Figure 6.

Myeloid cell recruitment to circulating tumor cells (CTCs). CTCs are cancer cells that escape their primary site into the bloodstream, becoming seeds of metastasis. CTCs utilize immune cells, especially myeloid cells and platelets, to survive and disseminate into distant tissues. CTCs can express ICAM-1, and thus recruit and retain MAC-1 (αMβ2 integrin)-expressing neutrophils. Those neutrophils adhere to ICAM-1-expressing endothelium at the same time, thus guiding CTCs to extravasate into distant tissue sites. CXCL8 from CTCs help retain and activate neutrophils in CTC-neutrophil microaggregates while the neutrophils precondition endothelium for tumor cell extravasation by secreting VEGF and MMPs. Monocytes might have a similar process for CTCs to adhere to and extravasate endothelium. CTCs can interact with myeloid cells via platelets. CTC-platelet complex binds to neutrophils via the interaction between molecules on platelets and neutrophils, such as P-Selectin/PSGL-1, GPIbα/MAC-1, αIIbβ3/fibrinogen/MAC-1. Platelets further sustain the ternary complex by producing chemokines to recruit, retain, and activate neutrophils, and by facilitating coagulation in the complex. Tissue factor (TF) derived from CTCs or primary tumor sites drives the CTC-platelet-myeloid cell complex formation. Metastatic tumor cells can express VCAM-1 and tissue-resident α4β1⁺ macrophages promote survival of the VCAM-1⁺ tumor cells in the metastatic sites. Physical association of these two cells via α4β1–VCAM-1 interaction underlies the tumor cell survival. However, humans and mice have antitumoral innate immune mechanisms in blood and in the premetastatic sites to prevent tumor cell spread. Neutrophils, eosinophils, and monocytes block tumor cells in premetastatic sites by directly killing them or via recruiting cytotoxic lymphocytes and NK cells.