CXCL12 restricts tumor growth by suppressing the Ras, ERK1/2, c-Myc, and the immune checkpoint PD-L1 pathways
Yelena Kravtsova-Ivantsiv1, Gilad Goldhirsh1, Aaron Ciechanover1
1The Rappaport Faculty of Medicine and Research Institute, and the Rappaport Technion Integrated Cancer Center (R-TICC), Technion-Israel Institute of Technology, Haifa 3109601, Israel.
Abstract:
Cytokines constitute a family of proteins that modulate the immune system and are secreted by many cells. CXCL12, along with its receptor CXCR4, are essential players in numerous processes. Dysregulation of their function underlie the mechanism(s) of several pathologies, including malignancies. Here, we demonstrate an unexpected effect of the cytokine and its receptor: In both cells and animal models, CXCL12 restricts tumorigenicity of the human glioblastoma cells U87-MG and U-118, and of a cell line derived from PyMT mouse breast cancer. Overexpression of CXCL12 inhibits activation of the oncogene Ras which results in downregulation of its proliferative signals, such as reduced phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2), inhibition of c-Myc expression, and subsequent inhibition of cell cycle. Furthermore, CXCL12 induces downregulation of the growth differentiation factor 15 (GDF15), insulin-like growth factor-binding protein 6 (IGFBP6), and matrix metalloproteinase-3 (MMP3), which are implicated in sending metastases. Indeed, monitoring cell migration in vitro and generation of metastases in mice demonstrate that CXCL12 slows the migration of U87-MG and PyMT cells. Remarkably, overexpression of CXCL12 also downregulates the cell surface immune checkpoint protein programmed cell death-ligand 1 (PD-L1), resulting in recruitment of cytotoxic CD8 T cells into xenografts accompanied by their shrinkage. Overall, CXCL12 inhibits tumor growth through several distinct mechanisms: inhibition of cell cycle and migration, as well as impairment of immune checkpoint, thereby stimulating a strong host's immune response. The mechanism(s) that renders CXCL12 a tumor-promoting factor in certain cells and a suppressor in others has remained elusive.
Insights
CXCL12, a cytokine, unexpectedly restricts glioblastoma and breast cancer tumor growth by inhibiting cell proliferation, migration, and immune evasion. This discovery offers new insights into cancer therapy strategies.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Cytokines, including CXCL12 and its receptor CXCR4, are crucial immune modulators.
- Dysregulation of CXCL12/CXCR4 signaling is implicated in various pathologies, notably malignancies.
- The precise role of CXCL12 in cancer remains complex, with context-dependent tumor-promoting or suppressing effects.
Purpose of the Study:
- To investigate the unexpected tumor-restricting effects of CXCL12 in glioblastoma and breast cancer models.
- To elucidate the molecular mechanisms underlying CXCL12-mediated tumor suppression.
- To evaluate the impact of CXCL12 on tumor cell proliferation, migration, and immune response.
Main Methods:
- Overexpression of CXCL12 in human glioblastoma (U87-MG, U-118) and PyMT mouse breast cancer cell lines.
- Assessment of oncogene Ras activation and downstream proliferative signals (ERK1/2, c-Myc).
- Analysis of cell cycle progression, cell migration in vitro, and metastasis formation in vivo.
- Evaluation of immune checkpoint protein programmed cell death-ligand 1 (PD-L1) expression and CD8 T cell infiltration.
Main Results:
- CXCL12 overexpression inhibited Ras activation, leading to reduced ERK1/2 phosphorylation and c-Myc expression, thereby inhibiting cell cycle progression.
- CXCL12 downregulated GDF15, IGFBP6, and MMP3, factors associated with metastasis.
- CXCL12 significantly slowed tumor cell migration in vitro and reduced metastasis in vivo.
- Overexpression of CXCL12 downregulated PD-L1, enhancing CD8 T cell recruitment and leading to xenograft shrinkage.
Conclusions:
- CXCL12 acts as a tumor suppressor by inhibiting cell cycle, reducing migration, and enhancing anti-tumor immunity through PD-L1 downregulation.
- CXCL12 stimulates a potent host immune response against tumors.
- The dual role of CXCL12 as a tumor promoter or suppressor highlights the complexity of targeting this pathway in cancer therapy.
More Related Videos
Related Concept Videos
02:23Abnormal Proliferation
02:34Inhibition of Cdk Activity
02:38Mitogens and the Cell Cycle
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:38The Ras Gene
Ras is a...