Prostate cancer (PCa) is the most common cancer in males and the second leading cause of death from cancer in men.1 When PCa progresses from localised disease to castration resistance, the formation of incurable metastases, primarily in the bone, is almost inevitable. Therefore, understanding the factors that regulate homing and survival of metastatic cancer cells in the bone is important for the identification of new therapeutic targets.
The focus of our research is to elucidate and characterise the biological mechanisms that support PCa progression and promote the formation of metastasis. In previous work from our laboratory, Özdemir et al.2 described the molecular signature of the bone marrow/bone-specific response in PCa-induced osteoblastic bone metastasis. This study led to the identification of several factors that reinforced the establishment of the bone metastatic niche and that might represent innovative therapeutic targets and biomarkers in osteoblastic bone metastasis.
Importantly, although in PCa the bone lesions are typically osteoblastic, in many patients osteoblastic and osteolytic lesions coexist.3 Therefore, the objective of our current work is to characterise the subset of molecules that have a biological impact on the establishment of a common blastic and lytic bone marrow/bone-specific response.
Among these factors, our group previously identified melanoma cell adhesion molecule (MCAM) in the stroma of lytic and blastic lesions in preclinical models of PCa bone metastasis.2 MCAM is an adhesion molecule involved in cell-cell and cell-matrix interactions and can interact with other MCAM molecules (homophilic binding) or other ligands (heterophilic binding).4,5
Based on this notion, we knocked down the expression of MCAM on lytic and blastic human PCa cells in order to study its biological function in vitro and in vivo. MCAM knockdown reduced proliferation in PC-3M-Pro4 Luc2 tdTomato PCa cells and resulted in increased E-cadherin expression, which suggests that MCAM may be involved in the maintenance of a mesenchymal phenotype. It has been described how metastatic human PCa cells target the haematopoietic stem cell niche in the bone marrow at the level of an ‘endosteal’/ ‘osteoblast’ niche and a ‘vascular’/‘perivascular’ niche, as reviewed by Hensel and Thalmann.3 Therefore, we set up an in vitro model of an osteoblast niche6 to study the behaviour of PCa cells upon co-culture with osteoblasts and to measure the resulting effects on cancer stem/progenitor-like markers. We found that MCAM is required for the osteoblast-mediated induction of the metastasis-initiating marker aldehyde dehydrogenase (ALDH)7 on PCa cells. Moreover, MCAM knockdown prevented the increase in the size of the ALDHhigh subpopulation in PC-3M-Pro4 Luc2 tdTomato, mediated by human osteoblasts and prevented the establishment of bone metastasis in an intra-osseous animal model.
In conclusion, our data underscore the importance of MCAM in the maintenance of PCa bone metastasis and demonstrate that MCAM plays an important role when PCa cells localise in the bone. Altogether, MCAM appears to be a promising molecule to target the bone metastatic cascade in human PCa.