title: Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases.
abstract: Cross-talk between tumor cells and their microenvironment is critical for malignant progression. Cross-talk mediators, including soluble factors and direct cell contact, have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here, we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced prostate cancer growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche.
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan. etkeller@umich.edu joseph.sottnik@ucdenver.edu.
authors: Joseph L
authors: JL
authors: Sottnik
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors: Jinlu
authors: J
authors: Dai
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Honglai
authors: H
authors: Zhang
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors: Brittany
authors: B
authors: Campbell
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan. Department of Pathology, University of Michigan, Ann Arbor, Michigan. etkeller@umich.edu joseph.sottnik@ucdenver.edu.
authors: Evan T
authors: ET
authors: Keller
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology* / Q000556:secondary; D049109:Cell Proliferation / Q000502:physiology; D018946:Chemokine CCL5 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D009362:Neoplasm Metastasis; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology; D011312:Pressure; D011471:Prostatic Neoplasms / Q000473:pathology*; D059016:Tumor Microenvironment
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D020782:Matrix Metalloproteinases