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Supplementary Figure 4 from Tumor-Induced Pressure in the Bone Microenvironment Causes Osteocytes to Promote the Growth of Prostate Cancer Bone Metastases

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posted on 2023-03-30, 23:06 authored by Joseph L. Sottnik, Jinlu Dai, Honglai Zhang, Brittany Campbell, Evan T. Keller

Supplementary Figure 4: CCL5 promotes migration and invasion of PCa. A) CCL5 was measured in CM from non-pressurized MLO-Y4 cells after normalization by protein concentration. B) MLO-Y4 CM was incubated with neutralizing antibody (1 µg/ml) against CCL5 and isotype control antibody (1 µg/ml) before being used as a chemoattractant for PCa cell lines. Neutralization of CM derived CCL5 significantly inhibited PCa migration and invasion. C) Based upon measurements of CCL5 produced by OCy at 0 and 40 mmHg, recombinant CCL5 was added to 0 mmHg CM and used in migration and invasion assays. ELISA data was analyzed using Student's two-tailed unpaired t-test. All other data was analyzed by One-way ANOVA with Bonferroni post-test. All bars represent significant relationships of p<0.05.

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ARTICLE 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. Cancer Res; 75(11); 2151–8. ©2015 AACR.