Bcl2 levels were also observed. Moreover, proteomic profiling highlighted pivotal differentially regulated signaling molecules. The phenotypic effect observed in resveratrol-treated esophageal cells could be due to the stoichiometry per se of the fold changes observed in entities of key signaling pathways. Notably, the downregulation of Ku80 and other pivotal entities by resveratrol could be harnessed for chemo-radiation therapy to prevent DNA break repair after radiation therapy. Additionally, multilevel profiling has shed light on molecular and immune-modulatory signatures with implications for discovering novel treatments, including chemo-immunotherapy, for esophageal adenocarcinomas which are known to be aggressive cancers. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

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18 pages, 23701 KiB

Open AccessArticle

Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification

by Chenghui Zhou, Zhefang Wang, Jiahui Li, Xiaolin Wu, Ningbo Fan, Dai Li, Fanyu Liu, Patrick S. Plum, Sascha Hoppe, Axel M. Hillmer, Alexandar Quaas, Florian Gebauer, Seung-Hun Chon, Christiane J. Bruns and Yue Zhao

Cancers 2021, 13(10), 2403; https://doi.org/10.3390/cancers13102403 - 16 May 2021

Cited by 19 | Viewed by 3299

Abstract

Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

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16 pages, 3256 KiB

Open AccessArticle

Identification of TLR2 Signalling Mechanisms Which Contribute to Barrett’s and Oesophageal Adenocarcinoma Disease Progression

by Ewelina Flis, Gillian Barber, Ciara Nulty, Brian Keogh, Peter McGuirk, Akanksha Anand, Jacintha O’Sullivan, Michael Quante and Emma M. Creagh

Cancers 2021, 13(9), 2065; https://doi.org/10.3390/cancers13092065 - 25 Apr 2021

Cited by 6 | Viewed by 2432

Abstract

Chronic inflammation plays an important role in the pathogenesis of oesophageal adenocarcinoma (EAC) and its only known precursor, Barrett’s oesophagus (BE). Recent studies have shown that oesophageal TLR2 levels increase from normal epithelium towards EAC. TLR2 signalling is therefore likely to be important during EAC development and progression, which requires an inflammatory microenvironment. Here, we show that, in response to TLR2 stimulation, BE organoids and early-stage EAC cells secrete pro-inflammatory cytokines and chemokines which recruit macrophages to the tumour site. Factors secreted from TLR2-stimulated EAC cells are shown to subsequently activate TLR2 on naïve macrophages, priming them for inflammasome activation and inducing their differentiation to an M2/TAM-like phenotype. We identify the endogenous TLR2 ligand, HMGB1, as the factor secreted from EAC cells responsible for the observed TLR2-mediated effects on macrophages. Our results indicate that HMGB1 signalling between EAC cells and macrophages creates an inflammatory tumour microenvironment to facilitate EAC progression. In addition to identifying HMGB1 as a potential target for early-stage EAC treatment, our data suggest that blocking TLR2 signalling represents a mechanism to limit HMGB1 release, inflammatory cell infiltration and inflammation during EAC progression. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

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Review

Jump to: Editorial, Research

9 pages, 255 KiB

Open AccessReview

(Neo)Adjuvant Treatment of Locally Advanced Esophageal and Gastroesophageal Adenocarcinoma: Special Focus on Sex Differences

by Thomas Zander and Anna Dorothea Wagner

Cancers 2022, 14(4), 1088; https://doi.org/10.3390/cancers14041088 - 21 Feb 2022

Cited by 3 | Viewed by 1789

Abstract

Adenocarcinoma of the esophagus and gastroesophageal junction is a common disease. This disease is significantly more prevalent in men, although the main underlying risk factor has an equal sex distribution. In locally advanced disease, multimodal therapy has been developed as the standard in the western world. Neoadjuvant chemoradiotherapy or perioperative chemotherapy using the FLOT regimen was established as the standard. Most recently, adjuvant immunotherapy after neoadjuvant chemoradiotherapy and surgery has been introduced into the multimodal therapy. Substantial sex-specific differences in outcome in multimodal therapy have been described in retrospective subgroup analysis. Further studies are warranted to dissect the sex-specific differences in these treatment regimens. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

23 pages, 399 KiB

Open AccessReview

Modern Management of Esophageal Cancer: Radio-Oncology in Neoadjuvancy, Adjuvancy and Palliation

by Francesco Cellini, Stefania Manfrida, Calogero Casà, Angela Romano, Alessandra Arcelli, Alice Zamagni, Viola De Luca, Giuseppe Ferdinando Colloca, Andrea D’Aviero, Lorenzo Fuccio, Valentina Lancellotta, Luca Tagliaferri, Luca Boldrini, Gian Carlo Mattiucci, Maria Antonietta Gambacorta, Alessio Giuseppe Morganti and Vincenzo Valentini

Cancers 2022, 14(2), 431; https://doi.org/10.3390/cancers14020431 - 15 Jan 2022

Cited by 11 | Viewed by 4081

Abstract

The modern management of esophageal cancer is crucially based on a multidisciplinary and multimodal approach. Radiotherapy is involved in neoadjuvant and adjuvant settings; moreover, it includes radical and palliative treatment intention (with a focus on the use of a stent and its potential integration with radiotherapy). In this review, the above-mentioned settings and approaches will be described. Referring to available international guidelines, the background evidence bases will be reviewed, and the ongoing, more relevant trials will be outlined. Target definitions and radiotherapy doses to administer will be mentioned. Peculiar applications such as brachytherapy (interventional radiation oncology), and data regarding innovative approaches including MRI-guided-RT and radiomic analysis will be reported. A focus on the avoidance of surgery for major clinical responses (particularly for SCC) is detailed. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

18 pages, 344 KiB

Open AccessReview

Surgical Therapy of Esophageal Adenocarcinoma—Current Standards and Future Perspectives

by Wolfgang Schröder, Suzanne S. Gisbertz, Daan M. Voeten, Christian A. Gutschow, Hans F. Fuchs and Mark I. van Berge Henegouwen

Cancers 2021, 13(22), 5834; https://doi.org/10.3390/cancers13225834 - 21 Nov 2021

Cited by 9 | Viewed by 2843

Abstract

Transthoracic esophagectomy is currently the predominant curative treatment option for resectable esophageal adenocarcinoma. The majority of carcinomas present as locally advanced tumors requiring multimodal strategies with either neoadjuvant chemoradiotherapy or perioperative chemotherapy alone. Minimally invasive, including robotic, techniques are increasingly applied with a broad spectrum of technical variations existing for the oncological resection as well as gastric reconstruction. At the present, intrathoracic esophagogastrostomy is the preferred technique of reconstruction (Ivor Lewis esophagectomy). With standardized surgical procedures, a complete resection of the primary tumor can be achieved in almost 95% of patients. Even in expert centers, postoperative morbidity remains high, with an overall complication rate of 50–60%, whereas 30- and 90-day mortality are reported to be <2% and <6%, respectively. Due to the complexity of transthoracic esophagetomy and its associated morbidity, esophageal surgery is recommended to be performed in specialized centers with an appropriate caseload yet to be defined. In order to reduce postoperative morbidity, the selection of patients, preoperative rehabilitation and postoperative fast-track concepts are feasible strategies of perioperative management. Future directives aim to further centralize esophageal services, to individualize surgical treatment for high-risk patients and to implement intraoperative imaging modalities modifying the oncological extent of resection and facilitating surgical reconstruction. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

18 pages, 2053 KiB

Open AccessReview

Machine Learning for Future Subtyping of the Tumor Microenvironment of Gastro-Esophageal Adenocarcinomas

by Sebastian Klein and Dan G. Duda

Cancers 2021, 13(19), 4919; https://doi.org/10.3390/cancers13194919 - 30 Sep 2021

Cited by 5 | Viewed by 3157

Abstract

Tumor progression involves an intricate interplay between malignant cells and their surrounding tumor microenvironment (TME) at specific sites. The TME is dynamic and is composed of stromal, parenchymal, and immune cells, which mediate cancer progression and therapy resistance. Evidence from preclinical and clinical studies revealed that TME targeting and reprogramming can be a promising approach to achieve anti-tumor effects in several cancers, including in GEA. Thus, it is of great interest to use modern technology to understand the relevant components of programming the TME. Here, we discuss the approach of machine learning, which recently gained increasing interest recently because of its ability to measure tumor parameters at the cellular level, reveal global features of relevance, and generate prognostic models. In this review, we discuss the relevant stromal composition of the TME in GEAs and discuss how they could be integrated. We also review the current progress in the application of machine learning in different medical disciplines that are relevant for the management and study of GEA. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

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16 pages, 291 KiB

Open AccessReview

Towards Personalized Treatment Strategies for Esophageal Adenocarcinoma; A Review on the Molecular Characterization of Esophageal Adenocarcinoma and Current Research Efforts on Individualized Curative Treatment Regimens

by Sanne J. M. Hoefnagel, Jurjen J. Boonstra, Marjolein J. A. M. Russchen and Kausilia K. Krishnadath

Cancers 2021, 13(19), 4881; https://doi.org/10.3390/cancers13194881 - 29 Sep 2021

Cited by 6 | Viewed by 2210

Abstract

Esophageal cancers confer a major health challenge and are highly aggressive malignancies with poor prognosis. Esophageal adenocarcinoma (EAC) is one of the two major histopathological subtypes of esophageal cancer. Despite advances in treatment modalities, the prognosis of patients with EAC remains poor, with a 5-year survival rate that rarely exceeds 30% in patients treated with curative intent. Chemoradiotherapy followed by resection is the treatment of choice for EAC patients, which are deemed to be curable. Current patient stratification and treatments are based on outcomes from clinical trials. Unfortunately, the molecular heterogeneity of EAC which determines the chemo- and radiosensitivity of these cancers are not taken into account. A more personalized approach in the treatment of EAC could improve patient outcomes. This review aims at summarizing literature on translational and clinical research in the field of EAC which could be of importance to develop personalized approaches. As suggested by the TCGA, expression data features molecular classifications by different platforms, including miRNA, genomic mutations and reverse-phase protein arrays. Here, we summarize literature on transcriptomic, data-driven approaches to identify distinct subtypes of EAC associated with molecular features. These novel classifications may determine the responsiveness to chemo(radio)therapy and help to identify novel molecular targets within cell signaling pathways. Moreover, we discuss the current clinical research efforts on tailored treatment regimens for patients with EAC taking into account the heterogeneous response to chemoradiotherapy. We summarize the evidence regarding active surveillance instead of immediate surgical resection after application of neoadjuvant chemo(radio)therapy in EAC. We consider that in future patients with complete response to chemo(radio)therapy, predicted by (transcriptomic) biomarkers, might benefit most from this approach. Finally, challenges to overcome for current findings to be implemented in clinical practice and move the field forward are being discussed. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

11 pages, 656 KiB

Open AccessReview

Oligometastatic Adenocarcinoma of the Esophagus: Current Understanding, Diagnosis, and Therapeutic Strategies

by Michael P. Rogers, Anthony J. DeSantis and Christopher G. DuCoin

Cancers 2021, 13(17), 4352; https://doi.org/10.3390/cancers13174352 - 28 Aug 2021

Cited by 3 | Viewed by 2682

Abstract

Esophageal adenocarcinoma is an aggressive cancer of increasing incidence and is associated with poor prognosis. The early recognition of synchronous and metachronous oligometastasis in esophageal adenocarcinoma may allow for prompt intervention and potentially improved survival. However, curative approaches to oligometastatic esophageal disease remain unproven and may represent an area of emerging divergence of opinion for surgical and medical oncologists. We sought to identify the current understanding and evidence for management of oligometastatic esophageal adenocarcinoma by performing a thorough review of the available literature. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

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21 pages, 773 KiB

Open AccessReview

Genomic and Transcriptomic Characteristics of Esophageal Adenocarcinoma

by Sascha Hoppe, Christoph Jonas, Marten Christian Wenzel, Oscar Velazquez Camacho, Christoph Arolt, Yue Zhao, Reinhard Büttner, Alexander Quaas, Patrick Sven Plum and Axel Maximilian Hillmer

Cancers 2021, 13(17), 4300; https://doi.org/10.3390/cancers13174300 - 26 Aug 2021

Cited by 4 | Viewed by 3497

Abstract

Esophageal adenocarcinoma (EAC) is a deadly disease with limited options for targeted therapy. With the help of next-generation sequencing studies over the last decade, we gained an understanding of the genomic architecture of EAC. The tumor suppressor gene TP53 is mutated in 70 to 80% of tumors followed by genomic alterations in CDKN2A, KRAS, ERBB2, ARID1A, SMAD4 and a long tail of less frequently mutated genes. EAC is characterized by a high burden of point mutations and genomic rearrangements, resulting in amplifications and deletions of genomic regions. The genomic complexity is likely hampering the efficacy of targeted therapies. Barrett’s esophagus (BE), a metaplastic response of the esophagus to gastro-esophageal reflux disease, is the main risk factor for the development of EAC. Almost all EACs are derived from BE. The sequence from BE to EAC provides an opportunity to study the genomic evolution towards EAC. While the overlap of point mutations between BE and EAC within the same patient is, at times, surprisingly low, there is a correlation between the complexity of the genomic copy number profile and the development of EAC. Transcriptomic analyses separated EAC into a basal and a classical subtype, with the basal subtype showing a higher level of resistance to chemotherapy. In this review, we provide an overview of the current knowledge of the genomic and transcriptomic characteristics of EAC and their relevance for the development of the disease and patient care. Full article

(This article belongs to the Special Issue Current and Future Treatment Strategies for Esophageal Adenocarcinoma)

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