Biology of osteoclast activation in cancer

Bone is a frequent site of cancer metastasis. Bone metastases can result in bone destruction or new bone formation. Bone destruction is mediated by fa ctors produced or induced by tumor cells that stimulate formation and activ ation of osteoclasts, the normal bone-resorbing cells. Local bone destructi on also occurs in patients with osteoblastic metastases and may precede or occur simultaneously with increased bone formation. Several factors, includ ing interleukin IL-6, receptor activator of NF-kappaB (RANK) ligand, parath yroid hormone-related protein (PTHrP), and macrophage inflammatory protein- l-alpha (MIP-1 alpha), have been implicated as factors that enhance osteocl ast formation and bone destruction in patients with neoplasia. PTHrP seems to be the major factor produced by breast cancer cells that induces osteocl ast formation through upregulation of RANK ligand. Enhanced RANK ligand exp ression also plays an important role in bone destruction in patients with m yeloma. RANK ligand can act to enhance the effects of other factors produce d by myeloma cells or in response to myeloma cells, such as MIP-1 alpha and /or IL-6, to induce osteoclast formation. Understanding of the molecular me chanisms responsible for osteoclast activation in osteolytic metastases sho uld lead to development of novel therapeutic approaches for this highly mor bid and potentially fatal complication of cancer.