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Review
. 2023 Apr 21;11(1):21.
doi: 10.1038/s41413-023-00260-1.

Bone serves as a transfer station for secondary dissemination of breast cancer

Yufan Huang  1   2   3 , Hongli Wang  1   2   3 , Xiaomin Yue  1   2   3 , Xiaoqing Li  4   5   6
Affiliations
Review

Bone serves as a transfer station for secondary dissemination of breast cancer

Yufan Huang et al. Bone Res. .

Abstract

Metastasis is responsible for the majority of deaths among breast cancer patients. Although parallel polyclonal seeding has been shown to contribute to organ-specific metastasis, in the past decade, horizontal cross-metastatic seeding (metastasis-to-metastasis spreading) has also been demonstrated as a pattern of distant metastasis to multiple sites. Bone, as the most frequent first destination of breast cancer metastasis, has been demonstrated to facilitate the secondary dissemination of breast cancer cells. In this review, we summarize the clinical and experimental evidence that bone is a transfer station for the secondary dissemination of breast cancer. We also discuss the regulatory mechanisms of the bone microenvironment in secondary seeding of breast cancer, focusing on stemness regulation, quiescence-proliferation equilibrium regulation, epigenetic reprogramming and immune escape of cancer cells. Furthermore, we highlight future research perspectives and strategies for preventing secondary dissemination from bone.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Model of breast cancer cell (BCC) dissemination. a Parallel polyclonal model supposing that multiple distant metastases originate from polyclonal organ-specific primary breast cancer cells due to the heterogeneity of cancer cells. b–f Bone is supposed to be a horizontal cross-metastatic transfer station for secondary dissemination of breast cancer. The perivascular niche (b), mesenchymal stem cells (c), osteogenic niche (d), osteoclasts (e), adipocyte niche (f) and hypoxic state (g) have been considered to regulate the quiescence-proliferation equilibrium by increasing cancer cell stemness, regulating specific signaling pathways and facilitating epigenetic reprogramming. BCC breast cancer cell, JAG1 jagged 1, ZEB1 zinc finger E-box binding homeobox 1, CXCR4 C-X-C chemokine receptor type 4, SDF1 stromal cell-derived factor 1, TGFB transforming growth factor beta, POSTN periostin, TSP1 endothelial-derived thrombospondin 1, MSCs mesenchymal stem cells, EV extracellular vesicle, CX43 connexin 43, FGF fibroblast growth factor, PDGF platelet-derived growth factor, EZH2 enhancer of zeste homolog 2, GJ gap junction, hAJ heterotypic adherens junction, VCAM1 vascular cell adhesion molecule 1, ITGA4B1 integrin α4β1, RANKL nuclear factor-κB ligand, PTHrP parathyroid hormone-related protein, M-CSF macrophage colony stimulating factors, TNF tumor necrosis factors, IL interleukin, BMP bone morphogenetic protein. This figure was created using the BioRender website
Fig. 2
Fig. 2
The bone marrow microenvironment facilitates disseminated tumor cell (DTC) escape from immune surveillance. a Breast cancer cell (BCC)-derived colony-stimulating factors (CSFs) and cytokines (CKs) induce the rapid generation of myeloid-derived suppressor cells (MDSCs) from hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in bone marrow. Monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) suppress T lymphocyte (T cell) activity. b Silencing of the interferon regulatory factor 7 (IRF7) pathway in breast cancer cells, reducing interferons (IFNs), restricts immunosurveillance by selective modulation of MDSCs and natural killer (NK) effectors in the bone marrow. c Tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced erythroid precursor (EPC)-differentiated myeloid cells (EDMCs) mediate immunosuppression for cancer cells to escape surveillance. d Jagged 1 (JAG1)-overexpressing BCCs increase the secretion of interleukin-6 (IL6) and WNT1-inducible signaling pathway protein 1 (WISP1), helping to recruit macrophages (Mϕs). Recruited Mϕs are activated in the NOTCH pathway and increase the secretion of CD14 and CD93 to inhibit CD8+ T-cell activation and decrease the cytotoxic killing of tumor cells. e Latency competent cancer (LCC) cells, including disseminated tumor cells (DTCs) in bone marrow, escape NK cell-mediated clearance by inhibition of the WNT pathway and downregulation of UL16-binding protein (ULBP) ligands. This figure was created using the BioRender website
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