Anoikis pathways in cancer therapeutics

To the Editor: Approximately one-sixth of all deaths worldwide can be attributed to cancer, a disease characterized by its capacity for metastasis, which significantly complicates treatment strategies.1 Anoikis, a specialized form of programmed cell death triggered by cell detachment from the extracellular matrix (ECM), plays a critical role in normal development, tissue homeostasis, and the pathogenesis of various diseases, including tumor metastasis.2 Anoikis resistance, which occurs when detached cells circumvent death signaling pathway to survival, is considered a hallmark of metastasis in cancers. Recent studies have illuminated the role of anoikis as a potential barrier to the metastasis of cancer cells, particularly in malignancies such as glioblastoma, gastric cancer, non-small cell lung cancer (NSCLC), and breast cancer.3 However, the mechanistic underpinnings of anoikis/anoikis resistance in certain cancers remain poorly understood, warranting further investigation. This study aims to elucidate the relationship between anoikis/anoikis resistance and cancer, providing a theoretical framework to guide future research. Previous studies have established that various factors, including cell adhesion molecules, cell detachment and directional migration, cytoskeletal dynamics, apoptotic signaling, fatty acid metabolism regulators, and immune regulation, play vital roles in mediating anoikis resistance. Specifically, cell adhesion molecules, such as cadherins, integrins, and selectins, are essential for the integrity of the ECM. Disruption of E-cadherin, for instance, has been closely linked to increased metastatic potential, while E-selectin and Claudin-1 have also been implicated in the regulation of anoikis resistance. Integrins, notably α5β1 and αvβ3, activate signaling pathways like the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, which can enhance anoikis resistance.4 Growth factors are regulatory molecules, predominantly proteins or sterols, that stimulate cell growth, proliferation, differentiation, inflammation, immunity, tissue healing, and survival. These factors operate by interacting with their target receptors, which promotes or cancels their function. These receptors are transmembrane proteins that bind to specific growth factors, transmitting signals into the intracellular space. Growth factors can regulate the process of anoikis during cancer development by interacting with receptors such as the epidermal growth factor receptor (EGFR), transforming growth factor beta (TGF-β), insulin-like growth factor (IGF), VEGF, fibroblast growth factor (FGF), PDGFR, and adrenoceptor, among others.5 Cell detachment and directional migration also significantly affect apoptosis and anoikis. Chemokines, including interleukins, orchestrate interactions within the tumor microenvironment (TME) to promote tumor growth, influencing pathways like PI3K/AKT and extracellular signal-regulated kinase (ERK) 1/2. These pathways can disrupt the equilibrium between pro-apoptotic and anti-apoptotic proteins, thus fostering anoikis resistance. Caveolin-1 (CAV1) stabilizes membrane structures and contributes to tumor progression by aiding cell migration and anchorage-independent growth, interfacing with signaling molecules like Fyn kinase and Mcl-1 in the integrin and EGFR-ITGB1 pathways. Epithelial-mesenchymal transition (EMT), marked by the mesenchymal transformation of epithelial cells, is implicated in enhanced motility, invasiveness, and the evasion of anoikis, through altered expression of adhesion molecules, cytoskeletal reorganization, and activation of signaling cascades like PI3K/AKT, Notch, and Wnt, which support the resistance mechanism.6 Changes in the cytoskeleton and its regulators, such as βIII-tubulin and Rho GTPases, are critical in cancer progression. For instance, βIII-tubulin has been shown to impact metastasis and treatment resistance in NSCLC through the phosphatase and tensin homolog (PTEN)/AKT pathway.7 RhoA has been implicated in promoting cell invasion and migration, whereas RhoB appears to inhibit proliferation and facilitate anoikis.8 The dysregulation of lipid metabolism, particularly involving enzymes like carnitine palmitoyl transferase I (CPT1A) and fatty acid synthase (FASN), is recognized as a hallmark of cancer, contributing to anoikis resistance and metastatic potential. FASN plays a role in regulating energy metabolism and structural integrity, influencing pathways such as phospho-ERK (p-ERK)1/2 and B-cell lymphoma-extra-large (Bcl-xL); Meanwhile, CPT1A, involved in fatty acid oxidation, affects redox homeostasis and cancer cell survival, thereby positioning both enzymes as potential therapeutic targets in various cancers, including gastric, colorectal, and ovarian cancers.9 Importantly, therapeutic strategies targeting these metabolic pathways align with advancements in cancer immunotherapy, which harness the immune system to combat malignancies, as guided by emerging insights into immune regulation within the TME.10 Within this immune-metabolic interplay, key modulators such as angiopoietin-like protein (ANGPTL) 2 can influence anoikis resistance through the nuclear factor kappa B (NF-κB) pathway in ovarian cancer.11 Furthermore, CD24 has emerged as a critical factor associated with innate immunity evasion, and was demonstrated in ovarian cancer cells to promote anoikis resistance, proliferation, and metastasis, establishing it as a therapeutic target for inducing mutation and inhibiting metastasis, thereby highlighting its promise for novel immunotherapeutic strategies.12 Targeting anoikis effectively blocks the survival and distant colonization of circulating tumor cells, offering a novel strategy to inhibit metastasis. Current therapeutic approaches are categorized into two major classes: natural products and synthetic compounds, which restore cancer cell sensitivity to anoikis by modulating key signaling pathways. Literature indicates that natural compounds with diverse biological activities can effectively modulate anoikis, such as flavonoids, terpenoids, organic acids, and alkaloids. While natural products show great potential, synthetic drugs also exhibit significant therapeutic effects, often with heightened specificity. Key targets of these targeted agents encompass B-cell lymphoma-2 (Bcl-2), EGFR, integrins, mammalian target of rapamycin (mTOR), Src family kinase (Src), TGF-β, and tropomyosin receptor kinases (Trks). Presently, anti-cancer drugs that target anoikis mechanisms are increasingly being integrated into clinical treatment protocols. EGFR inhibitors, such as erlotinib and gefitinib, have shown efficacy in treating various malignancies, including glioma and NSCLC. However, their effectiveness as monotherapies for glioblastoma multiforme remains limited. Nevertheless, combinatory approaches involving radiotherapy or other agents like Bevacizumab have demonstrated improved patient outcomes. In hepatocellular carcinoma, growth factor receptor inhibitors such as sorafenib are established as first-line treatments, with ongoing investigations aimed at optimizing second-line therapies post-sorafenib. Compounds like regorafenib are emerging as potential alternatives for first-line therapy. Additionally, integrin inhibitors such as cilengitide, when used in conjunction with radiotherapy, suggest a potential adjuvant role in glioma treatment, although their efficacy as monotherapies remains limited. Src inhibitors, including dasatinib, and mTOR pathway modulators like metformin are under investigation for their roles in prostate cancer, with varying success in enhancing clinical outcomes or patient survival. Figure 1 schematically depicts the molecular mechanisms and regulatory factors involved in anoikis/anoikis resistance during cancer progression.Figure 1: Schematic illustration of the molecular mechanisms and regulatory factors involved in anoikis/anoikis resistance during cancer progression. The diagram centers on the process of cancer cell detachment from the extracellular matrix, anoikis activation, and anoikis resistance acquisition. It encompasses multiple regulatory aspects: cell adhesion molecules, growth factors CAV1: Caveolin-1; CD24: Cluster of differentiation 24; CPT1A: Carnitine palmitoyltransferase 1A; ECM: Extracellular matrix; EGFR: Epidermal growth factor receptor; EMT: Epithelial-mesenchymal transition; FASN: Fatty acid synthase; FGF: Fibroblast growth factor; IGF: Insulin-like growth factor; PDGFR: Platelet-derived growth factor receptor; Rho GTPases: Rho guanosine triphosphatases; TGF-β: Transforming growth Factor-β; TME: Tumor microenvironment; VEGF: Vascular endothelial growth factor.In summary, anoikis, a form of programmed cell death induced by detachment from the ECM, plays a pivotal role in curbing cancer metastasis. It inhibits metastasis by obstructing tumor cell detachment and re-adhesion through integrins and sensory proteins that regulate key pathways, including focal adhesion kinase (FAK)/Src. Nonetheless, cancer cells can evade anoikis through metabolic adaptations, underscoring the necessity to elucidate resistance mechanisms. Research into anoikis has catalyzed the development of small molecules, antibodies, and recombinant compounds that target growth factors, cell adhesion, apoptotic signaling, and immune responses. Despite this progress, clinical applications remain limited due to insufficient research and safety concerns. While synthetic therapies are available, the untapped potential of natural compounds, particularly from traditional medicine, warrants further investigation. A deeper understanding of the direct links between anoikis and cancer is essential to advance therapeutic strategies in oncology. Funding This study was supported by the National Natural Science Foundation of China (Nos. 82474191 and 82104534), the Natural Science Foundation of Sichuan Province (No. 2024NSFSC2115), and the Sichuan Province Science Research Special Funding Project for Postdoctoral Fellows (No. 2022BSH044). Conflicts of interests None.