Cancer cell growth is highly dependent on a growth permissive microenvironment (stroma). Prostate and mammary cancer (PCa and MCa) cells preferentially metastasize to bone, where they induce either an osteoblastic or osteolytic response. These opposite stromal responses suggest that different cancers adopt distinct strategies to hijack the bone marrow/bone stroma for their growth support. However, the molecular cues underlying these divergent responses are largely elusive. We exploited the sufficient divergence between human and mouse RNA sequences to dissect the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive PCa cells (VCaP and C4-2B) and of pro-osteolytic PCa and MCa cells (PC-3 and MDA-MB-231 respectively). A robust induction of genes involved in osteogenesis and angiogenesis dominates the stroma response in osteoblastic bone metastasis. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and the local interference with hematopoiesis (myelophthisis). Angiogenesis and skeletogenesis are the predominant biological processes also in the stroma response to osteolytic bone metastasis. However, this stroma transcriptome differs substantially from that of osteoblastic lesions and reveals not only activation of pro-osteoclastogenic signals, but also interference with pro-osteoblastogenic factors. Thus, the osteolytic lesions seem to be not only the result of exaggerated bone resorption, but also of inhibition of bone formation. Importantly, the stem cell niche type and molecular components amplified are markedly different between osteoblastic and osteolytic lesions. This suggests different growth support requirements between osteinductive and pro-osteolytic cancer cells and, thus, the need for a differential therapeutic targeting aiming at interfering with tumour growth in osteoblastic and osteolytic lesions.