Naslov
ULOGA NEKROPTOZE U TUMORU MOKRAĆNOG MJEHURA
(THE ROLE OF NECROPTOSIS IN BLADDER CANCER)

Autori
Haupt, Benedikt-Eduard

Vrsta, podvrsta i kategorija rada
Ocjenski radovi, diplomski rad, diplomski

Fakultet
Medicinski fakultet

Mjesto
Split

Datum
15.07

Godina
2020

Stranica
52

Mentor
Korać Prlić, Jelena

Ključne riječi
novotvorine mokraćnog mjehura, nekroptoza
(urinary bladder neoplasm, necroptosis)

Sažetak
Objectives: Although great progress has been achieved in terms of bladder cancer management, survival rates for muscle invasive bladder cancer are still dismal, which warrants for the search of new therapeutic approaches. Necroptosis is a programmed type of cell death, whose role has not been fully elucidated in bladder cancer. The objective of this study is to assess the prevalence of necroptosis at different time points during tumor progression and to investigate whether induction or inhibition of necroptosis influences tumor growth. Methods: This study used two distinct murine bladder cancer models. The first one was an autochthonous BBN-induced bladder cancer model. The second one was a subcutaneous tumor model, made using MB49 cells. Mice with subcutaneous tumors were treated with Necrostatin-1s and Shikonin, two compounds that should have the opposite effects of inhibition and induction of necroptosis, respectively. The tumors were analyzed using gene expression studies, immunohistochemistry and immunoblotting. Results: It was shown that necroptotic cell death is a late finding during tumor development and that necroptosis and apoptosis occur in separate hotspots in BBN- induced bladder cancers. Necrostatin-1s significantly accelerated tumor growth. This effect on tumor growth tapered off and was not significantly present by the end of the experiment. Further, Necrostatin-1s did not show the expected inhibitory effect on necroptosis. Shikonin-treated mice had significantly smaller tumor volumes by the end of the experiment and it was shown that Shikonin induced both necroptosis and apoptosis. Additionally, it was observed that Shikonin increased the number of T-regulatory cells in subcutaneous tumors. Conclusion: Necroptotic cell death is a late finding during tumor development, indicating that this type of cell death primarily occurs towards invasive tumor stages. Necroptosis and apoptosis occur in separate hotspots, presumably because the inflammatory environment in one part of the tissue dictates the type of cell death being activated. Necrostatin-1s accelerates tumor growth, which allows one to hypothesize that necroptosis is protective against tumor progression. Shikonin slows down tumor growth likely via a dual induction of necroptosis and apoptosis. This justifies the use of Shikonin in autochthonous induced bladder cancer models, such as in the BBN-induced bladder cancer model. Were Shikonin to show the same antitumorigenic results in the BBN-induced bladder cancer model and other preclinical models, more clinical trials could be conducted with the purpose of gaining more data on this new compound and its possible clinical applications.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA