1. Introduction
Prostate cancer is the most frequent form of cancer in males and a leading cause of cancer death among men of all races [1]. Bone metastasis is very common in patients with advanced prostate cancer and is associated with high mortality and morbidity [2,3]. Cancer metastasis is a complex process where the cancer cells detach from the primary site, undergo epithelial–mesenchymal transition, travel through the circulatory or lymphatic systems, and form secondary tumors [2,3]. It has been hypothesized that the bone microenvironment serves as a rich “soil” by secreting factors that promote survival and propagation of cancer cells [2,3]; in turn tumors secrete factors that alter the bone microenvironment to promote metastatic colonization [2,3]. Multiple factors involved in bone metastasis, including growth factors, cytokines and matrix metalloproteinases [3,4,5], have already been identified, however, the mechanisms responsible for bone metastasis are not yet fully understood. Development of new therapies for the prevention and treatment of prostate cancer bone metastasis depends on understanding the dynamic reciprocal interactions between prostate cancer and the bone microenvironment.
Osteoblasts are bone forming cells of mesenchymal origin that are responsible for the synthesis and mineralization of bone matrix [6]. Prostate cancer cells interact with mesenchymal-derived tissue at the site of metastasis, which subsequently alters the bone microenvironment and contributes to the malignant progression of prostate cancer [4]. Many studies have previously investigated cancer–osteoblast interactions in the context of bone metastasis [7,8,9]. A number of such studies have used in vitro co-culture models [8,9,10] to explore osteoblast-tumor cell interactions and successfully identified numerous factors that contribute to bone metastasis [5,8,9,10]. However, it is likely that there are other key molecules that remain unidentified.
Gene expression profiling using microarrays has proven effective in studying changes of large sets of transcripts, simultaneously. In this study, we investigated prostate cancer–osteoblast interactions using microarrays to identify novel factors that contribute to prostate cancer metastasis to bone. We co-cultured highly invasive PC3 cells with either immortalized or primary osteoblasts and profiled gene expression changes. Gene expression data analysis identified several genes, including Il6, Tgfb2, Cxcl1, Mmp13, Ctgf, Sost and lncRNA MALAT1, differentially regulated in co-cultures compared to monocultures. We also identified Sost as a regulator of MALAT1 in PC3 cells. This study provides novel insights into cellular responses in relation to prostate cancer–osteoblast interactions with potential therapeutic implications.