Bone Cancer Treatment

Osteoblasts in Prostate Cancer Metastasis to Bone

Prostate cancer is the most commonly diagnosed cancer in males and the second leading cause of death from cancer in men. Surgical and hormonal therapies have shown beneficial effects only for early-stage, hormone-responsive disease. Cancer cells that become hormone-independent also become highly invasive, and they reach a clinical stage associated with an increased incidence of skeletal metastases as the disease progresses. Most patients with advanced prostate cancer will experience complications from bone metastases that are incurable. The involvement of the skeleton by metastatic prostate cells occurs in a predictable manner, with lesions tending to appear first in the axial skeleton and subsequently in the appendicular skeleton. Owing to its effects on both haematopoiesis and bone structure, metastasis to bone is a major cause of morbidity for patients with advanced prostate cancer. Replacement of haematopoietic tissues in the bone marrow by the metastatic prostate cancer cells leads to anaemia and increases the susceptibility to infection. Bone overgrowth can lead to pain, fractures and spinal-cord compression, the latter of which can lead to HEMIPARESIS or PARESIS.

However, metastases from the relatively uncommon neuroendocrine tumours of the prostate also produce osteolytic lesions

Role of osteoblasts and osteoclasts in bone remodelling.
Bone mass is maintained by a balance between the activity of osteoblasts (right), which form bone, and osteoclasts (left), which break it down. Normally, bone formation and bone resorption are closely coupled processes involved in the normal remodelling of bone. Osteoblasts make bone by producing a matrix that then becomes mineralized. Osteoblasts also regulate osteoclast activity through expression of cytokines such as receptor activator of nuclear factor-κB ligand (RANKL), which activates osteoclast differentiation, and osteoprotegerin (OPG), which inhibits RANKL. Factors that are known to stimulate osteoblast proliferation or differentiation are bone morphogenetic protein (BMP), transforming growth factor-β (TGFβ), insulin-like growth factor (IGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and WNT. The WNT antagonist DKK blocks osteoblast proliferation. Osteoclasts are large multinucleate cells that break down bone and are responsible for bone resorption.

The classic bone-forming appearance of bone metastases from prostate cancer is apparent on both radiographical and histological analyses. Plain radiographs (X-rays) demonstrate characteristic osteoblastic lesions. Histopathological analysis of prostate cancer bone metastases typically shows substantial numbers of osteoblasts adjacent to prostate cancer cells, whereas few or no osteoblasts can be seen in normal bone or in bone metastases from other types of cancer (kidney and lung cancers, and most cases of breast cancer), which most often show osteoclasts in cancer-affected regions. The observation that prostate cancer metastasis to bone is associated with increased osteoblast activity is supported by the finding that serum levels of markers of osteoblast proliferation, such as bone-specific alkaline phosphatase, are increased in patients with metastatic prostate cancer.

A cascade of events is required for prostate cancer cells to metastasize to bone. Prostate cancer cells must first localize, or 'home', to the bone, and tumour progression then occurs there. Although the two characteristic features of metastases from prostate cancer (tropism for bone and osteoblastic lesions) were reported long ago, it has not been clear whether the bone overgrowth typical of these lesions was a mere reflection of tumour growth within the bone, or whether bone growth is an important determinant of prostate tumour progression. Recent data indicate that the ability of prostate cancer cells to induce bone formation seems to be essential for tumour progression at this site. How do the features of prostate cancer cells influence osteoblast biology, and how do these features facilitate the formation of lesions in bone