From Bone Marrow Reserve to Metastatic Niche: How Neutrophil-Lineage Cells Shape Skeletal Colonization

Area of Science:

• Oncology
• Immunology
• Skeletal Biology

Background:

• Bone metastasis involves a complex marrow ecosystem where neutrophils are generated, retained, and reprogrammed.
• Disseminated tumor cells exploit bone marrow niches, interacting with neutrophils for homing and survival.

Purpose of the Study:

• To review the multifaceted roles of neutrophils and their subsets in skeletal colonization by cancer cells.
• To discuss molecular pathways and cellular interactions linking neutrophils to bone metastasis progression and immunotherapy resistance.

Main Methods:

• Literature review focusing on neutrophil-lineage cells in bone metastasis.
• Analysis of signaling pathways (e.g., CXCR2, CXCR4/CXCL12) and cellular interactions (e.g., CTC-neutrophil clustering).
• Evaluation of evidence hierarchy and methodological limitations in current research.

Main Results:

• Neutrophils, including tumor-associated neutrophils and PMN-MDSCs, significantly influence skeletal colonization.
• Specific pathways like CXCL5/CXCR2 and CTNND1-CXCR4/CXCL12 are implicated in linking neutrophils to bone metastasis in breast and prostate cancer.
• Mechanisms like NET-mediated remodeling and immune suppression contribute to skeletal progression.

Conclusions:

• Selective reprogramming or functional inhibition of pro-metastatic neutrophils is a more promising therapeutic approach than broad neutrophil depletion.
• Understanding context-dependent neutrophil programs is crucial for developing biomarkers and combination therapies for skeletal metastases.
• Further research is needed to clarify mechanisms extrapolated from non-skeletal models.