Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical trials. A better understanding of the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia is needed for future clinical application. Here, we investigated the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia in patients with localized PCa, in order to apply PIMO as a prognostic tool and to identify potential biomarkers for future clinical translation.
A total of 39 patients with localized PCa were recruited and administered oral PIMO before undergoing radical prostatectomy (RadP). Immunohistochemical staining for PIMO was performed on 37 prostatectomy specimens with staining patterns evaluated and clinical association analyzed. Whole genome bisulfite sequencing was performed using laser-capture of microdissected specimen sections comparing PIMO positive and negative tumor areas. A hypoxia related methylation molecular signature was generated by integrating the differentially methylated regions with previously established RNA-seq datasets.
Three PIMO staining patterns were distinguished: diffuse, focal, and comedo-like. The comedo-like staining pattern was more commonly associated with adverse pathology. PIMO-defined hypoxia intensity was positively correlated with advanced pathologic stage, tumor invasion, and cribriform and intraductal carcinoma morphology. The generated DNA methylation signature was found to be a robust hypoxia biomarker, which could risk-stratify PCa patients across multiple clinical datasets, as well as be applicable in other cancer types.
Oral PIMO unveiled clinicopathologic features of disease aggressiveness in localized PCa. The generated DNA methylation signature is a novel and robust hypoxia biomarker that has the potential for future clinical translation.
BMC cancer. 2024 Jun 18*** epublish ***
Xinpei Ci, Sujun Chen, Rui Zhu, Mojgan Zarif, Rahi Jain, Wangyuan Guo, Matthew Ramotar, Linsey Gong, Wenjie Xu, Olivia Singh, Sheila Mansouri, Gelareh Zadeh, Gong-Hong Wei, Wei Xu, Robert Bristow, Alejandro Berlin, Marianne Koritzinsky, Theodorus van der Kwast, Housheng Hansen He
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., MOE Key Laboratory of Metabolism and Molecular Medicine and Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China., Division of Cancer Sciences, University of Manchester, Manchester, UK., Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. ., Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. ., Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. ., Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .