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. 2022 Nov 22;14(23):5727. doi: 10.3390/cancers14235727

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© 2022 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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Interactions of tumor cells with the bone microenvironment. (A). Tumor cells in the bone microenvironment secrete tumor-related factors to act on osteoblasts, and the interaction of RANKL produced by osteoblasts with RANK expressed on osteoclasts stimulates osteoclast maturation and differentiation, leading to metastatic bone destruction. Bone resorption results in the release of various growth factors, such as TGF-β, IGFs, FGFs, PDGF, and BMPs, as well as Ca²⁺, which further promote the growth of tumor cells and form a vicious cycle of tumor growth–bone destruction. (B). A broader conception of this vicious cycle is the interactions between tumor cells and multiple cells in the bone microenvironment, which jointly participate in osteolytic bone destruction: mesenchymal skeletal stem cells (MSCs) produce osteoblasts, stromal cells, fibroblasts, and adipocytes; MSCs also promote the expansion and homing of hematopoietic stem cells (HSCs). Hematopoietic stem and progenitor cells (HSPCs) produce CD8+ T cells, CD4+ T cells, MDSCs, macrophages, and osteoclasts. CD8+ T cells directly kill recognized tumor cells and inhibit tumor growth. CD4+ T cells inhibit immune functions. MDSCs exert an immunosuppressive effect through the actions of a variety of tumor derived factors, such as VEGF, TGF-β, and PGE2, and differentiate into osteoclasts. Macrophages interact with tumor cells and differentiate into osteoclasts. VEGF is produced by tumor cells or endothelial cells upon tumor stimulation, to form a new blood supply that promotes tumor growth and reproduction. The ECM contains various growth factors, such as TGF-β and IGFs, which are released as a result of osteoclast resorption, to regulate the growth of tumor cells. PTHrP = parathyroid hormone-related peptide; IL-6 = interleukin-6; IL-8 = interleukin-8; IL-11 = interleukin-11; PGE2 = prostaglandin E2; TNF = tumor necrosis factor; TGF-β = transforming growth factor beta; IGFs = insulin-like growth factors; FGFs = fibroblast growth factors; PDGF = platelet-derived growth factor; BMPs = bone morphogenetic proteins; VEGF = vascular endothelial growth factor; ECM = extracellular matrix.

Interactions of tumor cells with the bone microenvironment. (A). Tumor cells in the bone microenvironment secrete tumor-related factors to act on osteoblasts, and the interaction of RANKL produced by osteoblasts with RANK expressed on osteoclasts stimulates osteoclast maturation and differentiation, leading to metastatic bone destruction. Bone resorption results in the release of various growth factors, such as TGF-β, IGFs, FGFs, PDGF, and BMPs, as well as Ca²⁺, which further promote the growth of tumor cells and form a vicious cycle of tumor growth–bone destruction. (B). A broader conception of this vicious cycle is the interactions between tumor cells and multiple cells in the bone microenvironment, which jointly participate in osteolytic bone destruction: mesenchymal skeletal stem cells (MSCs) produce osteoblasts, stromal cells, fibroblasts, and adipocytes; MSCs also promote the expansion and homing of hematopoietic stem cells (HSCs). Hematopoietic stem and progenitor cells (HSPCs) produce CD8+ T cells, CD4+ T cells, MDSCs, macrophages, and osteoclasts. CD8+ T cells directly kill recognized tumor cells and inhibit tumor growth. CD4+ T cells inhibit immune functions. MDSCs exert an immunosuppressive effect through the actions of a variety of tumor derived factors, such as VEGF, TGF-β, and PGE2, and differentiate into osteoclasts. Macrophages interact with tumor cells and differentiate into osteoclasts. VEGF is produced by tumor cells or endothelial cells upon tumor stimulation, to form a new blood supply that promotes tumor growth and reproduction. The ECM contains various growth factors, such as TGF-β and IGFs, which are released as a result of osteoclast resorption, to regulate the growth of tumor cells. PTHrP = parathyroid hormone-related peptide; IL-6 = interleukin-6; IL-8 = interleukin-8; IL-11 = interleukin-11; PGE2 = prostaglandin E2; TNF = tumor necrosis factor; TGF-β = transforming growth factor beta; IGFs = insulin-like growth factors; FGFs = fibroblast growth factors; PDGF = platelet-derived growth factor; BMPs = bone morphogenetic proteins; VEGF = vascular endothelial growth factor; ECM = extracellular matrix.