Anoikis

Anoikis Overview

• Anoikis: A form of programmed cell death triggered when cells detach from the extracellular matrix (ECM), preventing inappropriate cell growth in new locations, thus discouraging metastatic spread.

• Key Features in Cancer: Resistance to anoikis is crucial for cancer progression, allowing cells to survive and proliferate in detachment or inappropriate attachment situations.

Mechanisms of Anoikis Resistance

• Integrin Repertoire Changes: Cancer cells adapt by altering integrin expression to survive in various environments.

• Pro-Survival Signals Activation: Various pathways (oncogene activation, growth factor receptor overexpression, sustained autocrine signaling) activate anti-apoptotic signals, enabling survival upon detachment.

• Tumor Microenvironment Influence: Factors such as matrix stiffness, oxidative stress, and soluble factors can enhance anoikis resistance, leading to metabolic alterations in cancer cells.

Molecular Pathways of Anoikis

• Caspases Role: Anoikis culminates in caspase activation, leading to apoptosis.

• Intrinsic Pathway: Triggered by mitochondrial perturbations, controlled by Bcl-2 family proteins.

• Extrinsic Pathway: Initiated by death receptors (e.g., Fas, TNFR), leading to caspase-8 activation and subsequent apoptosis.

Protective Mechanisms in Healthy Cells

• Cell Adhesion to ECM: Integrin engagement triggers survival signals, preventing apoptosis; specific integrins (α5β1, αvβ3) are crucial for protecting against anoikis.

• Lack of Adhesion During Migration: Cells in temporary non-adhesive states (e.g., during migration) are still protected through signaling active during movement.

• Cell-Cell Contacts: Cadherins contribute to survival signaling, preventing anoikis; blocking cadherin binding induces anoikis.

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Key Players in Anoikis Resistance

• Growth Factor Receptors: Overexpression or activation of various receptor tyrosine kinases (e.g., EGFR, TrkB) promotes survival signalling.

• Hypoxia and ROS: Chronic oxidative stress can lead to pro-survival signaling, rendering cancer cells resistant to anoikis.

• Metabolic Adaptations: Cancer cells exhibit metabolic reprogramming (Warburg effect) to support proliferation and survival during detachment.

Anoikis Resistance in Cancer Cells

• Integrin Switch: Abnormal integrin expression profiles contribute to anoikis resistance during cancer progression.

• Constitutive Pro-Survival Pathway Activation: Signaling pathways such as PI3K/Akt and MAPK are critical for anoikis resistance.

• Epithelial-Mesenchymal Transition (EMT): This process facilitates detachment and enables cancer cells to migrate by altering adhesion properties while enhancing resistance to apoptotic signals.

• MicroRNA Regulation: MiRNAs can modulate elements of the cell survival pathway, influencing resistance to anoikis and cellular plasticity.

Implications and Therapeutic Targets

• Potential Therapies: Targeting key pathways involved in anoikis resistance represents a promising strategy for anti-metastatic therapies.

• Understanding Signalling Hierarchies: Identifying critical mechanistic players in anoikis resistance may enhance therapeutic efficacy by focusing on cancer cells' survival mechanisms during detachment.