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. 2021 Dec 10;11:780264. doi: 10.3389/fonc.2021.780264

Figure 3.

Figure 3

The role of osteoclast and CXCR/CXCL axis in OS metastasis. (A) Highly expressed CXCL12. The CXCR4/CXCL12 (SDF-1) interaction is critical for OS metastasis in the lung, which is further strengthened by MSC via secreting VEGF. MSC-derived IL-8 induces OS cell anoikis resistance by activating CXCR1/Akt signaling. Another receptor CXCR7 expressed on OS cells promotes lung metastasis and enhances the malignancy activity of CXCR4. (B) RANK-Fc binds to RANK as a potent RANKL antagonist to inhibit osteoclast formation and activity, which can reduce OS metastasis, partly by suppressing ERK. Controversially, metastasis-competent OS cells induce loss of ACP5+ osteoclasts, which in turn enhances metastasis. Herein, we used dotted lines to indicate this contradiction. VEGF exhibits prometastatic effects on OS cells while PEDF shows the opposite by regulating angiogenesis. (C) In primary bone site, OS epigenetically downregulates CXCL12 expression by DNMT1, impairs cytotoxic T-cell homing to the tumor site, and this chemokine gradient of CXCL12 drives the metastasis of OS cells to the lung. ACP5/TRAP, osteoclast-specific tartrate-resistant acid phosphatase 5; PEDF, pigment epithelium-derived factor; YY1, Yin Yang 1 protein; CXCL12, C–X–C motif chemokine 12; DNMT1, DNA methyltransferase 1; CXCR4, chemokine receptor 4; AMD3100, CXCR4 antagonist.