Ovarian cancer is the most lethal malignancy of the female reproductive system. Due to its insidious early symptoms and the absence of specific screening modalities, approximately 70% of patients are diagnosed at an advanced stage. Despite continuous advances in surgery, chemotherapy, targeted therapy, and other treatment approaches, the 5-year survival rate for advanced-stage patients remains below 30%. Intraperitoneal metastasis and therapeutic resistance pose major clinical challenges in the management of this disease.
Ovarian cancer exhibits a distinct propensity for metastasis to fat-rich sites, such as the omentum and peritoneum. Historically, research on the ovarian tumor microenvironment (TME) has largely focused on immune cells, whereas the role of adipose tissue and its derived stem cells (ADSCs) in tumor progression has been insufficiently addressed. "We observed that adipose tissue from ovarian cancer patients often displays senescent features, which may provide a permissive niche for tumor growth," noted the corresponding author of the study.
Through a series of in vitro and in vivo experiments, the research team confirmed that ovarian cancer cells actively induce adipose tissue dysfunction and ADSC senescence, which in turn trigger metabolic abnormalities including glucose intolerance and insulin resistance—creating favorable conditions for tumor metastasis. Further mechanistic investigations revealed that extracellular vesicles secreted by ovarian cancer cells (OC-EVs) act as key messengers in this process.
These vesicles are enriched with the pro-inflammatory cytokine IL-1β. Upon interaction with ADSCs, they activate the intracellular NF-κB signaling pathway: on the one hand, this induces ADSCs to enter a senescent state; on the other hand, it promotes inflammasome formation and the release of inflammatory factors such as IL-1β and IL-18. This forms a "inflammation-senescence" vicious cycle that continuously remodels the TME. Analysis of clinical samples further validated that the degree of adipose tissue senescence in ovarian cancer patients is closely correlated with tumor progression, with significantly elevated expression of the senescence marker CDKN2A in adipose tissue from advanced-stage patients. Based on these findings, the research team explored two targeted therapeutic strategies, both achieving remarkable efficacy:
The first strategy employs the senolytic combination of dasatinib plus quercetin (DQ). In a murine model of ovarian cancer intraperitoneal metastasis, DQ treatment significantly ameliorated adipose tissue senescence, markedly reduced intraperitoneal reactive oxygen species (ROS) levels, improved glucose metabolism and insulin sensitivity, and ultimately led to a substantial decrease in the number of tumor metastases, effectively delaying tumor progression.
The second strategy utilizes resveratrol, a natural antioxidant. As an NF-κB pathway inhibitor, resveratrol not only directly suppresses the formation of ovarian cancer spheroids but also reverses the senescent phenotype of ADSCs and reduces adipose tissue inflammation by inhibiting the NF-κB and MAPK3 signaling pathways, thereby exerting dual anti-senescence and anti-tumor effects. In vivo experiments demonstrated that resveratrol treatment significantly alleviated metabolic disorders in mice, reduced tumor burden, and lowered the risk of intraperitoneal metastasis.
"The core innovation of this study lies in that we did not directly target cancer cells themselves, but rather cut off the 'nutrient supply and metastatic routes' on which tumors rely by regulating senescent adipocytes in the TME," the research team emphasized. Traditional tumor therapies often damage normal tissue stromal cells, leading to their senescence and promoting tumor recurrence. In contrast, the "senescent cell-targeting" strategy proposed in this study provides a new breakthrough for addressing therapeutic resistance and recurrence.
Notably, both quercetin and resveratrol are naturally occurring compounds with favorable biosafety profiles, laying a solid foundation for their subsequent clinical translation. The research team stated that future work will focus on optimizing administration regimens, exploring combination applications with chemotherapy and immunotherapy, and conducting clinical studies to verify their therapeutic efficacy in ovarian cancer patients.
This study was led by Jia Lü (first author) from Shanghai Fourth People's Hospital; Associate Researcher Lian Wang from Shanghai Tenth People's hospital; and Professor Wei Bao (corresponding author) from Shanghai General Hospital and Shanghai First Maternity and Infant Hospital. The research was supported by multiple grants, including the National Natural Science Foundation of China and clinical projects from the Shanghai Municipal Health Commission.
