br Introduction Once metastatic breast cancer cells

Introduction Once metastatic breast cancer NVP 231 are in the bone marrow, they hijack signals coming from the normal bone remodelling process and promote bone degradation [1]. Bone degradation is caused by osteoclasts, which have the unique property to dissolve bone mineral and degrade the bone matrix. These features make them a predominant actor in bone metastasis formation. This review describes how osteoclasts contribute to bone degradation and skeletal tumour growth.
Bone physiology
Osteolytic bone metastasis: the “Vicious Cycle” Once metastatic cancer cells colonize bone, they do not, on their own, destroy bone. They interact with osteoblasts, the normal bone-forming cells, and osteoclasts to induce massive bone degradation. In turn, bone-derived growth factors and calcium released from resorbed bone stimulate skeletal tumour growth. This relationship between bone resorption and tumour growth is called the “vicious cycle” (Fig. 1). This is the reason why anti-resorptive drugs such as bisphosphonates and denosumab, a human monoclonal antibody directed against RANKL, are used in clinic, as palliative treatment, to interfere with this vicious cycle [8].
Conclusion
Is there a role for systemic factors in formation of pre-metastatic niches in the bone? Bone is a common site for metastatic spread of solid tumors, particularly for patients with metastatic breast and prostate cancers [1]. Here, we specifically focus on the factors impacting the bone microenvironment that thereby influence bone metastasis, which is the cause of significant patient mortality and morbidity and is currently incurable. At present, very little is known about systemic processes that influence bone metastasis. Increasingly, efforts are being directed toward this area of investigation with the notion that a better understanding of systemic processes that influence bone metastasis should aid discovery of therapeutic approaches that aim to eradicate or reduce disease burden in the bone. Results from studies using pre-clinical metastasis models have revealed that primary tumor-derived circulating factors can affect various tissue microenvironments, even in the absence of observable metastases to those tissues, to make them a more hospitable environment for seeding and colonization of tumor cells that eventually disseminate from the primary tumor [2,3]. This process was termed “pre-metastatic niche” formation and most of what is known in this regard was gleaned from pre-clinical studies of lung metastasis. Much less is known about cancer-derived circulating factors that establish pre-metastatic niches in the bone. On one hand, the paucity of information may be due to the fact that there are very few bone metastasis models currently available to researchers. On the other hand, the bone microenvironment may inherently provide a favorable environment for disseminated tumor cells, thus eliminating the need for pre-metastatic modulation. The fact that disseminated tumor cells are frequently detected in bone marrow aspirates of cancer patients who are tested in this manner [4] favors the idea that disseminating tumor cells find a ready-made niche in the bone microenvironment. Traditionally, bone metastatic niches have been defined as microdomains within the bone that support tumor cell seeding and outgrowth via paracrine interactions, and can be comprised of hematopoietic cells, a variety of mesenchymal stromal cells, osteoblasts, osteoclasts, and/or vascular cells [1] (Fig. 1). Within these microdomains, a number of chemokines and integrins that are endogenously expressed by various bone stromal cells to regulate mobilization and homing of hematopoietic cells are also thought to aid tumor cell recruitment to bone [1]. For example, bone stroma derived CXCL12 (SDF-1α) has been demonstrated to recruit CXCR4-expressing neuroblastoma cells [5]. Likewise, differentiating osteoclasts secrete CCL22, which was shown to promote bone metastasis of CCR4-expressing breast cancer cells [6]. Additionally, osteoblasts express a number of factors, including CCL12, which has been correlated with increased tropism of CCR7-expressing metastatic breast cancer cells [7].