Elsevier

Joint Bone Spine

Volume 84, Issue 6, December 2017, Pages 677-684
Joint Bone Spine

Review
Pathophysiology of bone metastases from solid malignancies

https://doi.org/10.1016/j.jbspin.2017.05.006Get rights and content

Abstract

Bone metastases are common complications of many cancers. Among the mechanisms that set the scene for the development of bone metastases, several are shared by all forms of metastatic dissemination (pre-metastatic niche formation and chemotactic attraction of malignant cells, which invade the host tissue) and others are specific of bone tissue (homing of malignant cells to bone marrow niches and acquisition of an osteomimetic cell phenotype). After a latency period that can last several years, the malignant cells can proliferate into tumors that alter the normal bone remodeling process by inducing dysregulation of osteoblast and osteoclast function. These metastases may be lytic, characterized by major bone destruction; sclerotic, with excess bone formation; or mixed. Osteolysis occurs when the tumor cells stimulate osteoclast activity and inhibit osteoblast activity, whereas the opposite effects lead to bone sclerosis. Moreover, the mineralized bone matrix plays a major role in the formation of bone metastases, as its degradation releases growth factors and calcium that exert mitogenic effects on tumor cells. Thus, bone metastases are the site of a vicious circle in which mechanisms involved in bone resorption/formation promote tumor growth and vice versa.

Introduction

The dissemination of malignant cells from the primary tumor to other sites involves a sequence of highly selective steps known as the metastatic cascade [1]. It has been estimated that only 0.02% of malignant cells entering the bloodstream produce clinically detectable metastases [2]. The metastatic cascade starts with the release of malignant cells by the primary tumor. These cells then invade the adjacent healthy tissue and enter the bloodstream by crossing the basal membrane of blood vessels or lymphatics (intravasation) [1]. The malignant cells must then exit the vessels (extravasation) and colonize a new organ at a distance from the primary tumor, where they proliferate into a metastasis (secondary tumor) [1]. Malignant cells colonizing new organs may remain dormant for months or years before starting to proliferate [3]. Colonization of organs by malignant cells occurs, not at random, but according to the seed and soil theory first put forward in 1889 by the British surgeon Stephen Paget [4]. This theory holds that malignant cells (seed) can colonize an organ only if the microenvironment (soil) is conducive to their implantation. The seed and soil theory has been validated by numerous studies demonstrating that the sites of metastases (e.g., bone, liver, lungs, or brain) vary with the site of the primary tumor (Fig. 1) [5], [6]. For instance, metastases to the bone are common complications of breast, prostate, and lung cancer (Fig. 1). The development of bone metastases adversely affects survival and quality of life.

Here, we describe the molecular mechanisms that allow malignant cells to colonize the bone marrow, where they may either remain dormant or proliferate. Proliferation of the malignant cells leads to alterations in bone turnover and subsequently to bone destruction, which is responsible for a high burden of morbidity (bone pain, pathological fractures, neurological compromise, and hypercalcemia).

Section snippets

Factors involved in metastatic niche formation

Studies in experimental animals suggest that, even before becoming clinically detectable, primary tumors release soluble factors into the bloodstream that prepare the soil in which disseminating cells may subsequently grow into metastases. Among these soluble factors, exosomes play a prominent role. Exosomes are secreted by cells as small vesicles about 100 nm in diameter [7]. They are surrounded by a membrane that exhibits the same orientation as the cell membrane, with a few nanoliters of

Mechanisms associated with tumor cell homing to the osteogenic niche

Osteogenic niches are anatomical structures found in the bone marrow in contact with bone. They maintain hematopoietic stem cells in a dormant state via heterotypic cell-cell interactions with pre-osteoblasts. Receptors and their ligands potentially involved in these interactions include CXCR-4/CXCL-12 (pre-osteoblasts express the ligand and hematopoietic stem cells the chemoreceptor). Therefore, tumor cells that express CXCR4 compete with hematopoietic stem cells for space within the

Mechanisms associated with adaptation of metastatic cells to the bone microenvironment

Tumor cells disseminated to the bone marrow and located in the pre-metastatic and/or osteogenic niches must adapt to the bone microenvironment. This requirement probably explains why tumor cells from some types of cancer become dormant after colonizing the bone marrow. To adapt to the bone microenvironment, the tumor cells must express genes normally expressed by bone cells. This process, known as osteomimicry, allows tumor cells to proliferate within the bone microenvironment.

Mechanisms responsible for the formation of osteolytic metastatic lesions

Bone metastases are very often osteolytic, i.e., associated with the destruction of a large amount of bone (Fig. 4). The tumor cells release various factors that alter bone remodeling by stimulating osteoclast function and inhibiting osteoblast function.

Mechanisms responsible for the formation of sclerotic (blastic) bone metastases

Some bone metastases are sclerotic, due to the production of excess bone, or mixed (Fig. 4). Bone sclerosis occurs when tumor cells release factors capable of inhibiting osteoclast function and stimulating osteoblast function.

Contribution of tumor angiogenesis to the progression of bone metastases

The contribution of tumor blood vessels to the progression of metastases is less well known for the bone than for other tissues. In general, when the normal vascular supply to a tissue is no longer sufficient to meet the nutrient and oxygen needs of the tumor, activation of hypoxia-inducible factor (HIF) in the tumor cells occurs and stimulates the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), platelet-derived growth

Conclusion and prospects

Recent research has explained why some cancers preferentially metastasize to bone and induce either osteolytic or sclerotic bone metastases. The new data highlight the major role played by the bone tissue in providing a haven (niches) for metastatic cells, where they can adapt to the bone microenvironment (osteomimicry) and proliferate. Pathophysiological observations indicating a key contribution of osteoclasts in osteolysis have led to the use of bisphosphonates (which inhibit bone

Disclosure of interest

The author declares that he has no competing interest.

Acknowledgments

I am grateful to the Inserm and Claude-Bernard Lyon-1 University for their support.

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