title: Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma.
abstract: Leiomyoma are common tumors arising within the uterus that feature excessive deposition of a stiff, disordered extracellular matrix (ECM). Mechanical stress is a critical determinant of excessive ECM deposition and increased mechanical stress has been shown to be involved in tumorigenesis. Here we tested the viscoelastic properties of leiomyoma and characterized dynamic and static mechanical signaling in leiomyoma cells using three approaches, including measurement of active RhoA. We found that the peak strain and pseudo-dynamic modulus of leiomyoma tissue was significantly increased relative to matched myometrium. In addition, leiomyoma cells demonstrated an attenuated response to applied cyclic uniaxial strain and to variation in substrate stiffness, relative to myometrial cells. However, on a flexible pronectin-coated silicone substrate, basal levels and lysophosphatidic acid-stimulated levels of activated RhoA were similar between leiomyoma and myometrial cells. In contrast, leiomyoma cells plated on a rigid polystyrene substrate had elevated levels of active RhoA, compared to myometrial cells. The results indicate that viscoelastic properties of the ECM of leiomyoma contribute significantly to the tumor's inherent stiffness and that leiomyoma cells have an attenuated sensitivity to mechanical cues. The findings suggest there may be a fundamental alteration in the communication between the external mechanical environment (extracellular forces) and reorganization of the actin cytoskeleton mediated by RhoA in leiomyoma cells. Additional research will be needed to elucidate the mechanism(s) responsible for the attenuated mechanical signaling in leiomyoma cells.
authors: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
authors: John M
authors: JM
authors: Norian
authors: Carter M
authors: CM
authors: Owen
authors: Juan
authors: J
authors: Taboas
authors: Casey
authors: C
authors: Korecki
authors: Rocky
authors: R
authors: Tuan
authors: Minnie
authors: M
authors: Malik
authors: William H
authors: WH
authors: Catherino
authors: James H
authors: JH
authors: Segars
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000328:Adult; D001696:Biomechanical Phenomena; D002478:Cells, Cultured; D055119:Elastic Modulus; D004548:Elasticity; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009215:Myometrium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D014594:Uterine Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D014599:Uterus; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D015778:Minor Histocompatibility Antigens; D011518:Proto-Oncogene Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein