Ischemic Injury Drives Tumor Growth via Accelerated Hematopoietic Aging

Area of Science:

• Immunology
• Oncology
• Hematology

Background:

• Peripheral artery disease (PAD) is linked to increased cancer risk.
• Aging-related changes in hematopoietic stem and progenitor cells (HSPCs) contribute to cardiovascular disease (CVD) and cancer.
• The role of altered hematopoiesis in CVD-driven tumor progression remains unclear.

Purpose of the Study:

• Investigate cancer growth after peripheral ischemia.
• Analyze HSPC bone marrow compartment changes.
• Uncover mechanisms linking altered hematopoiesis to oncogenesis.

Main Methods:

• Monitor mammary cancer cell growth in mice post-hind limb ischemia (HLI) or sham surgery.
• Assess tumor immune microenvironment, circulatory immune cells, and HSPC compartment via flow cytometry.
• Perform single-cell RNA and ATAC sequencing on HSPCs; conduct bone marrow transplantation.

Main Results:

• HLI increased monocyte/neutrophil output, decreasing lymphocytes, driven by myeloid-biased HSCs.
• Accelerated breast cancer growth and increased immunosuppressive cells (Tregs, monocytes) observed.
• Multiomic analyses revealed HLI-induced inflammatory and aging signatures in progenitors; effects were transmissible via bone marrow transplantation.

Conclusions:

• Peripheral ischemia promotes HSC inflammaging and lasting anti-tumoral immunity alterations.
• This process accelerates breast tumor growth.
• Long-term reprogramming of innate immune responses contributes to accelerated oncogenesis.