Circulating cancer-associated macrophage-like cells and macrophage-related cytokines in obese patients with advanced breast cancer who undergo neoadjuvant chemotherapy

Abstract

Purpose: Cancer-associated macrophage-like cells (CAMLs) are rare, gigantic, and atypical circulating cells found exclusively in the peripheral blood of patients with solid cancers. Obesity-induced hypoxia attracts macrophages to the tumor microenvironment, where they contribute to establishing chronic inflammation, leading to cancer progression. We hypothesized that obese patients with advanced breast cancer may have CAML profiles different from those of nonobese patients, and these profiles may correlate with proinflammatory markers or other macrophage-related markers. Methods: We prospectively collected 20 mL of peripheral blood from patients diagnosed with stage 2-4 breast cancer. We identified CAMLs using the CellSieve microfiltration system and in parallel quantified the proinflammatory and macrophage-related markers using a multiplex cytokine panel. We further evaluated C-X-C chemokine receptor type 4 (CXCR4) expression in CAMLs to investigate its relationship to the macrophage differentiation. We estimated the association between CAML characteristics and body mass index (BMI), body composition, and cytokines/chemokines. Results: Thirty patients were included in the study, and 28 samples were analyzed. Higher BMI was significantly correlated with the increased maximum CAML size (P = 0.035). Patients with higher BMIs had significantly increased macrophage-colony stimulating factor (M-CSF) levels in plasma (P = 0.007), and obese patients trended towards higher tumor necrosis factor-alpha, MIP-1α and M-CSF expression (P <0.10). Body composition analysis showed that the M-CSF and SAT amounts were significantly correlated (P = 0.010). MIP-1α expression was significantly correlated with average CXCR4 CAML expression (P = 0.003). Conclusion: We discovered larger CAML size was associated with SAT-dominant obesity with increased macrophage-related and proinflammatory markers in obese than in nonobese breast cancer patients.

Keywords: breast neoplasm; inflammation; macrophages; neoadjuvant therapy; obesity.