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Review
. 2021 Feb 8:8:600373.
doi: 10.3389/fmolb.2021.600373. eCollection 2021.

The Role of Cancer Stem Cells in Drug Resistance in Gastroesophageal Junction Adenocarcinoma

Kate Dinneen  1   2 , Anne-Marie Baird  1 , Ciara Ryan  2 , Orla Sheils  1
Affiliations
Review

The Role of Cancer Stem Cells in Drug Resistance in Gastroesophageal Junction Adenocarcinoma

Kate Dinneen et al. Front Mol Biosci. .

Abstract

Gastroesophageal junction adenocarcinomas (GEJA) have dramatically increased in incidence in the western world since the mid-20th century. Their prognosis is poor, and conventional anti-cancer therapies do not significantly improve survival outcomes. These tumours are comprised of a heterogenous population of both cancer stem cells (CSC) and non-CSCs, with the former playing a crucial role in tumorigenesis, metastasis and importantly drug resistance. Due to the ability of CSCs to self-replicate indefinitely, their resistance to anti-cancer therapies poses a significant barrier to effective treatment of GEJA. Ongoing drug development programmes aim to target and eradicate CSCs, however their characterisation and thus identification is difficult. CSC regulation is complex, involving an array of signalling pathways, which are in turn influenced by a number of entities including epithelial mesenchymal transition (EMT), microRNAs (miRNAs), the tumour microenvironment and epigenetic modifications. Identification of CSCs commonly relies on the expression of specific cell surface markers, yet these markers vary between different malignancies and indeed are often co-expressed in non-neoplastic tissues. Development of targeted drug therapies against CSCs thus requires an understanding of disease-specific CSC markers and regulatory mechanisms. This review details the current knowledge regarding CSCs in GEJA, with particular emphasis on their role in drug resistance.

Keywords: cancer stem cells; drug resistance; epithelial mesenchymal transition; gastroesophageal junction adenocarcinoma; microRNA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Mechanisms of drug resistance. Multiple different mechanisms contribute to the development of drug resistance in cancer. These include the interaction between the tumour and its microenvironment; secretion of paracrine growth factors which promote tumour growth; tumour heterogeneity; physical barriers and the ‘undruggable genome’, which refers to mutations which have not yet been targeted by anti-cancer therapies. The blue cells in the background are B lymphocytes. The green cells in the background are T lymphocytes. The bright green cells in the tumour mass are cancer stem cells.
FIGURE 2
FIGURE 2
Response of tumours to conventional and targeted drug therapies. Tumours are comprised of a heterogenous mix of cancer cells, including both cancer stem cells (CSC) and non-CSC. Conventional anti-cancer therapies primarily target non-CSCs, allowing CSCs to selectively survive and propagate, producing a tumour mass comprised of both CSC and non-CSC subclones. By comparison, some novel precision medicine therapies target CSCs, eradicating the CSC population. The residual non-CSC population have no capacity for self-renewal and thus the tumour regresses or is eradicated, leading to clinical remission. Bright green cells indicate CSCs.
FIGURE 3
FIGURE 3
Relationship between epithelial mesenchymal transition and stemness properties. The process of epithelial mesenchymal transition involves a loss of epithelial phenotypic traits and a concurrent acquisition of a mesenchymal phenotype. EMT is associated with the development of stemness traits, including invasiveness, metastasis and drug resistance. These processes are tightly regulated by overlapping signalling pathways.
FIGURE 4
FIGURE 4
Summary of factors which contribute to tumorigenesis, drug resistance and metastasis. Cancer stem cells (CSC), microRNAs (miRNA) and the epithelial/mesenchymal (E/M) phenotype each contribute to the development of tumorigenesis, drug resistance and metastasis across a range of malignancies, including gastroesophageal junction adenocarcinoma (GEJA). E/M and certain miRNAs have been shown to regulate the acquisition of stemness properties in cancer cells. A selection of regulatory pathways which govern CSC regulation are listed, in addition to a selection of miRNAs shown to play a role in regulation of CSCs in gastric and oesophageal adenocarcinomas. A selection of phenotypic stability factors which regulate the E/M hybrid state are also listed.
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References

    1. Abdi E., Latifi-Navid S., Zahri S., Yazdanbod A., Pourfarzi F. (2019). Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives. Cancer Med. 8, 6114–6126. 10.1002/cam4.2497 - DOI - PMC - PubMed
    1. Aires A., Ocampo S. M., Simões B. M., Josefa Rodríguez M., Cadenas J. F., Couleaud P., et al. (2016). Multifunctionalized iron oxide nanoparticles for selective drug delivery to CD44-positive cancer cells. Nanotechnology 27, 065103 10.1088/0957-4484/27/6/065103 - DOI - PubMed
    1. Ajani J. A., Wang X., Song S., Suzuki A., Taketa T., Sudo K., et al. (2014). ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients. Mol. Oncol. 8, 142–9. 10.1016/j.molonc.2013.10.007 - DOI - PMC - PubMed
    1. Al-Batran S. E., Hofheinz R. D., Pauligk C., Kopp H. G., Haag G. M., Luley K. B., et al. (2016). Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 17, 1697–1708. 10.1016/S1470-2045(16)30531-9 - DOI - PubMed
    1. Al-Batran S. E., Homann N., Pauligk C., Goetze T. O., Meiler J., Kasper S., et al. (2019). Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393, 1948–1957. 10.1016/S0140-6736(18)32557-1 - DOI - PubMed