T-cadherin and tissue
Cadherins comprise a family of cell-cell adhesion proteins critical to architecture and function of tissues in developing and adult organisms. T-cadherin (T-cad) is peculiar in structure: it lacks transmembrane and cytosolic domains and is membrane-anchored via a GPI moiety, implying distinct functions and molecular circuitry. We have hypothesized that the "functional predestination" of T-cad is the control of tissue architecture through both “guiding” navigation of moving structures or segregation of functional tissue compartments and "guarding" integrity of functionally connected tissue layers. T-cad Expression is altered in cardiovascular disorders and cancers. We focus on delineating T-cad-dependent cellular functions and signal pathway utilization in vascular and cancer cells, with the broader goal being to define basic biological mechanisms underlying T-cad-mediated control of tissue homeostasis.
T-cadherin in the vasculature
T-cad Expression is upregulated on vascular smooth muscle cells (SMC) and endothelial cells (EC) during atherosclerosis and restenosis. Using in vitro and in vivo approaches we have previously identified angiogenic and survival functions for T-cad in EC. Relevant signal effectors include PI3K/Akt/mTOR, GSK3β, β-catenin, p38MAPK and RhoA/Rac GTPases and membrane molecular adaptors include Grp78, ILK and integrin β3. T-cad is shed from activated/damaged EC as a component of microparticles (MP), which via homophilic-based interactions can serve local/distal protective signaling functions during conditions of endothelial injury or dysfunction. These studies support T-cad upregulation as a modulator of survival/reparative behavior of EC in cardiovascular disorders.
However, sustained T-cad up-regulation in EC can have deleterious consequences of promoting endothelial insulin resistance (Fig. 1). One explanation for the ability of T-cad to impact insulin signaling is that its adaptor recruitment activates signaling responses that converge with the insulin-insulin receptor (IR)-dependent pathway at the level of common intracellular targets. Alternatively, T-cad may directly increase IR pathway activity through T-cad/IR co-association in lipid raft domains. Control of the IR signal cascade by T-cad represents a novel cadherin-based signaling pathway at the crossroads of vascular and metabolic disorders.
Current investigations address the contribution of T-cad to SMC (patho)biology.
T-cadherin in cancer
T-cad has been implicated in cancer progression primarily on the basis of genetic and epigenetic studies. We apply multidisciplinary in vitro and in vivo experimental approaches to understand the cellular functions and molecular mechanisms of action of T-cad in tumour biology. Immunohistochemical analysis of human skin showed that decrease/loss of T-cad in squamous cell carcinoma (SCC) tumors occurs in association with acquisition of the invasive/malignant phenotype (Fig. 2A). In vitro and in vivo investigations show that T-cad loss in SCC promotes cell elongation, cell cluster disorganization, motility and invasive/metastatic potential (Fig. 2B and C), effects which are due to enhanced EGFR pathway activity. T-cad gain or loss respectively recruit or release EGFR from lipid raft domains, suggesting that T-cad acts as a negative auxiliary regulator of EGFR in SCC. We postulated that modulation of EGFR activity by T-cad could be a regulatory mechanism common to other RTKs. Using several cancer cell lines including prostate and colon carcinoma cells we found that T-cad regulates activity of both EGFR and IGF-1R and their cross talk. This is relevant to evolution of drug resistance.
Modulation of growth factor receptor tyrosine kinase activity and cross-talk may be a common mechanistic principle underlying T-cad-dependent control of vascular and epithelial (tumour) cells behavior (Fig. 3). T-cad dysfunction carries consequences for receptor complementarity and cell migration, proliferation, invasion, differentiation and polarity, which are key determinants of vascular (dys)function/remodeling and of tumour progression/metastasis.
Prof. Dr. Paul Erne
Division of Cardiology Kantonsspital Luzern
Detection of early atherosclerosis and the vulnerable patient
Despite major advances in understanding of plaque biology, diagnosis and treatment, atherosclerosis remains a leading cause of morbidity and mortality. Atherosclerosis is clinically silent long before plaque rupture and ensuing cardiovascular events. Detection of preclinical atherosclerosis and the shift from “indolent” to acute ischemic disease has great clinical benefit, yet remains a diagnostic challenge. Atherosclerosis profiling using a multi-marker diagnostic paradigm comprising physical characteristics and lesional composition of vessels, endothelium function, plasma biomarkers of endothelial damage/dysfunction (ED) and inflammatory status and specific relationships between these parameters could improve risk stratification of patients and determination of treatment measures. We have compiled a wide-ranging clinical data base on a large cohort of study subjects (including healthy individuals, patients without cardiovascular risk factors, and patients with different stages of atherosclerosis defined on the basis of angiographic and IVUS data) and a corresponding bank of plasma samples and blood leukocyte isolates for biomarker analysis. We have established links between vascular shear stress and coronary vessel calcification and between ED and morphology of coronary atherosclerotic plaques. We have also demonstrated that levels of plasma T-cad correlate with ED, invoking T-cad as a biomarker of early atherosclerosis. Currently we are examining the link between oxidative processes in the vessel and initiation of atherosclerosis, endothelial dysfunction and plaque burden by exploring the potential use of oxidized phospholipid species as disease biomarkers.