Roles of Integrins in Gastrointestinal Cancer Metastasis

Integrins are a large family of heterodimeric transmembrane receptors which mediate cell adhesion and transmit signals to the cell interior. The mechanistic roles of integrins have long been an enigma in cancer, given its complexity in regulating different cellular behaviors. Recently, however, increasing research is providing new insights into its function and the underlying mechanisms, which collectively include the influences of altered integrin expression on the aberrant signaling pathways and cancer progression. Many studies have also demonstrated the potentiality of integrins as therapeutic targets in cancer treatment. In this review, we have summarized these recent reports and put a particular emphasis on the dysregulated expression of integrins and how they regulate related signaling pathways to facilitate the metastatic progression of gastrointestinal cancer, including gastric cancer (GC) and colorectal cancer (CRC), which will address the crucial roles of integrins in gastrointestinal cancer.

The mechanics of single cross-links which mediate cell attachment at a hydrogel surface

The mechanical properties of single cross-links which mediate cell adhesion are explored by force spectroscopy.

Trafficking of Adhesion and Growth Factor Receptors and Their Effector Kinases

Cell adhesion to macromolecules in the microenvironment is essential for the development and maintenance of tissues, and its dysregulation can lead to a range of disease states, including inflammation, fibrosis, and cancer. The biomechanical and biochemical mechanisms that mediate cell adhesion rely on signaling by a range of effector proteins, including kinases and associated scaffolding proteins. The intracellular trafficking of these must be tightly controlled in space and time to enable effective cell adhesion and microenvironmental sensing and to integrate cell adhesion with, and compartmentalize it from, other cellular processes, such as gene transcription, protein degradation, and cell division. Delivery of adhesion receptors and signaling proteins from the plasma membrane to unanticipated subcellular locales is revealing novel biological functions. Here, we review the expected and unexpected trafficking, and sites of activity, of adhesion and growth factor receptors and intracellular kinase partners as we begin to appreciate the complexity and diversity of their spatial regulation.

Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions

Integrins are transmembrane receptors that, upon activation, bind extracellular matrix (ECM) or cell surface ligands and link them to the actin cytoskeleton to mediate cell adhesion and migration1,2. One model for the structural transitions mediating integrin activation termed “the cytoskeletal force hypothesis” posits that force transmitted from the cytoskeleton to ligand-bound integrins acts as an allosteric stabilizer of the extended-open, high-affinity state3. Since cytoskeletal forces in migrating cells are generated by centripetal “retrograde flow” of F-actin from the cell leading edge, where integrin-based adhesions are initiated4,5, this model predicts that F-actin flow should align and orient activated, ligand-bound integrins in integrin-based adhesions. Here, polarization-sensitive fluorescence microscopy of GFP-αVβ3 integrin chimeras in migrating fibroblasts shows that integrins are aligned with respect to the axis of FAs and the direction of F-actin flow, and this alignment requires binding immobilized ligand and talin-mediated linkage to a flowing cytoskeleton. Polarization imaging and Rosetta modelling of chimeras engineered to orient GFP differentially with respect to the integrin headpiece suggest that ligand-bound αVβ3 integrin may be markedly tilted by the force of F-actin flow. These results show that actin cytoskeletal forces actively sculpt an anisotropic molecular scaffold in FAs that may underlie the ability of cells to sense directional ECM and physical cues.

Integrin Signaling as a Cancer Drug Target

Integrins are transmembrane receptors that mediate cell adhesion to neighboring cells and to the extracellular matrix. Here, the various modes in which integrin-mediated adhesion regulates intracellular signaling pathways impinging on cell survival, proliferation, and differentiation are considered. Subsequently, evidence that integrins also control crucial signaling cascades in cancer cells is discussed. Lastly, the important role of integrin signaling in tumor cells as well as in stromal cells that support cancer growth, metastasis, and therapy resistance indicates that integrin signaling may be an attractive target for (combined) cancer therapy strategies. Current approaches to target integrins in this context are reviewed.

Matrix Metalloproteinases Contribute to Neuronal Dysfunction in Animal Models of Drug Dependence, Alzheimer's Disease, and Epilepsy

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimer's disease, and epilepsy.

The Drosophila afadin homologue Canoe regulates linkage of the actin cytoskeleton to adherens junctions during apical constriction

Cadherin-based adherens junctions (AJs) mediate cell adhesion and regulate cell shape change. The nectin–afadin complex also localizes to AJs and links to the cytoskeleton. Mammalian afadin has been suggested to be essential for adhesion and polarity establishment, but its mechanism of action is unclear. In contrast, Drosophila melanogaster’s afadin homologue Canoe (Cno) has suggested roles in signal transduction during morphogenesis. We completely removed Cno from embryos, testing these hypotheses. Surprisingly, Cno is not essential for AJ assembly or for AJ maintenance in many tissues. However, morphogenesis is impaired from the start. Apical constriction of mesodermal cells initiates but is not completed. The actomyosin cytoskeleton disconnects from AJs, uncoupling actomyosin constriction and cell shape change. Cno has multiple direct interactions with AJ proteins, but is not a core part of the cadherin–catenin complex. Instead, Cno localizes to AJs by a Rap1- and actin-dependent mechanism. These data suggest that Cno regulates linkage between AJs and the actin cytoskeleton during morphogenesis.

Nanotechnology: Better Materials for All Implants

Nanotechnology is being used to mimic structural components of our tissues in synthetic materials intended for various implant applications. Recent studies have highlighted that when compared to flat or micron rough surfaces, surfaces with nanofeatures promote optimal initial protein interactions necessary to mediate cell adhesion and subsequent tissue regrowth. This has been demonstrated for a wide range of implant chemistries (from ceramics to metals to polymers) and for a wide range of tissues (including bone, vascular, cartilage, bladder, and the central and peripheral nervous system). Importantly, these results have been seen at the in vitro and in vivo level. This short review paper will cover some of the more significant advancements in creating better implants through nanotechnology efforts.

Recognizing glycans: Mammalian sugar-binding receptors

The diversity of glycans makes them potentially information-rich structures that can be recognized by receptors that mediate cell adhesion, glycoprotein trafficking and other biological processes. Many well-understood examples of glycan–receptor interactions exist, but are there enough receptors to account for the number of glycans that are being identified?