Interplay between red blood cells and circulating tumor cells: clinical and molecular evidence of a putative pro-metastatic axis.

Recent evidence suggests that red blood cells (RBCs) may actively regulate course of tumor disease, whereas red cell distribution width (RDW) might even serve as surrogate marker of tumor progression. Here, we investigated the clinical and molecular significance of RDW in breast (BrCa) and d’Amico high-risk prostate cancer (PCa) patients. Higher RDW (RDWhigh) was associated with metastatic disease, poorer survival, therapy resistance, elevated circulating tumor cell (CTC) counts, proinflammatory mediators profiles and some comorbidities such as cardiological disorders or diabetes. Gene expression analysis of primary tumors from patients characterized by RDWhigh revealed deregulation of genes involved in inflammation, immune modulation, cell adhesion, and migration. Using imaging flow cytometry (imFC), we identified for the first time direct RBC-CTC interactions (CTCRBC) in almost 9% of PCa patients. The presence of CTCRBC correlated with lymph node involvement and shorter time-to-biochemical recurrence. Those CTCs interacting with RBCs displayed predominantly epithelial phenotype and lacked protrusions. Collectively, these results provide clinical and molecular evidence that RBCs can modulate tumor progression both indirectly, potentially through systemic inflammation, and directly, via physical interactions with CTCs. Importantly, our findings highlight the potential of RDW, a routinely measured blood parameter, as a simple and clinically meaningful biomarker of tumor progression and dissemination.