Metastases, rather than primary tumours, are responsible for most cancer deaths. To prevent these deaths, improved ways to treat metastatic disease are needed. Blood flow and other mechanical factors influence the delivery of cancer cells to specific organs, whereas molecular interactions between the cancer cells and the new organ influence the probability that the cells will grow there. Inhibition of the growth of metastases in secondary sites offers a promising approach for cancer therapy.

Dissemination and growth of cancer cells in metastatic sites

Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.

/pdf/microenvironmental-regulation-of-metastasis-49v9l5nr6y.pdf

Microenvironmental regulation of metastasis

Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation. In this study the physiological role of OPG is investigated by generating OPG-deficient mice. Adolescent and adult OPG-/- mice exhibit a decrease in total bone density characterized by severe trabecular and cortical bone porosity, marked thinning of the parietal bones of the skull, and a high incidence of fractures. These findings demonstrate that OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-deficient mice also exhibit medial calcification of the aorta and renal arteries, suggesting that regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.

/pdf/osteoprotegerin-deficient-mice-develop-early-onset-1ru19aan8l.pdf

osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification

Extract: Cancer frequently spreads to bone, a process termed bone metastasis. Up to 70% of patients with breast cancer or prostate cancer, and 15 to 30% of patients with lung, colon, bladder or kidney cancer develop bone metastasis. Once tumors go to bone, such as in patients with breast cancer or prostate cancer, they are incurable, and only 20% of patients with breast cancer are still alive five years after they are found to have bone metastasis. It is estimated that about 350,000 people die with bone metastasis each year in the United States. Bone metastasis causes severe bone pain and can result in fractures without any injury, as well as other life-threatening conditions. There are two major types of bone metastasis, one in which bone destruction is the predominant feature and the other one in which new bone formation is predominant. Bone metastasis where bone destruction is the predominant feature is known as osteolytic, and that in which new bone formation is the primary feature is called osteoblastic. This classification for metastasis is really two extremes of a continuum because many patients can have both osteolytic and osteoblastic or mixtures of both in their bone metastasis. In fact, patients with prostate cancer who usually have bone metastasis that shows increased new bone formation also have increased bone destruction in the same lesions.

Mechanisms of bone metastasis.

Immune evasion in cancer: Mechanistic basis and therapeutic strategies

Solid cancers metastasize to bone by a multistep process that involves interactions between tumor cells and normal host cells. Some tumors, most notably breast and prostate carcinomas, grow avidly in bone because the bone microenvironment provides a favorable soil. In the case of breast carcinoma, the final step in bone metastasis (namely bone destruction) is mediated by osteoclasts that are stimulated by local production of the tumor peptide parathyroid hormone-related peptide (PTH-rP), whereas prostate carcinomas stimulate osteoblasts to make new bone. Production of PTH-rP by breast carcinoma cells in bone is enhanced by growth factors produced as a consequence of normal bone remodeling, particularly activated transforming growth factor-beta (TGF-beta). Thus, a vicious cycle exists in bone between production by the tumor cells of mediators such as PTH-rP and subsequent production by bone of growth factors such as TGF-beta, which enhance PTH-rP production. The metastatic process can be interrupted either by neutralization of PTH-rP or by rendering the tumor cells unresponsive to TGF-beta, both of which can be accomplished experimentally. The osteoclast is another available site for therapeutic intervention in the bone metastatic process. Osteoclasts can be inhibited by drugs such as the new-generation bisphosphonates; as a consequence of this inhibition, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia. However and possibly even more importantly, there is also a reduction of tumor burden in bone. In experimental situations, this has clearly been shown to affect not only morbidity but also survival. The precise mechanism by which bisphosphonates inhibit osteoclasts is still unclear and may represent a combination of inhibition of osteoclast formation as well as increased apoptosis in mature osteoclasts. However, studies with potent bisphosphonates such as ibandronate, pamidronate, and risedronate have clearly documented that reduction of bone turnover and osteoclast activity leads to beneficial effects not only on skeletal complications associated with metastatic cancer, but also on tumor burden in bone.

Mechanisms of bone metastasis

Osteolytic and osteoblastic metastases are often the cause of considerable morbidity in patients with advanced prostate and breast carcinoma. Breast carcinoma metastasis to bone occurs because bone provides a favorable site for aggressive behavior of metastatic cancer cells. A vicious cycle arises between cancer cells and the bone microenvironment, which is mediated by the production of growth factors such as transforming growth factor beta and insulin growth factor from bone and parathyroid hormone-related protein (PTHrP) produced by tumor cells. Osteolysis and tumor cell accumulation can be interrupted by inhibiting any of these limbs of the vicious cycle. For example, bisphosphonates (e.g., pamidronate, ibandronate, risedronate, clodronate, and zoledronate) inhibit both bone lesions and tumor cell burden in bone in experimental models of breast carcinomametastasis. Neutralizing antibodies to PTHrP, which inhibit PTHrP effects on osteoclastic bone resorption, also reduce osteolytic bone lesions and tumor burden in bone. Other pharmacologic approaches to inhibit PTHrP produced by breast carcinoma cells in the bone microenvironment also produce similar beneficial effects. Identification of the molecular mechanisms responsible for osteolytic metastases is crucial in designing effective therapy for this devastating complication.

Mechanisms of osteolytic bone metastases in breast carcinoma.

Osteoporosis and periodontal disease both represent examples of abnormal bone remodeling. As knowledge of the cellular and molecular events in the normal bone remodeling process has accumulated in the last decade, better understanding of the pathophysiology of bone loss associated with periodontal disease and with aging has occurred. This short review does not attempt to include all aspects of this topic but covers specific areas in which there have been recent advances. (1) Observations made in the last few years have indicated that a hierarchy of both receptor and nonreceptor tyrosine kinases may be involved in normal osteoclastic bone resorption and that certain members of these tyrosine kinase families may mediate cytokine effects. Studies in the op/op variant of murine osteopetrosis have shown that normal production of monocyte-macrophage colony-stimulating factor 1 (M-CSF, also called CSF-1) and activation of its receptor (the receptor tyrosine kinase c-fms) are required for normal osteoclast formation. (2) Studies in mice made deficient in nonreceptor tyrosine kinase by gene knockout have shown that expression of this nonreceptor tyrosine kinase is required for normal osteoclast action and ruffled border formation, although not for osteoclast formation. (3) Recent studies have shown that in addition to prostaglandins of the E series, other arachidonic acid metabolites may be involved in normal and abnormal osteoclastic bone resorption. 5-Lipoxygenase metabolites, the leukotrienes, stimulate isolated osteoclasts to form resorption pits as well as cause osteoclastic bone resorption in organ cultures of neonatal mouse calvariae. These compounds, which are unstable in tissue culture media, are readily inhibitable by agents that inhibit 5-lipoxygenase enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokines and growth factors in the regulation of bone remodeling

BACKGROUND

The bone destruction in myeloma patients is largely responsible for the clinical features of the disease. However, only recently has attention focused on identifying and developing drugs targeted specifically at the osteolysis. Receptor activator of NF-κB ligand (RANKL), macrophage inflammatory protein (MIP)-1α, and proteasomal function have been implicated in the pathogenesis of myeloma and associated bone disease. We provide “proof of principle” in preclinical myeloma models that these are indeed valid molecular targets in development of novel therapeutics.



METHODS

The efficacy of antagonists of RANKL and MIP-1α bioactivities (RANK.Fc and neutralizing monoclonal anti-MIP-1α antibody) in ameliorating osteolysis and reducing tumor burden was evaluated in a mouse model in which murine myeloma 5TGM1 cells are injected intravenously into syngeneic mice. In addition, the activity of a petidyl aldehyde proteasome inhibitor (proteasome inhibitor-1 [PSI]) on tumor growth was tested in a murine 5TGM1 plasmacytoma model and in mice intravenously inoculated with 5TGM1 cells.



RESULTS

RANK.Fc and anti-MIP-1α antibody inhibited the development and progression of osteolytic lesions and significantly reduced tumor load assessed by serum monoclonal paraprotein titers. Intratumoral injections of PSI inhibited growth of 5TGM1 plasmacytomas and induced tumor regression in some cases. In addition, systemic administration of PSI significantly prolonged time to onset of paraplegia in tumor-bearing mice.



CONCLUSIONS

The results highlight the critical roles of RANKL and MIP-1α in the development and progression of myeloma and provide a basis for future evaluation in myeloma patients of novel therapeutics that disrupt interactions of RANKL and MIP-1α with their cognate receptors. The data also suggest that further studies in preclincal myeloma models aimed at identifying other proteasome inhibitors with antitumor efficacy would be worthwhile. Cancer 2003;97(3 Suppl):813–7. © 2003 American Cancer Society.



DOI 10.1002/cncr.11133

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.11133

Gregory R. Mundy

Papers

Mechanisms of bone metastasis

Mechanisms of osteolytic bone metastases in breast carcinoma.

Cytokines and growth factors in the regulation of bone remodeling

Receptor activator of NF-κB ligand, macrophage inflammatory protein-1α, and the proteasome: Novel therapeutic targets in myeloma