Abstract
Prostate and breast cancers frequently metastasize to bone. The physiological bone homeostasis is perturbed once cancer cells proliferate at the bone metastatic site. Tumors are complex structures consisting of cancer cells and numerous stroma cells.In this study, we show that osteolytic cancer cells (PC-3 and MDA-MB231) induce transcriptome changes in the bone/bone marrow microenvironment (stroma). This stroma transcriptome differs from the previously reported stroma transcriptome of osteoinductive cancer cells (VCaP). While the biological process “angiogenesis/vasculogenesis” is enriched in both transcriptomes, the “vascular/axon guidance” process is a unique process that characterizes the osteolytic stroma. In osteolytic bone metastasis, angiogenesis is denoted by vessel morphology and marker expression specific for arteries/arterioles. Interestingly, intra-tumoral neurite-like structures were in proximity to arteries. Additionally, we found that increased numbers of mesenchymal stem cells and vascular smooth muscle cells, expressing osteolytic cytokines and inhibitors of bone formation, contribute to the osteolytic bone phenotype.Osteoinductive and osteolytic cancer cells induce different types of vessels, representing functionally different hematopoietic stem cell niches. This finding suggests different growth requirements of osteolytic and osteoinductive cancer cells and the need for a differential anti-angiogenic strategy to inhibit tumor growth in osteolytic and osteoblastic bone metastasis.
Highlights
Prostate and breast cancers are frequently diagnosed solid cancers that often metastasize to bone [1, 2]
We took advantage of bone metastasis xenograft models to identify the molecular changes in the bone/ bone marrow stroma in response to osteolytic cancer cells
The principal component analysis (PCA) plot showed a distinct separation of control bone samples from the cancer cell-xenografted samples, showing that osteolytic cancer cells alter the bone/bone marrow stroma transcriptome (Figure 1B)
Summary
Prostate and breast cancers are frequently diagnosed solid cancers that often metastasize to bone [1, 2]. Bone metastases are diagnosed in approximately 70% of advanced prostate and breast cancer patients [3]. Proliferation of cancer cells at the bone metastatic site causes a number of skeletal-related events, such as severe pain, fractures, spinal cord/intervertebral nerve www.oncotarget.com compression and hypercalcemia. Once disseminated cancer cells proliferate at the bone metastatic site, normal bone physiology, characterized by balanced bone formation and resorption, is perturbed. Prostate cancer cells preferentially induce osteoblastic bone metastasis, whereas breast cancer cells predominantly display an osteolytic bone phenotype. These two distinct stroma responses suggest that cancer cells have different growth requirements
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