Abstract
With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC. In this review, we present the landscape of CTCs from migration, to the presence in circulation, biologic properties, and morphologic heterogeneities. We evaluated clinical implications of CTCs in GC patients, including diagnosis, prognosis, and therapeutic management, as well as their application in immunotherapy. On the one hand, major challenges in using CTCs in GC were analyzed, from the differences of cut-off values of CTC positivity, to techniques used for sampling, storage conditions, and CTC molecular markers, as well as the unavailability of relevant enrichment and detection techniques. On the other hand, we discussed future perspectives of using CTCs in GC management and research, including the use of circulating tumor microembolies; of CTC checkpoint blockade in immunotherapy; and of organoid models. Despite the fact that there are remaining challenges in techniques, CTCs have potential as novel biomarkers and/or a non-invasive method for diagnostics, prognostics, and treatment monitoring of GC, particularly in the era of precision medicine.
Highlights
According to data from the International Agency for Research on Cancer, over 1 million new cases of gastric cancer (GC) were found in the past year, and GC was determined to be the third highest cause of cancer-related mortalities worldwide [1,2]
Other studies have demonstrated this correlation between elevated production of cytokines and Circulating tumor cells (CTCs) [43,44,45]. These findings suggest that CTCs exhibit a cytokine-mediated interaction which aids in CTC survival, transendothelial migration and metastatic development
Several oncogenic proliferation-triggering miRNA such as miR-543 [76] targeting Sirtuin 1 (SIRT1), miR-106a targeting tissue inhibitor of metalloproteinases 2 (TIMP2) [77], or miR-17 which targets a number of genes involving in tumorigenesis, disease progression, invasion, and metastasis of GC [78,79] have been suggested as candidate markers for GC diagnosis
Summary
According to data from the International Agency for Research on Cancer, over 1 million new cases of gastric cancer (GC) were found in the past year, and GC was determined to be the third highest cause of cancer-related mortalities worldwide [1,2]. In areas where endoscopic screenings are regularly conducted, such as Japan, a significantly high five-year survival rate is achieved due to the increased possibility for early tumor resection [4]. This survival rate can drop to less than 5% if the patient is diagnosed at later stages (IIIB to IV) (https://www.cancer.net/). Several biomarkers have been successfully identified and widely used for GC diagnosis and prognosis, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4) [5] Those biomarkers display less than 40% positivity rates, and their sensitivities and specificities are modest [5,6]. We discussed the challenges and future perspectives of CTC use in the diagnosis, prognosis, and treatment of GC
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