Pathobiological functions and clinical implications of annexin dysregulation in human cancers

Abstract

Annexins are an extensive superfamily of structurally related calcium- and phospholipid-binding proteins, largely conserved and widely distributed among species. Twelve human annexins have been identified, referred to as Annexin A1-13 (A12 remains as of yet unassigned), whose genes are spread throughout the genome on eight different chromosomes. According to their distinct tissue distribution and subcellular localization, annexins have been functionally implicated in a variety of biological processes relevant to both physiological and pathological conditions. Dysregulation of annexin expression patterns and functions has been revealed as a common feature in multiple cancers, thereby emerging as potential biomarkers and molecular targets for clinical application. Nevertheless, translation of this knowledge to the clinic requires in-depth functional and mechanistic characterization of dysregulated annexins for each individual cancer type, since each protein exhibits varying expression levels and phenotypic specificity depending on the tumor types. This review specifically and thoroughly examines the current knowledge on annexin dysfunctions in carcinogenesis. Hence, available data on expression levels, mechanism of action and pathophysiological effects of Annexin A1-13 among different cancers will be dissected, also further discussing future perspectives for potential applications as biomarkers for early diagnosis, prognosis and molecular-targeted therapies. Special attention is devoted to head and neck cancers (HNC), a complex and heterogeneous group of aggressive malignancies, often lately diagnosed, with high mortality, and scarce therapeutic options.

Annexin‐A5 and annexin‐A6 silencing prevents metastasis of breast cancer cells in zebrafish

“…In addition, we observed that silencing of ANXA5 and ANXA6 has no effect on cell growth in vitro (Figure 3c). This result was surprising, since both annexins have been associated with growth‐promoting and ‐inhibiting features (Grewal et al., 2021; Prieto‐Fernández et al., 2022). Actually, we showed that sgANXA6 MDA‐MB‐231 cells proliferate more rapidly than control cells, while sgANXA5 MDA‐MB‐231 cells exhibited a slower growth than both other cell types (Figure S5).…”

“…To date, no potential therapy targeting ANXA5 or ANXA6 has been reported (Prieto‐Fernández et al., 2022). Inhibiting membrane repair of cancer cells with therapeutic antibodies would be a good option since it has been shown that a monoclonal anti‐ANXA6 antibody significantly decreases the invasiveness of pancreatic, lung, and breast cancer cells in vitro (O'Sullivan et al., 2017).…”

“…Data from the literature serve as the first basis of this working hypothesis. Although few studies have linked membrane repair to cancer, several of them have indeed found fortuitously a positive correlation between key actors of membrane repair and tumor invasion (Jaiswal et al., 2014; Lauritzen et al., 2015; Leung et al., 2013; Prieto‐Fernández et al., 2022). In addition, the hypothesis is supported by our experimental data, which provided an in cellulo proof of principle.…”

Lysine Acetylome of Breast Cancer-Derived Small Extracellular Vesicles Reveals Specific Acetylation Patterns for Metabolic Enzymes

“…Annexin family members can regulate various cellular functions including vesicle trafficking, vesicle fusion, plasma membrane repair, promotion of membrane segregation and actin cytoskeleton dynamic regulation [ 63 , 64 , 65 , 66 ]. Dysregulation of annexins has been associated with multiple cancers including BC, and these proteins have emerged as potential biomarkers and pharmacological targets for medical applications [ 67 ]. Quantitative mass spectrometry-based proteomic analyses revealed significantly higher ANXA1 protein expression in more invasive glioblastoma cells [ 68 ].…”

Annexin A1, A2, A5, and A6 involvement in human pathologies

“…In mammalian tissues, annexins appear widely, but variably expressed. 10,75 In human cancers normal expression patterns appear to be disrupted 75 (and see later discussion). Of course, tissues are made up not only of many different cell types, but also cells at different stages of differentiation, activity, and the cell cycle.…”