Matrix rigidity induces osteolytic gene expression of metastatic breast cancer cells

• Published in: PloS one 2010-11, Vol.5 (11), p.e15451
• Main Authors: Ruppender, Nazanin S, Merkel, Alyssa R, Martin, T John, Mundy, Gregory R, Sterling, Julie A, Guelcher, Scott A
• Format: Article
• Language: English
• Subjects: Actomyosin; Algorithms; Biocompatibility; Biology; Bone cancer; Bone diseases; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Bone remodeling; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer genetics; Cancer metastasis; Cell adhesion & migration; Cell Culture Techniques - methods; Cell Line, Tumor; Cellular manufacture; Contractility; Developmental stages; Elasticity; Engineering; Environmental factors; Extracellular matrix; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks - drug effects; Glycerol; Growth factors; Humans; Hydrogels; Kinases; Lungs; Materials Science; Medicine; Metastases; Metastasis; Neoplasm Metastasis; Osteoclasts; Osteoclasts - metabolism; Osteoclasts - pathology; Osteolysis; Osteolysis - genetics; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - genetics; Parathyroid Hormone-Related Protein - metabolism; Pharmacology; Potassium; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Rho-associated kinase; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; Rigidity; Signaling; Smooth muscle; Studies; Substrate inhibition; Substrates; Transforming Growth Factor beta - pharmacology; Transforming growth factors; Tumor cells; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015451

Nearly 70% of breast cancer patients with advanced disease will develop bone metastases. Once established in bone, tumor cells produce factors that cause changes in normal bone remodeling, such as parathyroid hormone-related protein (PTHrP). While enhanced expression of PTHrP is known to stimulate osteoclasts to resorb bone, the environmental factors driving tumor cells to express PTHrP in the early stages of development of metastatic bone disease are unknown. In this study, we have shown that tumor cells known to metastasize to bone respond to 2D substrates with rigidities comparable to that of the bone microenvironment by increasing expression and production of PTHrP. The cellular response is regulated by Rho-dependent actomyosin contractility mediated by TGF-ß signaling. Inhibition of Rho-associated kinase (ROCK) using both pharmacological and genetic approaches decreased PTHrP expression. Furthermore, cells expressing a dominant negative form of the TGF-ß receptor did not respond to substrate rigidity, and inhibition of ROCK decreased PTHrP expression induced by exogenous TGF-ß. These observations suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis, which is especially important in metastatic cancer since many cancers (such as those of the breast and lung) preferentially metastasize to bone.