Neutrophil Cyto‐Pharmaceuticals Suppressing Tumor Metastasis via Inhibiting Hypoxia‐Inducible Factor‐1α in Circulating Breast Cancer Cells

Abstract

Circulating tumor cells (CTCs) are reported as the precursor of tumor metastases, implying that stifling CTCs would be beneficial for metastasis prevention. However, challenges remain for the application of therapies that aim at CTCs due to lack of effective CTC-targeting strategy and sensitive therapeutic agents. Herein, a general CTC-intervention strategy based on neutrophil cyto-pharmaceuticals is proposed for suppressing CTC colonization and metastasis formation. Breast cancer 4T1 cells are infused as the mimic CTCs, and 4T1 cells trapped are first elucidated in neutrophil extracellular traps (NETs) expressing high levels of hypoxia-inducible factor-1𝜶 (HIF-1𝜶) due to NET formation and thus promoting tumor cell colonization through enhanced migration, invasion and stemness. After verifying HIF-1𝜶 as a potential target for metastasis prevention, living neutrophil cyto-pharmaceuticals (CytPNEs) loaded with HIF-1𝜶 inhibitor are fabricated to therapeutically inhibit HIF-1𝜶. It is demonstrated that CytPNEs can specially convey the HIF-1𝜶 inhibitor to 4T1 cells according to the inflammatory chemotaxis of neutrophils and down-regulate HIF-1𝜶, thereby inhibiting metastasis and prolonging the median survival of mice bearing breast cancer lung metastasis. The research offers a new perspective for understanding the mechanism of CTC colonization, and puts forward the strategy of targeted intervention of CTCs as a meaningful treatment for tumor metastasis.

Roles of mitochondrial fusion and fission in breast cancer progression: a systematic review

“…Hypoxia is a typical feature of the microenvironment of solid tumors, as well as a significant activator of migration and invasion. Hypoxia has been shown to affect cellular activity by stabilizing HIF-1α and HIF-1α, which are linked to distant metastasis and a poor prognosis, and upregulation is more common in breast cancer metastases than in the initial tumor [ 61 ]. Han et al found that the expression of Drp1 was higher in metastatic MDA-MB-231 cells than in non-metastatic MCF-7 cells and hypoxia further increased Drp1 expression and induced mitochondrial fission in MDA-MB-231 cells but not in MCF-7 cells.…”

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

“…Downregulation of neutrophil HIF-1α can effectively inhibit NET-mediated circulating tumor cell (CTC) metastasis and prolong the median survival of mice with breast cancer lung metastasis. 321 However, some experiments have shown the anticancer effects of NK cells. Hypoxia favors neutrophil viability and function.…”

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

“…HIF-1α inhibitor-loaded living neutrophil cytopharmaceuticals (Cy-tPNEs) were developed to block HIF-1α, thereby inhibiting metastasis and prolonging the median survival. 295 Numerous genes are involved in the control of HIF-1, which has significant effects. 296 To accommodate for tumor hypoxia, the downstream HIF-1α synthesis is advanced by the phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR.…”