Abstract
Purpose: Endometrial cancer is highly prevalent and lacking noninvasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve the understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for noninvasive diagnostic and prognostic tests. Experimental Design: Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n = 66) and nonmalignant conditions (n = 108), and global untargeted metabolomics was performed. Using the metabolite data (n = 920), we completed a multivariate biomarker discovery analysis. Results: We analyzed grade 1/2 endometrioid carcinoma (n = 53) and other endometrial cancer subtypes (n = 13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (P < 0.0001), tryptophan (P < 0.0001), and glutamate (P < 0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q < 0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. Conclusions: Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement in diagnosis. The metabolic dysregulation described in this article linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighboring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of noninvasive diagnostics can improve both the acceptability and accessibility of diagnosis.
| Original language | English |
|---|---|
| Pages (from-to) | 3073-3087 |
| Number of pages | 15 |
| Journal | Clinical Cancer Research |
| Volume | 30 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - 15 Jul 2024 |
| Externally published | Yes |
Funding
We would like to thank the participants enrolled in the study and acknowledge Regina Montero and Elisa Martinez for their kind assistance in participant recruitment, sample, and clinical data collection. We would also like to thank Dr. Nicole Jimenez for her kind assistance in exploring the metabolic origin of our metabolites. This study was funded by the Mary Kay Foundation (M.M. Herbst-Kralovetz), the Valley Research Partnership (D.M. Chase and M.M. Herbst-Kralovetz), the Phoenix Friends Foundation (M.M. Herbst-Kralovetz), the National Cancer Institute of the National Institutes of Health under award number P30 CA023074 (M.M. Herbst-Kralovetz), and the Arizona Biomedical Research Center (ABRC) Arizona Investigator Grant #39084114 (P. \u0141aniewski and M.M. Herbst-Kralovetz) and support provided to P.L. through the Guiding U54 Investigator Development to Sustainability (GUIDeS) program under the award for the Partnership of Native American Cancer Prevention funded by the National Cancer Institute of the National Institutes for Health award number U54CA143924 (M.M. Herbst-Kralovetz)
| Funders | Funder number |
|---|---|
| Phoenix Friends Foundation | |
| Mary Kay Ash Foundation | |
| National Cancer Institute | |
| Valley Research Partnership | |
| National Institutes of Health | P30 CA023074, U54CA143924 |
| Arizona Biomedical Research Center | 39084114 |
ASJC Scopus subject areas
- General Medicine
