Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin β3 and TGF-β receptor type II.

Page JM, Merkel AR, Ruppender NS, Guo R, Dadwal UC, Cannonier S, Basu S, Guelcher SA, Sterling JA
Biomaterials. 2015 64: 33-44

PMID: 26115412 · PMCID: PMC4681301 · DOI:10.1016/j.biomaterials.2015.06.026

Cancer patients frequently develop skeletal metastases that significantly impact quality of life. Since bone metastases remain incurable, a clearer understanding of molecular mechanisms regulating skeletal metastases is required to develop new therapeutics that block establishment of tumors in bone. While many studies have suggested that the microenvironment contributes to bone metastases, the factors mediating tumors to progress from a quiescent to a bone-destructive state remain unclear. In this study, we hypothesized that the "soil" of the bone microenvironment, specifically the rigid mineralized extracellular matrix, stimulates the transition of the tumor cells to a bone-destructive phenotype. To test this hypothesis, we synthesized 2D polyurethane (PUR) films with elastic moduli ranging from the basement membrane (70 MPa) to cortical bone (3800 MPa) and measured expression of genes associated with mechanotransduction and bone metastases. We found that expression of Integrin β3 (Iβ3), as well as tumor-produced factors associated with bone destruction (Gli2 and parathyroid hormone related protein (PTHrP)), significantly increased with matrix rigidity, and that blocking Iβ3 reduced Gli2 and PTHrP expression. To identify the mechanism by which Iβ3 regulates Gli2 and PTHrP (both are also known to be regulated by TGF-β), we performed Förster resonance energy transfer (FRET) and immunoprecipitation, which indicated that Iβ3 co-localized with TGF-β Receptor Type II (TGF-β RII) on rigid but not compliant films. Finally, transplantation of tumor cells expressing Iβ3 shRNA into the tibiae of athymic nude mice significantly reduced PTHrP and Gli2 expression, as well as bone destruction, suggesting a crucial role for tumor-produced Iβ3 in disease progression. This study demonstrates that the rigid mineralized bone matrix can alter gene expression and bone destruction in an Iβ3/TGF-β-dependent manner, and suggests that Iβ3 inhibitors are a potential therapeutic approach for blocking tumor transition to a bone destructive phenotype.

Published by Elsevier Ltd.

MeSH Terms (28)

Adenocarcinoma Animals Bone Neoplasms Breast Neoplasms Carcinoma, Squamous Cell Cell Line, Tumor Elastic Modulus Extracellular Matrix Female Gene Expression Regulation, Neoplastic Humans Integrin beta3 Kruppel-Like Transcription Factors Lung Neoplasms Mice Mice, Nude Neoplasm Proteins Nuclear Proteins Osteolysis Pliability Protein-Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Transfection Transforming Growth Factor beta Tumor Microenvironment Xenograft Model Antitumor Assays Zinc Finger Protein Gli2

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