Pathogenesis of Bone Metastases: Role of Tumor‐Related Proteins

INVESTIGATIONS ON the pathogenesis of cancer metastasis to bone have received increased attention by scientists worldwide. This is good news for patients that suffer from the problematic consequences of bone metastases from breast, prostate, thyroid, kidney, or lung cancer, but it also has highlighted the complexity of the disease process and the difficulties in studying the mechanisms of metastasis to bone in vivo and in vitro. Alterations in bone morphology and function caused by metastases are the result of sequential dysregulation of multiple genes, their protein products, and their respective biological functions in both cancer cells and normal cells that interact with the cancer. Knowledge of the pathobiology of the primary tumor, its progression with time to an invasive and metastatic phenotype, vascular spread to bone, entry into the bone microenvironment, growth in bone, and alteration of bone cell function and bone morphology will be required to understand the pathogenesis of bone metastases. This scope of knowledge necessitates the collaborative efforts of scientists with expertise in cancer and bone biology. It is important that we use our current understanding of cancer and bone pathophysiology to develop an accurate picture of the roles different genes and proteins play in the pathogenesis of bone metastases. There are significant challenges to studies of bone metastasis that may represent part of the reason why this field has received relatively limited attention in the past. These include the physical difficulty of manipulating bone as a tissue, the comparative difficulty of studying bone in vitro, the complexity of obtaining antemortem samples of bone metastases from human patients, and the relative lack of animal models that effectively mimic human disease. In all of these areas, great strides have been made, but much is yet to be accomplished. For example, it has been very difficult to identify animal models that mimic the osteoblastic metastases of prostate cancer in humans. In part, this is because of the fact that bone metastases are an uncommon phenomenon in animals with spontaneous cancer in contrast to humans. Mammary neoplasia is prevalent in rodents (mice and rats) and domestic dogs and cats. If these animals develop distant metastases it is usually to the lungs, and bone metastases are rare. In the absence of spontaneous animal models, experimental animal models have been developed, such as injection of tumor cells into the left ventricles of rodents or direct injection into bone. The definition of bone metastasis can vary depending on the endpoints examined, because the pathogenesis of bone metastasis by cancer is a multistep process. This is an important concept in correlating clinical and experimental data with the overall pathogenesis of bone metastasis. For example, bone metastasis can be defined as radiographic evidence of altered bone morphology using conventional X-ray radiology. This is an easily understood definition of metastasis but represents a late stage of disease progression and likely underestimates the extent of metastatic bone disease. Scintigraphy, computed tomography, magnetic resonance imaging, and histology will show significantly greater numbers of lesions. An experimental procedure that results in reduced numbers of metastases solely based on radiological evidence can be interpreted incorrectly as reducing the actual incidence of bone metastasis. In contrast, bone metastasis may be overestimated by sensitive procedures, such as polymerase chain reaction (PCR), which can identify intravascular tumor cells or latent tumor cells in the bone marrow compartment that might not progress to form destructive bone lesions.