Bone targeted therapy: modifying the soil to prevent metastatic seeding


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Robert Coleman

Cancer Research Centre, Weston Park Hospital, University of Sheffield, UK

Abstract

Bone is a fertile soil for metastatic tumour growth facilitated by complex interactions within the bone marrow microenvironment between cancer, bone and haematopoetic stem cells respectively. Tumour cell release of growth factors and cytokines disrupts the normally balanced coupling of osteoclastic bone resorption and osteoblastic bone formation through the activation of receptor activator of nuclear factor &61547;  ligand (RANKL), the principle regulator of osteoclast development and activation. In turn, increased levels of growth factors are released from bone resulting in continued stimulation of tumour cell proliferation, and creating a self-sustaining vicious cycle of osteolytic bone destruction. Interrupting these interactions would be expected to impede both the development of bone metastases and the survival of dormant cells in the marrow microenvironment, thus leaving fewer viable cells available for subsequent dissemination to extra-osseous sites.

Bisphosphonates are potent inhibitors of bone resorption that are known to reduce the risk of skeletal complications and prevent treatment induced bone loss. However, recent data suggest that bisphosphonate use, especially in breast cancer, may also modify the course of the disease by disrupting the metastatic process. There is a wealth of preclinical evidence to suggest that bone targeted treatments are able to modify the bone microenvironment and thereby reduce the risk of metastasis. Additionally, pre-clinical studies have reported direct anti-tumour effects of bisphosphonates, particularly in combination with chemotherapy. Clinical data from several randomised clinical trials suggest that bisphosphonates may prevent not only the development of bone metastases but also extraskeletal metastases and locoregional recurrence. The mechanisms underlying these observations are uncertain but may include a silencing and suppressive effect on dormant micrometastases in the bone marrow that, with conventional therapies that only target the tumour cell, remain able to seed to extra-skeletal sites.

It seems likely that we are on the threshold of a shift in adjuvant treatment to include treatments that modify the tumour microenvironment in addition to conventional anticancer therapy. However, definitive results from the multiple large ongoing randomised trials in breast, prostate and lung cancers are required before this approach can be considered a routine standard of care.