Anoikis resistance in gastric cancer: a comprehensive review

Abstract

Gastric cancer (GC) is a predominant malignant neoplasia responsible for cancer death worldwide. Because of the difficulty in early diagnosis as well as its high metastasis rate, GC shows an increasing incidence and poor prognosis. Conventional treatments for GC, such as chemotherapy, radiotherapy, and surgical resection, still fail to achieve curative effects because of drug resistance, a mechanism that leads to a reduction of 5-year survival for GC patients. Anoikis, a particular type of programmed cell death, is activated upon cancer cell detachment from the extracellular matrix, playing a crucial role in antagonizing the progression of several malignant tumors. Because GC cells metastasize mainly in the nearby sites in the peritoneum, a better comprehension of the molecular mechanisms involved in the anchorage-independent growth as well as metastatic spreading is crucial to counteract GC progression. In this context, this review critically examines the molecular mechanisms of anoikis, key pathways and regulatory networks, and the role of anoikis resistance in GC. Furthermore, it summarizes potential therapeutic strategies for targeting anoikis-resistant cells. By collecting and analyzing existing literature, this work aims to bridge gaps in the comprehension of the relation between anoikis resistance and GC pathophysiology, providing novel insights and directions for future research in this field.

Fig. 1. Intrinsic and extrinsic apoptosis pathways.

Cell death by anoikis is induced by the activation of the intrinsic or extrinsic apoptosis pathway. The intrinsic pathway is activated by stimuli that activate pro-apoptotic proteins, also known as BH-3-only proteins. These proteins inhibit the anti-apoptotic proteins Bcl-2/Bcl-xL, altering the permeability of the outer mitochondrial membrane and determining the release of cytochrome c. Thus, the apoptosome activation triggers caspase 9, an initiator caspase, and consequently, caspase 3, effector caspase. The interplay between IAP proteins and their inhibitors, Smac/Diablo, modulates cell death. In the extrinsic pathway, activated death receptors transduce external signals, ending up in the caspase 8 activation, an initiator caspase, and subsequently caspase 3. In the final stage, neo-formed apoptotic bodies are disrupted by immune cells. Integrin-ECM interactions play a key role in maintaining ECM integrity, which is linked to several key survival factors such as FAK and Src. Growth factor receptors, activated both in a ligand-dependent and -independent manner, cooperate with integrin and laminin to promote cell viability. Cell–cell interactions mediated by cadherins or other cell surface molecules activate signaling pathways similar to those triggered by ECM adhesion.

Fig. 2. Overview of genes-inducing anoikis resistance in gastric cancer metastasis.

Deregulation of Anoikis-Related Genes modulates transcriptional and metabolic pathways involved in cell detachment from ECM and promotes tumor dissemination.