Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Cardiac midkine expression regulates melanoma growth in vivo
V. Fischer1, M. Heckmann1, D. Finke1, V. Umansky2, S. Hille3, O. J. Müller3, N. Frey1, L. H. Lehmann1
1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Mannheim, Mannheim; 3Klinik für Innere Medizin III, Schwerpunkt Kardiologie und Angiologie, Universitätsklinikum Schleswig-Holstein, Kiel;

Background:
In industrial countries, heart failure and cancer are among the leading causes of death. As treatment for these diseases improves, they are increasingly common as co-morbidities. Heart failure has been shown to increase the likelihood of developing melanoma. While many shared risk factors of these diseases are known, the molecular basis of this observation is incompletely understood. Midkine (MDK) is a possible candidate for establishing such a link, as it has been shown to be increased in severe heart failure, as well as being elevated in patients with melanoma and poor prognosis. In this study we aimed to analyze the effects of an increase of MDK expression in cardiac tissue, to the development of melanoma in vivo.

Materials and Methods:
We investigated a cardiomyocyte-specific, AAV9-mediated MDK overexpression. To model the effects of cardiac MDK on tumor proliferation and metastases we injected RET-melanoma cells subcutaneously in animals (n=24) ± AAV-9 based MDK expression(n=12). We performed a cardiac phenotyping and characterized tumor progress in vivo using histological and imaging techniques (FDG-PET CT scan).

Result:
The Ratio of heart weight to tibia length was not significantly impacted by AAV9 induced MDK expression (n=11) compared to animals which were not injected with the virus (n=10, -
0.30 ± 0,49 p= 0.5476, unpaired t-test). Furthermore, there was no significant difference in left ventricular ejection fraction between groups (1.037% ± 1.288 SEM, p=0.4307, unpaired t-test). The cardiac expression of markers for pathological cardiac remodeling were unaltered (nppb, col1a1 and myh7 measured via qPCR, normalized to 18S Expression – nppb: 0.062 ± 0.05 SEM, p= 0.42 unpaired t-test; col1a1: -0.0009 ± 0,02 SEM, p= 0.7343, unpaired t-test; myh7: -0,330 ± 0,26 SEM p=0.2940 unpaired t-test). We also performed FDG-PET CT scans on a subset of animals with (n=3) and without (n=5) AAV9 injection, measuring the carduac uptake (13.83 ± 9.586 SEM, p= 0.1991, unpaired t-test). SUV of primary tumors was unchanged (1.157 ± 1.330 SEM, p= 0.4181, unpaired t-test). However, by automated histological analysis we found that AAV9 -based cardiac MDK expression lead to a significant increase in metastases in the spleen (n=11) compared to animals which were not injected with the virus (n=10, 0.015 ± 0.008 SEM; p=0.0245, unpaired t-test) while the primary tumor size remained unchanged (52,99mm³ ± 123,7 SEM, p=0.6735, unpaired t-test).

Conclusion:
Our data highlight the potential role of the cardiokine MDK in generation of metastasis in malignant melanoma. The identification of this intercellular communication pathway may represent a starting point for further research on the interactions between this cardiokine and oncologic diseases.


https://dgk.org/kongress_programme/jt2022/aP1251.html