Bone Microenvironment and Osteosarcoma Metastasis

Abstract

The bone microenvironment is an ideal fertile soil for both primary and secondary tumors to seed. The occurrence and development of osteosarcoma, as a primary bone tumor, is closely related to the bone microenvironment. Especially, the metastasis of osteosarcoma is the remaining challenge of therapy and poor prognosis. Increasing evidence focuses on the relationship between the bone microenvironment and osteosarcoma metastasis. Many elements exist in the bone microenvironment, such as acids, hypoxia, and chemokines, which have been verified to affect the progression and malignance of osteosarcoma through various signaling pathways. We thoroughly summarized all these regulators in the bone microenvironment and the transmission cascades, accordingly, attempting to furnish hints for inhibiting osteosarcoma metastasis via the amelioration of the bone microenvironment. In addition, analysis of the cross-talk between the bone microenvironment and osteosarcoma will help us to deeply understand the development of osteosarcoma. The cellular and molecular protagonists presented in the bone microenvironment promoting osteosarcoma metastasis will accelerate the exploration of novel therapeutic strategies towards osteosarcoma.

Keywords: bone microenvironment; metastasis; osteosarcoma; primary bone tumor; signal pathway.

Figure 1

Schematic diagram of the cross-talk between MSCs and OS cells in the bone microenvironment. MSCs directly secrete some factors or choose the extracellular vesicles as the carrier to transport miRNAs, growth factor, lipids, glutamate, lactase, which promote OS metastasis. Meanwhile, OS utilizes the acidic environment, hypoxia and extracellular vesicles inducing the MSCs secreting cell factors to facilitate their own growth and metastasis, like IL-8, IL-6, RelA, RelB, NF-κB1, CSF2/GM-CSF, CSF3/G-CSF, BMP2, CCL5, CXCL5, CXCL1. In addition, OS via secreted MCP-1, GRO-α, and TGF-β induces MSCs trans-differentiating the cancer-associated stem cells to express more MCP-1. GRO-α, IL-6, and IL-8 promote the MAT of OS. The solid arrows refer to the direction of the cell or factor from the MSCs. The dotted arrows refer to the direction of cells and factors from OS.

Figure 2

The PI3K/Akt signaling pathway converges to facilitate the progression OS. Most factors directly activate PI3K/Akt signaling pathway to promote the migration and invasion of OS. For example, overexpression of Fibulin-4, Fractalkine/CX3CR1, ZIC2, LINC0096, and lncRNA H19 promote the osteosarcoma metastasis through the activation of PI3K/Akt signal pathway. Meanwhile, GPNMB and DANCR/miR-33a-5p activate the PI3K/Akt pathway by promoting the expression of IGF-1 and AX, respectively. TSSC3 inhibits the phosphorylation of Src to activate the PI3K/Akt signaling pathway. Conversely, overexpression of LINC00628 inhibits the phosphorylation of PI3K and Akt. The solid lines refer to protein molecules and the dotted lines refer to non-coding RNAs in this figure. Black arrows show the promotion of molecules, while red dots show the inhibition of molecules.