Distinct nitrogen isotopic compositions of healthy and cancerous tissue in mice brain and head&neck micro-biopsies

Background: Cancerous cells can recycle metabolic ammonium for their growth. As this ammonium has a low nitrogen isotope ratio (¹⁵N/¹⁴N), its recycling may cause cancer tissue to have lower ¹⁵N/¹⁴N than surrounding healthy tissue. We investigated whether, within a given tissue type in individual mice, tumoral and healthy tissues could be distinguished based on their ¹⁵N/¹⁴N. Methods: Micro-biopsies of murine tumors and adjacent tissues were analyzed for ¹⁵N/¹⁴N using novel high-sensitivity methods. Isotopic analysis was pursued in Nude and C57BL/6 mice models with mature orthotopic brain and head&neck tumors generated by implantation of H454 and MEERL95 murine cells, respectively. Results: In the 7 mice analyzed, the brain tumors had distinctly lower ¹⁵N/¹⁴N than healthy neural tissue. In the 5 mice with head&neck tumors, the difference was smaller and more variable. This was at least partly due to infiltration of healthy head&neck tissue by tumor cells. However, it may also indicate that the ¹⁵N/¹⁴N difference between tumoral and healthy tissue depends on the nitrogen metabolism of the healthy organ in question. Conclusions: The findings, coupled with the high sensitivity of the ¹⁵N/¹⁴N measurement method used here, suggest a new approach for micro-biopsy-based diagnosis of malignancy as well as an avenue for investigation of cancer metabolism.