Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities

Abstract

Integrins are transmembrane receptors that possess distinct ligand-binding specificities in the extracellular domain and signaling properties in the cytoplasmic domain. While most integrins have a short cytoplasmic tail, integrin β4 has a long cytoplasmic tail that can indirectly interact with the actin cytoskeleton. Additionally, 'inside-out' signals can induce integrins to adopt a high-affinity extended conformation for their appropriate ligands. These properties enable integrins to transmit bidirectional cellular signals, making it a critical regulator of various biological processes.Integrin expression and function are tightly linked to various aspects of tumor progression, including initiation, angiogenesis, cell motility, invasion, and metastasis. Certain integrins have been shown to drive tumorigenesis or amplify oncogenic signals by interacting with corresponding receptors, while others have marginal or even suppressive effects. Additionally, different α/β subtypes of integrins can exhibit opposite effects. Integrin-mediated signaling pathways including Ras- and Rho-GTPase, TGFβ, Hippo, Wnt, Notch, and sonic hedgehog (Shh) are involved in various stages of tumorigenesis. Therefore, understanding the complex regulatory mechanisms and molecular specificities of integrins are crucial to delaying cancer progression and suppressing tumorigenesis. Furthermore, the development of integrin-based therapeutics for cancer are of great importance.This review provides an overview of integrin-dependent bidirectional signaling mechanisms in cancer that can either support or oppose tumorigenesis by interacting with various signaling pathways. Finally, we focus on the future opportunities for emergent therapeutics based on integrin agonists. Video Abstract.

Keywords: Bidirectional signaling mechanisms; Integrin; Integrin-targeting drugs; Tumorigenesis.

Fig. 1

Structure of the integrin β domain

Fig. 2

Integrin activation. Simplified binding interactions between integrin α/β subunit, extracellular ligand, FAK, Src and their activation components such as CAS, paxillin and talin

Fig. 3

Integrin signaling network in cancer. Integrin interaction with RTKs mediates uncontrolled mitogenic and survival or uncontrolled actin assembly to regulate mitogenic signaling as well as related gene expression via FAK-Src (integrin/RTKs) or ILK (integrin) signaling. Activated integrin signaling controls cancer initiation and tumor growth, cancer cell adhesion and adhesion-induced migration, invasion and metastasis. It is associated with incidence and mortality of cancers

Fig. 4

Integrin-mediated Rho GTPase signaling. Integrin associate with RTKs to mediate Rho GTPase subfamilies (RhoA, Rac and Cdc42) signaling via FAK-Src (integrin/RTKs) or ILK (integrin). Activation Rho GTPase signaling controls extension of lamellipodia and filopodia to form focal adhesions and actin stress fibers. Integrin association with the actin cytoskeleton by Rho GTPase is important for tumorigenesis and migration

Fig. 5

Crosstalk between integrin and TGFβ signaling. The combination of integrin and TGFβ signaling triggers canonical (Smads) and non-canonical (Rho GTPase and MAPKs) to induce EMT and malignant progression in cancer

Fig. 6

Integrin-mediated Hippo signaling. Integrin senses the extracellular mechanical cues to regulate the on/off switch of Hippo signaling. The Hippo core kinase cascade may be dispensable in the process of YAP/TAZ nuclear translocation by integrin activation. However, Rho GTPases, particularly RhoA contributes to YAP/TAZ dephosphorylation via regulating actin cytoskeleton dynamics

Fig. 7

Crosstalk between integrin and Wnt signaling. The combination of integrin and Wnt signaling triggers PI3K activation further regulating GSK3β, Ub-induced β-catenin degradation, nuclear location and Wnt targeting gene expression

Fig. 8

Crosstalk between integrin and metabolism including amino acid transport, aerobic glycolysis, glycolysis, glycolysis and mitochondrial respiration