Osteolytic cancer cells induce vascular/axon guidance processes in the bone/bone marrow stroma

// Janine Hensel 1, 2 , Antoinette Wetterwald 1, 2 , Ramzi Temanni 3 , Irene Keller 4, 5 , Carsten Riether 6, 7 , Gabri van der Pluijm 8 , Marco G. Cecchini 1, 2 and George N. Thalmann 1, 2 1 Urology, Department for BioMedical Research, University of Bern, Bern, Switzerland 2 Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland 3 Biomedical Informatics Division, Research Branch, Sidra Medical and Research Center, Doha, Qatar 4 Department for Biomedical Research, University of Bern, Bern, Switzerland 5 Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland 6 Tumor Immunology, Department for BioMedical Research, University of Bern, Bern, Switzerland 7 Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland 8 Department of Urology, Leiden University Medical Centre, Leiden, Netherlands Correspondence to: George N. Thalmann, email: urology.berne@insel.ch Janine Hensel, email: urology.berne@insel.ch Keywords: prostate and breast cancer; osteolytic bone metastasis; stroma; angiogenesis; axon guidance Received: December 12, 2017      Accepted: May 02, 2018      Published: June 22, 2018 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.