Abstract
Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.
Highlights
In the last decade, remarkable progress has been made in understanding the complex molecular mechanisms responsible for the onset and progression of human gastric cancer (GC)
There is emerging evidence suggesting that the accumulation of various stromal cells (SC) such as fibroblasts, endothelial cells, adipose tissue-derived stromal cells (ATDSC), several immune cells or inflammatory cells and bone marrow-derived stem cells (BMDSC) could be involved in drug resistance through cell-to-cell communication, tumor-to-stromal cell communication [38], and tumor-to-extracellular matrix (ECM) interaction [39]
One of the most recent pieces of evidence regarding this is the significant association found between the autophagy-related gene-5 (ATG-5) over-expression and poor overall survival in GC patients, and its involvement in CDDP chemo-resistance in vitro [109]
Summary
Remarkable progress has been made in understanding the complex molecular mechanisms responsible for the onset and progression of human gastric cancer (GC). Chemo-resistance of tumor cells occurs through two universally accepted mechanisms [19]: It may be already pre-existent at diagnosis, meaning that tumor cells are intrinsically resistant to the chemotherapeutic agent [20], or it can be induced after the exposure of cancer cells to the drug [21,22,23]. These two resistance profiles are defined as intrinsic and acquired resistance, respectively, and they are both related to tumor cells, as well as to tumor microenvironment (TME) characteristics [24,25]. We reviewed the recent literature on the molecular mechanisms by which GC cells promote intra and extra-cellular remodeling for overcoming anticancer drugs effects
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