Ovarian cancer remains the deadliest malignancy affecting the female reproductive system globally, largely owing to its silent progression and the absence of effective early detection methods. Most patients are diagnosed at advanced stages, with metastatic spread into the peritoneal cavity, which critically undermines therapeutic success. Despite sustained advances in surgical techniques, chemotherapeutic options, and targeted treatments, the five-year survival rate for patients presenting with late-stage ovarian cancer stubbornly remains below 30%. The pervasive challenges of intraperitoneal metastasis and acquired resistance to treatment have limited meaningful improvement in clinical outcomes, underscoring the urgent necessity for novel therapeutic paradigms.
What distinguishes ovarian cancer biologically is its predilection for metastasizing to adipose-rich microenvironments, predominantly the omentum and surrounding peritoneal fat. Historically, investigations into the ovarian tumor microenvironment (TME) have concentrated on immune cells—macrophages, lymphocytes, and related stromal components—leaving the role of adipose tissue and its resident adipose-derived stem cells (ADSCs) largely unexplored. Recent collaborative research spearheaded by scientists at Tongji University has shifted this paradigm by illuminating the pivotal function of senescence in ADSCs as a facilitator of tumor progression. They observed that adipose tissues harvested from ovarian cancer patients frequently exhibit hallmark indicators of cellular senescence, suggesting that these senescent niches may actively support tumor growth rather than merely being passive bystanders.
Employing a comprehensive suite of in vitro cell culture systems alongside rigorously controlled in vivo murine models, investigators demonstrated that ovarian cancer cells induce profound dysfunction within adipose tissue, characterized primarily by the induction of senescence in ADSCs. This senescent state disrupted normal metabolic homeostasis, manifesting as systemic glucose intolerance and insulin resistance. These metabolic abnormalities are not trivial; rather, they create an enabling environment favorable to tumor colonization and dissemination within the peritoneal cavity. Mechanistic analyses pinpointed extracellular vesicles (EVs) secreted by ovarian cancer cells—specifically those enriched with pro-inflammatory cytokines—as critical mediators in this intercellular crosstalk.
One key cytokine identified within the cargo of these ovarian cancer-derived extracellular vesicles (OC-EVs) is interleukin-1 beta (IL-1β), a potent inflammatory molecule. Upon delivery to ADSCs, IL-1β activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, an essential transcription factor complex involved in immune response regulation and inflammation. This activation triggers a dual cascade: first, it induces ADSCs to enter a senescent phenotype marked by permanent cell cycle arrest and altered secretory profiles; second, it stimulates inflammasome assembly, resulting in amplified secretion of additional inflammatory cytokines such as IL-1β itself and IL-18. This mechanistic loop establishes a self-perpetuating “inflammation-senescence” feedback cycle that drives continuous remodeling of the tumor microenvironment, thereby facilitating tumor progression.
Further validation using clinical adipose tissue specimens from ovarian cancer patients confirmed a strong correlation between the degree of ADSC senescence and disease advancement. Notably, the expression levels of CDKN2A, a recognized molecular marker of senescence encoding the p16^INK4a protein, were significantly elevated in adipose tissue samples from patients with advanced-stage ovarian tumors. This suggests that as ovarian cancer progresses, the senescent state within the adipose microenvironment intensifies, potentially amplifying tumor aggressiveness and metastatic potential. This insight steered the research team to develop innovative strategies aimed at targeting this tumorpromoting senescence to impede ovarian cancer spread.
The first promising therapeutic approach evaluated was the administration of a senolytic drug combination comprising dasatinib and quercetin (referred to as DQ). These agents selectively eliminate senescent cells by disrupting their survival pathways. In a preclinical mouse model of ovarian cancer intraperitoneal metastasis, DQ treatment effectively mitigated ADSC senescence within adipose tissue and concurrently reduced reactive oxygen species (ROS) accumulation, a hallmark of oxidative stress linked to senescence. Remarkably, treatment also restored systemic glucose metabolism and insulin sensitivity. Functionally, these metabolic and microenvironmental improvements translated into a significant reduction in tumor metastatic foci within the peritoneal cavity, indicating a pronounced delay in tumor progression.
Complementing the senolytic strategy, the research team explored resveratrol, a naturally-derived polyphenolic compound known for its antioxidant and anti-inflammatory properties. Resveratrol demonstrated potent inhibition of the NF-κB signaling pathway in ADSCs, directly suppressing the formation of ovarian cancer spheroids—multicellular aggregates resembling tumor architecture. By reversing the senescent phenotype of ADSCs and attenuating adipose tissue inflammation via simultaneous blockade of NF-κB and mitogen-activated protein kinase 3 (MAPK3) pathways, resveratrol exerted dual anti-senescence and anti-tumor effects. In vivo administration substantially alleviated metabolic disturbances, diminished overall tumor burden, and reduced the propensity for peritoneal metastases, highlighting its therapeutic potential.
The ground-breaking insight presented by this research is a shift away from targeting ovarian cancer cells directly. Instead, it focuses on disrupting the tumor’s reliance on senescent adipocytes within the TME, effectively severing the “nutrient supply lines” and metastatic channels critical to tumor survival and dissemination. Conventional anticancer therapies frequently induce senescence in normal stromal cells, paradoxically fostering an environment conducive to cancer recurrence and resistance. By contrast, selectively targeting senescent cells to remodel the microenvironment offers a novel route to overcoming these clinical obstacles.
Importantly, the senolytic agents quercetin and the antioxidant resveratrol, employed in these therapeutic strategies, are both naturally occurring compounds with established safety profiles. Their favorable biosafety positions them as viable candidates for rapid translation into clinical trials. The research team emphasized that future directions will focus on optimizing dosages and administration schedules, exploring combination regimens with existing chemotherapy and immunotherapy protocols, and conducting rigorous clinical investigations to assess efficacy and safety in ovarian cancer patients.
This pioneering study was led by Jia Lü from Shanghai Fourth People’s Hospital, with significant contributions from Associate Researcher Lian Wang of Shanghai Tenth People’s Hospital and Professor Wei Bao of Shanghai General Hospital and Shanghai First Maternity and Infant Hospital. The work was generously supported by multiple funding sources, including substantial grants from the National Natural Science Foundation of China alongside clinical research programs funded by the Shanghai Municipal Health Commission.
In conclusion, this comprehensive investigation highlights the critical role of senescent adipose-derived stromal cells in fostering an inflammatory and metabolically dysregulated microenvironment that promotes ovarian cancer progression. By unraveling the molecular mechanisms underpinning this phenomenon and demonstrating therapeutic reversal via senolytic and anti-inflammatory agents, this study lays the foundation for a transformative approach to managing advanced ovarian cancer. This paradigm shift, targeting the tumor-supportive stromal niche rather than cancer cells alone, promises a new frontier in combating treatment resistance and improving patient survival.
Subject of Research: Ovarian Cancer Tumor Microenvironment and Senescent Adipose-Derived Stem Cells
Article Title: Targeting Senescent ADSCs in Adipose Tissue: Tongji University Team Paves New Way for Ovarian Cancer Therapy
Web References: http://dx.doi.org/10.1007/s11427-024-3060-0
Image Credits: ©Science China Press
Keywords: ovarian cancer, tumor microenvironment, adipose-derived stem cells, cellular senescence, extracellular vesicles, IL-1β, NF-κB signaling, senolytics, dasatinib, quercetin, resveratrol, metabolic reprogramming, intraperitoneal metastasis
Tags: adipose tissue in ovarian canceradipose tissue microenvironmentadipose-rich metastasiscellular senescence and cancernovel therapeutic strategies for ovarian cancerovarian cancer therapyovarian cancer tumor progressionperitoneal metastasis in ovarian cancersenescence in ADSCstargeting senescent adipose-derived stem cellsTongji University ovarian cancer researchtumor microenvironment in ovarian cancer
