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Summary Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10 + GPR77 + CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10 + GPR77 + CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10 + GPR77 + CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10 + GPR77 + CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors. [ABSTRACT FROM AUTHOR]

Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression. In response to inflammatory stimuli, neutrophils become activated, releasing neutrophils extracellular traps (NETs) for the capture and eradication of pathogens, a phenomenon termed NETosis. With a deeper understanding of NETs, there is growing evidence supporting their role in cancer progression and their involvement in conferring resistance to various cancer therapies, especially concerning tumor reactions to chemotherapy, radiation therapy (RT), and immunotherapy. This review summarizes the roles of NETs in the tumor microenvironment (TME) and their mechanisms of neutrophil involvement in the host defense. Additionally, it elucidates the mechanisms through which NETs promote tumor progression and their role in cancer treatment resistance, highlighting their potential as promising therapeutic targets in cancer treatment and their clinical applicability., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2024.)

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10 + GPR77 + CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10 + GPR77 + CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10 + GPR77 + CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10 + GPR77 + CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)