Abstract
Simple SummaryTherapy resistance represents one of the major obstacles to curing cancer. Particular populations of tumor cells, known as cancer stem cells, are responsible for this resistance and, therefore, constitute key targets in the disease. In this review, we address the impact of cancer stem cells on therapy resistance in gastric cancer and we highlight the relevance of the different regulators of these cells that have been linked to resistance.Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, with an average 5-year survival rate of 32%, being of 6% for patients presenting distant metastasis. Despite the advances made in the treatment of GC, chemoresistance phenomena arise and promote recurrence, dissemination and dismal prognosis. In this context, gastric cancer stem cells (gCSCs), a small subset of cancer cells that exhibit unique characteristics, are decisive in therapy failure. gCSCs develop different protective mechanisms, such as the maintenance in a quiescent state as well as enhanced detoxification procedures and drug efflux activity, that make them insusceptible to current treatments. This, together with their self-renewal capacity and differentiation ability, represents major obstacles for the eradication of this disease. Different gCSC regulators have been described and used to isolate and characterize these cell populations. However, at the moment, no therapeutic strategy has achieved the effective targeting of gCSCs. This review will focus on the properties of cancer stem cells in the context of therapy resistance and will summarize current knowledge regarding the impact of the gCSC regulators that have been associated with GC chemoradioresistance.
Highlights
5-year survival rate of 32%, being of 6% for patients presenting distant metastasis
A growing body of evidence supports the notion that tumors are organized in a hierarchical fashion that is governed by cancer stem cells (CSCs), which are considered to be responsible for tumor origin, therapy resistance, recurrence and metastasis [18–21]
Regarding H. pylori’s involvement in the appearance of gastric cancer stem cells (gCSCs), it has been proposed that this population could derive from bone marrow-derived gastric stem cells (SCs) (BMDSCs) that have been recruited to the stomach in response to Helicobacter infection [31,32]
Summary
Gastric cancer (GC) is a global health problem that accounts for more than 1 million new cancer cases annually and that constitutes the fourth leading cause of cancer death worldwide (1,089,103 new cases and 768,793 deaths in 2020) [1]. The average 5-year survival rate for GC patients is 32%, being of 6% for patients presenting with cancer spread to distant parts of the body. The prognosis for patients with recurrent disease or metastasis is dismal, with a median survival of only 8 months [2]. The major risk factor for GC development is chronic infection by Helicobacter pylori (H. pylori) [3], a Gram-negative microaerophilic bacterium that colonizes the gastric mucosa and induces a series of sequential alterations that begin with non-atrophic gastritis, which eventually progresses to multifocal atrophic gastritis, intestinal metaplasia and dysplasia [4].
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