Key Takeaways & Executive Findings
- •• Serum lactate levels correlate with tumor grade and poor prognosis in ovarian cancer patients, suggesting lactate as a prognostic biomarker. • Lactate induces M2 polarization of macrophages, which promotes ovarian cancer cell proliferation and migration via CCL18 and Gpr132 signaling. • Mechanistically, lactate upregulates CCL18 expression through histone H3K18 lactylation, revealing a novel epigenetic regulatory pathway. • Targeting lactate or the lactate-CCL18 axis may offer new therapeutic strategies for ovarian cancer treatment.
Abstract
This study investigates the role of lactate in the genesis and progression of ovarian cancer (OV) and explores the underlying mechanisms. Serum lactate levels show a positive correlation with tumor grade and poor prognosis in patients with OV. Bioinformatics analysis identifies CCL18 as a lactate-related gene in OV. CCL18 is up-regulated in cancerous tissues and positively related to serum lactate levels in OV patients. THP-1 cells are exposed to phorbol-12-myristate-13-acetate for M0 macrophage induction. The results of RT-qPCR and ELISA for M1/M2 macrophage-related markers and inflammatory cytokines show that the exposure of lactate to macrophages induces M2 polarization. Based on the coculture of OV cells with macrophages, lactate-treated macrophages induces a significant increase in the proliferation and migration of OV cells. However, these effects can be reversed by silencing of Gpr132 in macrophages or treatment with anti-CCL18 antibody. Experiments using the xenograft model verify that the oncogenic role of lactate in tumor growth and metastasis relies on Gpr132 and CCL18. ChIP-qPCR and luciferase reporter assays reveal that lactate regulates CCL18 expression via H3K18 lactylation. In conclusion, lactate is a potential therapeutic target for OV. It is involved in tumorigenesis by activating CCL18 expression via H3K18 lactylation in macrophages.
1. Introduction
Ovarian cancer (OV), the sixth most common tumor in women, is the leading cause of death among gynecological cancers, with more than 300,000 new cases reported in 2020 worldwide [1]. Despite considerable advances in treatment strategies, including surgery and combination chemotherapy, OV continues to be associated with high mortality [2]. However, most patients with OV can be cured by currently available medication if they are diagnosed at early stages when the cancer is limited to the ovaries [3]. Therefore, further research is imperative to develop novel diagnostic and therapeutic strategies.
In recent years, targeted therapies focusing on the tumor microenvironment (TME) have become a research hotspot [4,5]. Glycolysis is a major pathway of energy metabolism in cancer cells, and lactate is the end product of the glycolytic pathway [6]. In the TME, soluble molecules released by cancer cells, including lactate, can activate oncogenic signaling and modulate surrounding cells. This mechanism is believed to play a key role in cancer progression [7,8]. As an important component of the TME, tumor-associated macrophages (TAMs) account for approximately 10% of the total cells within the tumor stroma [9]. TAMs have also been implicated in the aggressive phenotypes of cancer cells [10,11]. The acquisition of the M2 phenotype by the TAMs, which has a tumor-promoting function, is linked to poor prognosis in the context of several types of cancers [12,13].
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Jinrui Sun, Qinmei Feng, Yue He, Ming Wang, Yumei Wu (2026). Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024111
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Frequently Asked Questions
What is the role of lactate in ovarian cancer progression?
Lactate levels are elevated in ovarian cancer patients and correlate with tumor grade and poor prognosis. Lactate promotes tumorigenesis by inducing M2 polarization of macrophages, which in turn enhances cancer cell proliferation and migration through CCL18 and Gpr132 signaling.
How does lactate regulate CCL18 expression in macrophages?
Lactate upregulates CCL18 expression via histone H3K18 lactylation, a novel epigenetic modification. This was confirmed by ChIP-qPCR and luciferase reporter assays, showing that lactate induces lactylation at the CCL18 promoter.
What is the significance of CCL18 in ovarian cancer?
CCL18 is a chemokine that is upregulated in ovarian cancer tissues and positively correlates with serum lactate levels. It is involved in promoting tumor growth and metastasis by attracting and polarizing macrophages to an M2 phenotype, thereby creating a tumor-promoting microenvironment.
Could targeting lactate or CCL18 be a therapeutic strategy for ovarian cancer?
Yes, the study suggests that lactate and the lactate-CCL18 axis are potential therapeutic targets. Inhibiting lactate production or blocking CCL18 signaling could disrupt the tumor-promoting crosstalk between cancer cells and macrophages, offering new treatment avenues.
What experimental models were used in this study?
The study used clinical samples from ovarian cancer patients, THP-1 macrophage cell lines, coculture systems with ovarian cancer cells, and a xenograft mouse model to validate the findings. Techniques included RT-qPCR, ELISA, ChIP-qPCR, luciferase reporter assays, and immunohistochemistry.
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