A circulating biotarget in breast-tumor-bearing mice suffering from chemotherapy-induced cardiac dysfunction

Introduction Chemotherapy-induced cardiac dysfunction is a common clinical setting impacting the prognosis of patients with breast cancer. Circulating Dipeptidyl Peptidase 3 (cDPP3) is an emerging biomarker undergoing active research as a potential biotarget in patients with acute cardiac dysfunction, with preclinical experiments demonstrating it being a negative inotropic agent. Emerging data demonstrates that immune cells play an important role in its release in the circulation. Its intracellular form (DPP3) is also known to be upregulated in many cancer forms and functions as an anti-oxidative stress protein. Purpose The aim is to determine whether cDPP3 is elevated in a model of doxorubicin (Dox)-induced cardiotoxicity in tumor-bearing animals, if its inhibition improves cardiac function and to identify the source of this increase of cDPP3. Methods Two weeks prior to receiving a cumulative intraperitoneal dose of 24 mg/kg of Dox, DPP3+/+- or DPP3-/--mice were injected subcutaneously with 200k PY8119-cells (murine triple negative breast tumor expressing high protein levels of DPP3), and their heart function and plasmatic cDPP3 levels were monitored for three weeks after the start of the chemotherapy regimen. Procizumab (PCZ), the cDPP3-inhibiting antibody, was injected two weeks after the start of Dox and heart function monitored 24 hours and 7 days later. Results Dox-treatment in tumour-bearing Dox-treated DPP3+/+-mice induced significant cDPP3 increase two weeks after the start of the treatment (140 vs 44 A.U., p<0.05), concomitant to a significant decrease of fractional shortening (FS) (43.3 vs 52.1%, p<0.05). PCZ injection significantly improved cardiac function 24 hours and 7 days later compared to the control dox-treated tumour bearing animals. No improvement of cardiac function was seen in Dox-treated tumour-bearing DPP3-/--mice receiving PCZ. Comparing to other organs (kidney, spleen and heart of two healthy mice), the tumour released more DPP3 in its interstitial fluid. However, the tumour was not responsible for the release of cDPP3 after Dox-treatment since no activity was detected in the plasma of tumour-bearing Dox-treated DPP3-/--mice. In these animals, DPP3 activity was detected in the tumour interstitial fluid and in the protein extract of distant organs, suggesting a release from the tumour and a diffusion to other locations through a mechanism that does not implicate the bloodstream. Conclusion Plasma circulating DPP3 mediates cardiac dysfunction induced by Dox and PCZ is a promising treatment for this disease in tumour-bearing mice. The plasma increase of cDPP3 after Dox is not due to tumoral release. The tumour releases DPP3 locally and it spreads to distant organs through a mechanism that remains to be investigated.