Tumor Oxygenation in an Orthotopic Model of Breast Cancer: Impact of Dietary Nitrate Supplementation

Abstract

Introduction: Breast cancer (BC), the predominant non-melanoma cancer among women, is projected to escalate to more than 3 million new cases and ~1 million fatalities globally by 2040. Chronic and fluctuating low oxygen (O2) conditions within tumors favor malignant growth, decreased responsiveness to therapeutic interventions, and reduced patient survivability. Treatment strategies to combat tumor hypoxia are desperately needed. Dietary nitrate supplementation via beetroot juice (BRJ), which increases nitric oxide (NO) production through the nitrate-nitrite-NO pathway, has been demonstrated to increase skeletal muscle blood flow, improve mitochondrial effciency, and reduce metabolic demands. Specifically, BRJ improves interstitial oxygen pressures (PO2 is) in acidic, low oxygen environments such as that found in the tumor microenvironment. Therefore, we hypothesized that BRJ supplementation would increase PO2 is in BC tumors. Methods: Female Fischer 344 retired breeder rats (6-8 months old) were used in this investigation. Adenocarcinoma cells (MAT B III at 6 x 103) were injected into the mammary duct and tumor growth was monitored over 2 weeks. Once tumors reached ~5 mm in diameter, rats were randomly assigned to consume BRJ (1 mmol/kg/day; BRJ, n=3) or water (CON; n=3) for 5 days. Under pentobarbital anesthesia, tumor PO2 is measurements were obtained using phosphorescence quenching. Results: Tumor growth rate was decreased in BRJ compared to CON rats (0.5 ± 0.1 vs. 1.0 ± 0.1 mm/day; p<0.05). Heart rate and mean arterial pressure were not different between groups (P>0.05). Blood lactate was significantly decreased in BRJ compared to CON rats (0.5 ± 0.1 vs. 1.2 ± 0.1 mmol/L, p<0.05). There was an increase in mean tumor PO2 is in BRJ vs. control rats (6.9 ± 1.3 vs. 3.7 ± 0.47; p<0.05). Conclusions: This study offers promising preliminary insights into the potential of dietary nitrate supplementation as an adjunctive approach to BC treatment to increase tumor PO2 is and reduce tumor growth rate. Future and ongoing studies will increase the sample size, use fluorescent microspheres to measure tumor blood flow, and explore the potential for BRJ and other NO agonists to combat tumor hypoxia and the skeletal muscle dysfunction associated with cancer progression. This research was funded by the following sources: the Johnson Cancer Research Center Innovative Research Award and Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants at Kansas State University, the National Institute on Aging (Grant 1R15AG078060), and Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute (Grants 1F31HL167618-01 and 1F31HL170643-01). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.