ABC Transporters and Their Role in the Neoadjuvant Treatment of Esophageal Cancer

Abstract

The prognosis of esophageal cancer (EC) is poor, despite considerable effort of both experimental scientists and clinicians. The tri-modality treatment consisting of neoadjuvant chemoradiation followed by surgery has remained the gold standard over decades, unfortunately, without significant progress in recent years. Suitable prognostic factors indicating which patients will benefit from this tri-modality treatment are missing. Some patients rapidly progress on the neoadjuvant chemoradiotherapy, which is thus useless and sometimes even harmful. At the same time, other patients achieve complete remission on neoadjuvant chemoradiotherapy and subsequent surgery may increase their risk of morbidity and mortality. The prognosis of patients ranges from excellent to extremely poor. Considering these differences, the role of drug metabolizing enzymes and transporters, among other factors, in the EC response to chemotherapy may be more important compared, for example, with pancreatic cancer where all patients progress on chemotherapy regardless of the treatment or disease stage. This review surveys published literature describing the potential role of ATP-binding cassette transporters, the genetic polymorphisms, epigenetic regulations, and phenotypic changes in the prognosis and therapy of EC. The review provides knowledge base for further research of potential predictive biomarkers that will allow the stratification of patients into defined groups for optimal therapeutic outcome.

Keywords: ABC transporters; biomarker; cancer; chemotherapy; esophagus; prognosis; radiotherapy.

Figure 1

Schematic depiction of localization of ABC transporters within the cell and their major functions, with phospholipid, sterol and bile salts transporting ABCs in red; heme transporters in cyan; fatty acid transporters in violet; and ABCs with specific functions in black. Anticancer drugs transporters are underlined.

Figure 2

Schematic diagram of pathways and mechanisms of resistance. EMT, epithelial-to-mesenchymal transition.

Figure 3

Schematic overview of associations between ABC transporters and risk or progression of EC. Associations are symbolized by arrows (blue for protein, green for transcript, red for gene, and violet for miRNA). ABC transporters are shown in rectangles together with their major substrates (bile salts in yellow and anticancer drugs in red). EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma.

Figure 4

Survey of connections between ABC transporters and signaling pathways in EC and their major roles. Available inhibitors are in red. ↑ = upregulation; ↓ = downregulation; → = stimulation; Ⱶ = inhibition.