Crosstalk Signalling Role in Modulation of Drugs Side Effects

Susanna      P. Garamszegi; Nandor      Garamszegi

Abstract

Tumourigenesis is regulated by the complex cell-matrix signalling interactions that incorporate feedback mechanisms from constantly evolving microenvironments. Under normal circumstances, these matrix signalling processes together with infiltrating immune cells tightly control the extent of tissue remodelling. They are the key elements of regulated homeostatic repair of local matrix architecture and biological function. In contrast, the pathological tumourigenesis employing similar mechanisms and cellular components to change cellular phenotype promoting proliferation and transformation. However, there is a significant knowledge gap in our understanding about the network integration of different matrix induced signalling processes and their connection to drug side effects.

Using epithelial tumourigenesis as a model system, we show that drug actions and pathological conditions are associated with crosstalk signalling mechanisms. These processes functionally integrate microenvironmental cues and generate representative gene expression profiles that are different from those induced by the native ligand-driven signalling mechanisms. Particularly in this review, we are focusing on crosstalk signalling processes that are sensitive to transforming growth factor receptor type I (TβRI) inhibitor A83-01 (3-(6-Methyl-2-pyridinyl)-N-phenyl-4-(4-quinolinyl)-1H-pyrazole- 1-carbothioamide). This process is affecting inflammatory gene expression, epithelial to mesenchymal transition, migration, proliferation, and changes in metastatic gene expressional patterns. As a result, phenotypic and functional modifications to cells and their immediate microenvironments are unavoidable.

Here we demonstrate that future screening strategies for unintended drug side effects from molecular to systemic levels would benefit from future crosstalk signalling analysis. Thorough analysis could be used to forecast the diverse and highly variable gene expression patterns caused by pathological microenvironmental conditions which become apparent only in larger patient populations.

Keywords: Cell migration, extracellular matrix, invasion, microenvironmental change induced gene expression profiles, proliferation, signalling crosstalk