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Role of Mechanotransduction in Cancer: A Complex Problem Involving Gene Mutations and Altered Levels of Connection
1Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Background:
External and internal forces and tissue energy influence the structure and function of mammalian tissues during life in a gravitational field. Changing force (stress) and energy equilibria provide a dynamic means to regulate cell and tissue growth during development and maturation. However, genetic mutations and changes in expression of macromolecules involved in cell and extracellular matrix (ECM) equilibria lead to tumor formation.
Methods:
A model is presented illustrating connections between ECM, cell membranes, cell cyto- and nucleoskeletons, cell nucleus, and cell-cell junctions that promote energy storage, transmission, and dissipation. The effects of mutations involving changes in P53 and Coll 11A1 genes and changes in expression of collagens and collagen receptors, integrins, ILK, FAK, Talin, Paxillin, Kindlins, c-SRC, Actin, myosin light chain, Filamin A, E-cadherin, and beta catenin that have been reported to occur in cancerous lesions are examined.
Results:
When mutations or altered component expressions occur, mechanotransduction pathways are activated that lead to modified epithelial-mesenchymal (EMT) and endothelial-mesenchymal (ENT) transitions resulting in new cell division and deposition of ECM.
Conclusions:
It is hypothesized that changes in genes and expression of proteins in the connections between ECM and bound cells alter energy storage and dissipation. This leads to local stress concentrations that alter force and energy dynamic equilibria required to maintain homeostasis. Excess energy associated with broken connections within cells is dissipated through changes in myosin structure and function.
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