Abstract
The accumulation of tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is associated with malignant progression in cancer. However, the mechanisms by which the hypoxic TME facilitates TAM infiltration are not fully understood. This study showed that high ZEB1 expression in hypoxic cervical cancer cell islets was positively correlated with CD163+ TAM accumulation. ZEB1 in hypoxic cancer cells promoted the migration of TAMs in vitro and altered the expression of multiple chemokines, especially CCL8. Mechanistically, hypoxia-induced ZEB1 activated the transcription of CCL8, which attracted macrophages via the CCR2–NF-κB pathway. Furthermore, ZEB1 and CCL8 were independent prognostic factors in cervical cancer patients based on The Cancer Genome Atlas (TCGA) data analysis. In conclusion, hypoxia-induced ZEB1 exerts unexpected functions in cancer progression by fostering a prometastatic environment through increased CCL8 secretion and TAM recruitment; thus, ZEB1 may serve as a candidate biomarker of tumour progression and provide a potential target for disrupting hypoxia-mediated TME remodelling.
Highlights
Tumour hypoxia is an adverse factor in cervical cancer, and it is associated with a poor outcome regardless of the treatment modality[1]
Since ZEB1 is best known for driving Epithelial–mesenchymal transition (EMT) in cancer cells, we tested its function in the cervical hypoxic tumour microenvironment (TME) and its correlation with tumour-associated macrophages (TAMs) infiltration
The results led us to conclude that levels of ZEB1 were upregulated in the hypoxic area of human cervical cancer specimens, which in turn coincided with higher accumulation of CD163+ TAMs
Summary
Tumour hypoxia is an adverse factor in cervical cancer, and it is associated with a poor outcome regardless of the treatment modality[1]. The manipulation of hypoxic stress in Increasing evidence has demonstrated that tumour hypoxia affects the antitumour immune response by promoting local immune suppression and inhibiting immune killing functions[3]. Hypoxic zones in solid tumours are infiltrated by a large number of immunosuppressive cells, such as tumour-associated macrophages (TAMs), myeloidderived suppressor cells (MDSCs) and T-regulatory (Treg) cells. These cells are among the most widely studied immunosuppressive cells within the TME, and the role of tumour hypoxia in their recruitment and immunosuppressive functions has become clear[4,5]. Macrophages constitute a principal component of the immune infiltrate in solid tumours, and their heterogeneity in different microenvironments results in different immune responses[6].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
