Integrin-Mediated Tumorigenesis and Its Therapeutic Applications

Abstract

Integrins, a family of adhesion molecules generally exist on the cell surface, are essential for regulating cell growth and its function. As a bi-directional signaling molecule, they mediate cell-cell and cell-extracellular matrix interaction. The recognitions of their key roles in many human pathologies, including autoimmunity, thrombosis and neoplasia, have revealed their great potential as a therapeutic target. This paper focuses on the activation of integrins, the role of integrins in tumorigenesis and progression, and advances of integrin-dependent tumor therapeutics in recent years. It is expected that understanding function and signaling transmission will fully exploit potentialities of integrin as a novel target for tumors.

Targeting integrin α5β1 in urological tumors: opportunities and challenges

“…The α-subunits are mainly associated with receptor recognition and contribute to binding integrin receptors with cation-dependent fits. The β-subunits are associated with cell-to-mesenchyme and cell-to-cell signaling and are involved in cytoskeletal protein interactions and intracellular signaling ( 8 , 10 , 11 ). The α and β subunits both have a long extracellular structural domain and a short cytoplasmic tail; the cytoplasmic tail is connected to the actin cytoskeleton and intracellular signaling pathways such as SRC protein family kinases, focal adhesion kinase (FAK), Rho-GTPase family, mitogen-activated protein kinase (MAPK), protein kinase B (AKT), and integrin-linked protein kinase( ( 12 ).…”

Nintedanib‐αVβ3 Integrin Ligand Dual‐Targeting Conjugates towards Precision Treatment of Melanoma

“…In fact, melanoma cells can secrete their own ECM proteins, in response to drug therapy, via a mechano‐signalling loop that chiefly involves the β 1 integrin/focal adhesion kinase (FAK) pathway [21] . In addition to β 1 integrins, the role of α V β 3 integrins in tumour angiogenesis, proliferation, and metastasishas been fully elucidated and their innately low levels of expression in healthy cells means they can serve as both tumour biomarkers and therapeutic targets [22–26] …”

“…[21] In addition to β 1 integrins, the role of α V β 3 integrins in tumour angiogenesis, proliferation, and metastasishas been fully elucidated and their innately low levels of expression in healthy cells means they can serve as both tumour biomarkers and therapeutic targets. [22][23][24][25][26] Integrin ligand-based conjugates (alias Integrin Ligand-Small Molecule conjugates, IL-SM conjugates), where an integrin-recognizing small peptide (or peptidomimetic [27] ) is covalently linked to a small-molecule drug, are interesting molecular constructs in targeted therapy and are presently emerging as smart tools in precision medicine and paralleling the established domain of antibody-drug conjugates. [28] Indeed, IL-SM conjugates may well combine, or even synergize, the therapeutic competence of the single components -e. g. the antagonist behaviour of both the integrin ligand and the small molecule towards their respective biological targets -and in doing so, they surpass their role as selective vectors to integrin-overexpressing cells and in promoting possible integrin-mediated internalization upon ligand binding.…”

The power of heteronemin in cancers

“…Cellular uptake of the agent and actions of the drug on signal transduction pathways require further investigation, as do the mechanisms by which hormones and growth factors interfere with the heteronemin-induced anticancer activity [ 10 – 12 , 19 , 20 ]. The contributions of integrins in cancer progression have recently attracted attention in the literature [ 21 , 22 ]. We have studied integrin αvβ3-linked signal transduction pathways and have demonstrated that integrin αvβ3 contains a receptor site for thyroid hormone analogues that permits L -thyroxine (T 4 ), the principal secretory product of the thyroid gland, to induce cancer growth [ 23 ].…”