ReviewPathophysiology of bone metastases from solid malignancies
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.
References (41)
- et al.
Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases
Am J Pathol
(1998) The distribution of secondary growths in cancer of the breast
Lancet
(1889)- et al.
Metastatic stem cells: sources, niches, and vital pathways
Cell Stem Cell
(2014) - et al.
Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase
J Biol Chem
(2010) - et al.
The calcium-sensing receptor and the hallmarks of cancer
Biochim Biophys Acta
(2016) - et al.
A perspective on cancer cell metastasis
Science
(2011) - et al.
Mechanisms of disseminated cancer cell dormancy: an awakening field
Nat Rev Cancer
(2014) - et al.
Metastasis: from dissemination to organ-specific colonization
Nat Rev Cancer
(2009) - et al.
The landscape of metastatic progression patterns across major human cancers
Oncotarget
(2015) - et al.
Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials
Biochem Biophys Acta
(2013)
Tumour exosome integrins determine organotropic metastasis
Nature
S100 proteins in cancer
Nat Rev Cancer
Cancer and the chemokine network
Nat Rev Cancer
Involvement of chemokine receptors in breast cancer metastasis
Nature
Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone
Cancer Res
Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo
J Bone Min Res
CXCL10 promotes osteolytic bone metastasis by enhancing cancer outgrowth and osteoclastogenesis
Cancer Res
CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration, and survival of human prostate cancer cells
Cancer Res
Cancer to bone: a fatal attraction
Nat Rev Cancer
Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab
Nat Rev Drug Discov
Cited by (36)
Targeting bone microenvironments for treatment and early detection of cancer bone metastatic niches
2022, Journal of Controlled ReleaseCitation Excerpt :Osteoclasts are abnormally activated because they are regulated by transforming growth factor (TGF) and growth factors secreted by tumor cells, which can cause massive bone damage or bone loss and form a microenvironment conducive to tumor survival. Therefore, tumor cell proliferation can be indirectly inhibited by inhibiting osteoclast activity and restoring the balance between osteoclasts and osteoblasts [92]. For example, bisphosphonates are potent inhibitors of osteoclast activity.
Diagnostic and Interventional Radiology Considerations in Metastatic Bone Disease
2021, Operative Techniques in OrthopaedicsCitation Excerpt :It has been estimated that up to 17% of healthcare spending in oncology is driven by skeletal metastases,7 and as newer therapies emerge that enable longer patient survival, addressing the challenges posed by skeletal metastases will require the collaboration of a multidisciplinary team. Various structural and biochemical elements are involved in establishing osseous metastases; among the earliest factors in creating a premetastatic niche are exosomes secreted by the primary tumor that promote inflammatory changes in distant tissues, and chemokines like CXCL-10 and CXCL-12 that have been implicated in the migration of breast, prostate, and melanoma metastases to bone.8 Receptor activator of NF-κB (RANK) ligand, via interactions with its membrane receptor RANK that is expressed by osteoclasts and several cancers (breast, prostate, and lung), may also play a role in recruiting tumor cells to bone.8,9
Systemic Treatment of Bone Disease in Metastatic Urinary Malignancies
2020, European Urology FocusBone metastases from lung cancer: A paradigm for multidisciplinary onco-rheumatology management
2019, Revue du Rhumatisme (Edition Francaise)Conditional knockout of PDK1 in osteoclasts suppressed osteoclastogenesis and ameliorated prostate cancer-induced osteolysis in murine model
2023, European Journal of Medical Research