From the Journal of Clinical Investigation
Results from a recent study published in the Journal of Clinical Investigation by Shiozawa et al. from the University of Michigan and Harvard School of Dental Medicine provide new evidence for the mechanisms directing metastases of carcinomas into bone tissue, observed in 70% of patients with breast or prostate cancer and up to 30% of patients with lung, colon, stomach, bladder, uterine, rectal, thyroid or kidney carcinomas. Their work reveals that metastases target the skeleton by taking advantage of signals normally present in the hematopoietic stem cell (HSC) niche that are known to regulate HSC homing, quiescence and self renewal. Using a mouse model of metastasis, the authors demonstrate that metastasised human prostate cancer cells (PCa) directly compete with HSCs for residency within the HSC niche, preventing HSC engraftment by occupying the HSC niche and driving out HSCs into progenitor pools and the peripheral blood by driving HSC terminal differentiation. Further, they demonstrate the co-localisation of PCa cells and HSCs to the endosteal niche of the bone marrow, particularly to Anxa2-expressing osteoblasts (known to play a central role in HSC niche selection), indicating this to be the site of the HSC niche, the exact location and composition of which has been a controversial issue until now. Interestingly, decreasing the HSC niche size by ablating osteoblastic lineage cells decreased PCa parasitisation of the niche. Moreover, the authors were able to mobilize PCa cells out of the HSC niche by using agents known to cause HSCs to reenter the peripheral circulation. This work has identified three potential mechanisms that might be modulated to minimise metastasis of carcinoma cells into bone tissue, opening new possibilities for therapeutic intervention in metastatic cancer.