Cancer Center at Illinois (CCIL) member Wawrzyniec Dobrucki, a professor of bioengineering, led a systematic review and analysis of data from over 5,000 patients with cancer across 29 studies to investigate how Receptor for Advanced Glycation End-products (RAGE) expression correlates with cancer patient survival. Dobrucki worked with a research team that included Michael Nelappana, Goodluck Okoro, Catherine Applegate, Paweł Wityk, Leszek Kalinowski, and Iwona Dobrucka. The results of their study are published in bioRxiv.
RAGE has been implicated in driving cancer growth, aggression, and metastasis through the fueling of chronic inflammation in the tumor microenvironment. The Dobrucki lab’s systematic review summarized and analyzed current clinical and preclinical data to provide insight into the relationship between RAGE and cancer, cancer grade, metastasis, patient survival, and cellular processes. The team’s review and meta-analysis is the first comprehensive study through which both preclinical and clinical research in all available cancer types were assessed for correlations with RAGE expression and activation. The investigation demonstrated that RAGE does indeed play a significant role in cancer progression and that further research is warranted.
The CCIL asked Prof. Dobrucki to share more about RAGE and the implications of this critical study.
What is Receptor for Advanced Glycation End-products (RAGE), and what is the role of RAGE in cancer?
RAGE (Receptor for Advanced Glycation End-products) is a cell surface receptor that binds not only advanced glycation end-products (AGEs), toxic molecules formed from sugar and protein interactions, but also several other inflammatory ligands like HMGB1 and S100 proteins. These ligands are often released during tissue stress, damage, or chronic inflammation.
In cancer, RAGE plays a pivotal pro-tumorigenic role. When activated by these ligands, especially in the context of obesity, aging, or a Western-style diet, RAGE triggers powerful inflammatory signals (like NF-κB) that fuel cancer progression. It fosters a tumor-friendly microenvironment by promoting cancer cell survival, growth, migration, and resistance to therapy. Think of RAGE as a “molecular amplifier” of inflammation that turns a healing signal into a cancer-promoting one.
How does RAGE expression correlate with patient survival?
Our meta-analysis reveals a nuanced but critical pattern: in most cancer types, higher RAGE expression is strongly linked to worse patient survival, particularly in what we’ve termed pro-RAGE cancers (e.g., breast, prostate, colorectal, lung, ovarian, gastroesophageal cancers).
Specifically, in these cancers, high RAGE levels were associated with an odd-ratio (OR) of 0.42 for survival, meaning a significantly higher likelihood of death among patients with elevated RAGE expression. This suggests RAGE could serve as a valuable prognostic biomarker. However, in the so-called nulli-RAGE cancers (like some gastrointestinal and respiratory cancers), no such association was found, highlighting the complexity and context-dependency of RAGE’s role.
How did you select and recruit the patient data?
Our study followed rigorous systematic review and meta-analysis guidelines (PRISMA and Cochrane standards). We conducted a comprehensive search across PubMed, Web of Science, and Scopus (updated through July 2025), capturing all peer-reviewed clinical studies that directly measured RAGE expression in cancer patients versus normal tissue.
We included only studies that used validated methods like immunohistochemistry (IHC), ELISA, or Western blotting, and that reported clear outcome data, such as tumor grade, lymph node status, or survival. Among over 10,000 identified studies, a total of 52 clinical and 233 preclinical studies were included in the analysis. Data were carefully extracted using standardized forms, and quality was assessed using the Newcastle-Ottawa Scale to ensure robustness.
How would you summarize the implications of this research for a layperson sitting in a cancer clinic?
Imagine RAGE as a “gas pedal” in the body that gets stuck in the “on” position when inflammation runs unchecked which is common in the modern world due to diet, aging, or chronic disease. Our work shows that in many common cancers, this pedal is stuck down, pushing tumors to grow faster, spread further, and survive longer.
For a patient, this means that RAGE could help doctors identify tumors that are more aggressive before surgery. Also, it might explain why some cancers become resistant to treatment, because RAGE helps tumors “hide” from the immune system and survive stress. Most excitingly, we’ve already developed imaging tools to “see” RAGE non-invasively in the body (like a PET scan), opening the possibility to monitor treatment response over time without repeated painful biopsies. This isn’t just about understanding cancer, it’s about creating new, earlier, and more personalized ways to fight it.
Where does this research fit into the scope of your lab’s overarching cancer research goals?
This study is deeply embedded in our lab’s core mission: to develop new diagnostic imaging tools and translate inflammatory biology into novel therapies for solid tumors. Our work on RAGE began with breast and prostate cancer, where we identified it as a key player in tumor progression and therapy resistance. This meta-analysis confirms that RAGE is not just relevant in isolated cancers—but across a broad spectrum, with sufficient consistency to be a strong biomarker and therapeutic target.
Our broader objectives include: developing RAGE-targeted imaging agents (we’ve already shown this in prostate cancer via PET/CT), evaluating anti-RAGE drugs to block tumor progression and exploring dietary interventions (like reducing AGE-rich foods) as a low-risk adjuvant. This meta-analysis strengthens our argument that targeting the RAGE pathway could be a powerful, scalable strategy in cancer care.
What are the next steps in this research trajectory?
We’re actively pursuing several key next steps:
- Developing clinical RAGE imaging tools: we’re refining our RAGE-targeted multimodal tracer for use in routine PET scans and optical imaging, potentially enabling real-time monitoring of tumor aggression and treatment response.
- Testing anti-RAGE therapies: we are evaluating repurposed drugs (like Azeliragon/TTP488, alagebrium and glycyrrhizin) in preclinical models of aggressive cancers, especially those with high RAGE expression.
- Exploring dietary interventions: currently, we’re performing studies to assess whether a low-AGE diet can slow tumor growth or improve outcomes when combined with standard therapies.
- Mechanistic follow-up: we’re diving deeper into why RAGE drives poor outcomes following radiation therapy.
“Ultimately, our goal is to turn RAGE from a lab biomarker into a clinical tool—a practical, translatable lever to improve cancer diagnosis, prognosis, and treatment.”
Wawrzyniec Dobrucki
Associate Professor, Biongineering
CCIL Research Program and Theme
- Program: Cancer Technology and Data Science
- Theme: Cancer Imaging
Research Focus
Wawrzyniec Dobrucki’s studies focus on developing multimodal imaging strategies to track myocardial and peripheral angiogenesis with targeted molecular imaging agents. His current research explores the effects of dietary modulation on prostatic neuroendocrine differentiation and the efficacy of anticancer treatment. He is currently a co-investigator for a study on breast cancer and cholesterol and a study on nanotherapeutics for cancer treatment. He demonstrates the importance of nanoparticle imaging-agent size and chemical functionalization, and the feasibility of molecular imaging of cancer with various nanoparticle types, through his research. His research in imaging strategies will eventually lead to individualized programs for disease prevention through advanced diagnosis, risk stratification, and targeted therapies, resulting in more successful and efficient health care.
Editor’s notes:
The paper “The Role of the Receptor for Advanced Glycation End-Products in Cancer: Evidence from a Systematic Review and Meta-Analysis“ published in bioRxiv is available here (https://www.biorxiv.org/content/10.64898/2026.02.13.705839v1).
DOI: https://doi.org/10.64898/2026.02.13.705839
Wawrzyniec Dobrucki is Associate Professor in the Department of Bioengineering, the Neil and Carol Ruzic Scholar of Biomedical and Translational Sciences in the Carle Illinois College of Medicine, and an affiliate of the Beckman Institute for Advanced Science and Technology and the Carl R. Woese Institute for Genomic Biology.
He can be reached at dobrucki@illinois.edu
This story was written by Jonathan King, CCIL Communications Specialist.