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Evolving cancer–niche interactions and therapeutic targets during bone metastasis

Nature Reviews Cancer volume 22, pages 85–101 (2022)Cite this article

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Abstract

Many cancer types metastasize to bone. This propensity may be a product of genetic traits of the primary tumour in some cancers. Upon arrival, cancer cells establish interactions with various bone-resident cells during the process of colonization. These interactions, to a large degree, dictate cancer cell fates at multiple steps of the metastatic cascade, from single cells to overt metastases. The bone microenvironment may even influence cancer cells to subsequently spread to multiple other organs. Therefore, it is imperative to spatiotemporally delineate the evolving cancer–bone crosstalk during bone colonization. In this Review, we provide a summary of the bone microenvironment and its impact on bone metastasis. On the basis of the microscopic anatomy, we tentatively define a roadmap of the journey of cancer cells through bone relative to various microenvironment components, including the potential of bone to function as a launch pad for secondary metastasis. Finally, we examine common and distinct features of bone metastasis from various cancer types. Our goal is to stimulate future studies leading to the development of a broader scope of potent therapies.

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Fig. 1: The journey of DTCs towards bone metastasis and beyond.
Fig. 2: The possible relationship between different microenvironment niches during early-stage bone metastasis.
Fig. 3: The relationship between primary tumour and the vicious cycle of late-stage bone metastasis in various cancer types.
Fig. 4: Emerging therapeutic targets in bone metastasis.

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Acknowledgements

The authors thank H. Chan and L. Michie for editing the manuscript. X.H.-F.Z. is supported by US Department of Defense DAMD W81XWH-16-1-0073, DAMD W81XWH-20-1-0375, NCI R01CA183878, NCI R01CA251950, NCI R01CA221946, NCI R01CA227904, NCI U01CA252553, Breast Cancer Research Foundation and McNair Foundation. R.L.S. is supported by US DOD KCRP W81XWH-20-1-0895, and UT MD Anderson Cancer Center Knowledge Gap Award and Institutional Research Grant.

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Authors and Affiliations

  1. Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Robert L. Satcher

  2. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Xiang H.-F. Zhang

  3. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Xiang H.-F. Zhang

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Xiang H.-F. Zhang

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  1. Robert L. Satcher
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The authors contributed equally to all aspects of the article.

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Correspondence to Xiang H.-F. Zhang.

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Glossary

Osteoblasts

Cells that are responsible for synthesis and mineralization of new bones during development and bone remodelling. They are derived from mesenchymal linage, usually localize at the surface of bone matrix and can differentiate into osteocytes.

Osteocytes

Cells that are derived from osteoblasts and become embedded in the bone matrix.

Osteoclasts

Cells that are responsible for resorption of bones. They are derived from myeloid cell lineage. Matured osteoclasts are multinuclear and function in close coordination with osteoblasts.

Mesenchymal stem cells

(MSCs). Cells that are multipotent and responsible for the production of mesenchymal cells, including osteoblasts, chondrocytes, adipocytes and fibroblasts.

Haematopoietic stem cells

(HSCs). Cells that are multipotent and responsible for production of all blood cells.

Type H capillaries

Vascular networks in the bone marrow that continue from arterioles and precede sinusoid vein vessels. They are surrounded by osteoprogenitor cells and couple osteogenesis and angiogenesis.

Type L capillaries

Sinusoid veins that continue from the H-type capillaries and converge on central vein in the medullar cavity of bone marrow.

Premetastatic niche

Potential destination of metastasis in distant organs before the actual arrival of metastatic cells. It is different from normal tissue because of interactions with bone marrow-derived cells stimulated by primary tumours.

Endosteal niche

The microenvironmental location at the endosteal surface. It is enriched with osteoblasts and osteoprogenitors as well as osteoclasts. Transplanted haematopoietic stem cells often adhere to this niche.

Epithelial-to-mesenchymal transition

(EMT). A process through which epithelial cells lose cell–cell adhesions and other epithelial traits but acquire mesenchymal characteristics, including migration and invasion. Recent studies demonstrate that EMT is a continuum and there exists a hybrid status with both epithelial and mesenchymal features. The hybrid EMT phenotype has been linked to cancer stemness, or the ability to regenerate a tumour.

Metastatic organotropism

The observations that metastasis does not occur randomly to all organs but rather preferentially affects a specific set of distant organs.

Darwinian selection

A process of evolution whereby individuals with greatest fitness among a population survive the selective pressure exerted by the environment. In cancer biology, it was adopted to understand how cancer cells with the most enabling genetic traits progress and expand over other cancer cells under the selective pressure from the microenvironment.

Perivascular niche

The microenvironmental location adjacent to a blood vessel. The components include endothelial cells, pericytes and haematopoietic stem cells. The pericytes exhibit mesenchymal stem cell activities.

Osteogenic niche

The microenvironmental locations including endosteum and trabecular bones, where osteogenesis occurs. It is enriched with osteoblasts and precursor cells. It overlaps with the endosteal niche, but also includes trabecular bones while lacking the osteoclast component by definition.

Phenotypic plasticity

The potential of a cell to alter its phenotypic characteristics in response to environmental stimuli. The ability to switch between epithelial and mesenchymal phenotypes is considered one example of phenotypic plasticity.

Osteogenesis

The process of osteoblast and osteocyte differentiation and formation of new bones.

Cabozantinib

A small-molecule inhibitor of the tyrosine kinases Met, VEGFR2, AXL and RET. It is approved to treat medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma.

Embolization

Blockade of blood vessels by an agglomeration of cancer cells or other substance.

Periostin

An extracellular matrix component encoded by the POSTN gene. It is a ligand of integrins and has important roles in the niche supporting normal and cancer stem cells.

Endothelial tip cells

Endothelial cells that sprout branches of blood vessels.

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Satcher, R.L., Zhang, X.HF. Evolving cancer–niche interactions and therapeutic targets during bone metastasis. Nat Rev Cancer 22, 85–101 (2022). https://doi.org/10.1038/s41568-021-00406-5

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