Influence of induced diabetes mellitus on hormonal profile of Lewis lung carcinoma in BALB/c Nude mice

Purpose of the study. The assessment of diabetes mellitus (DM) effect on levels of sex hormones in tumor and peritumoral tissues in BALB/c Nude mice with Lewis lung carcinoma (LLC).

Materials and methods. The study included 42 male and female BALB/c Nude mice aged 8–9 weeks weighing 21–22 g. Alloxan-induced DM was reproduced in mice of the main group, and then LLC was transplanted. Levels of estrone (E1), estradiol (E2), testosterone (T), progesterone (P4) and prolactin (PRL), as well as steroid hormone receptors: estrogens (REα, REβ), androgens (RA), and progesterone (RP4) were measured by RIA and ELISA in samples of tumor and peritumoral tissues. Animals with LLC without DM were used as controls. The statistical analysis was performed using the Statistica 10 program; differences were considered significant at p < 0.05.

Results. DM in males was reproduced only after a double injection of alloxan, and was characterized by lower blood glucose levels compared to females. The growth of LLC in animals with alloxan-induced DM was possible only in female BALB/c Nude mice; in BALB/c Nude males, the tumor could not be transplanted either independently or in combination with DM. Females in the main group showed greater average tumor volumes throughout the experiment and reduced survival, compared to the control group. Tumor samples from females with LLC+DM were more saturated with sex steroids, but depleted in steroid hormone receptors, which probably contributed to the ability to avoid the body's regulatory signals.

Conclusion. The growth of LLC in presence of induced DM was sex-dependent, since the tumor could not be transplanted to male mice. DM affected the levels of sex steroids and their receptors tumor tissues in female BALB/c Nude mice.

1. Subramanian M, Wojtusciszyn A, Favre L, Boughorbel S, Shan J, Letaief KB, Pitteloud N, Chouchane L. Precision medicine in the era of artificial intelligence: implications in chronic disease management. J Transl Med. 2020;18(1):472. doi:10.1186/s12967-020-02658-5.

2. Kotieva I.M., Kit O.I., Frantsiyants E.M., Bandovkina V.A., Kaplieva I.V., Trepitaki L.K., Cheryarina N.D., Pogorelova Yu.A., Blikyan M.V. Vliyanie khronicheskoi boli na uroven' polovykh gormonov, prolaktina i gonadotropnykh gormonov v syvorotke krovi i patologicheski izmenennoi kozhe u samok myshei v dinamike rosta zlokachestvennoi melanomy.Izvestiya vysshikh uchebnykh zavedenii. Severo-Kavkazskii region. Seriya: Estestvennye nauki. - 2018. - № 2 (198). - С. 106-116. (in Russ.)

3. Panigrahi G, Ambs S. How Comorbidities Shape Cancer Biology and Survival. Trends Cancer. 2021;7(6):488-495. doi:10.1016/j.trecan.2020.12.010.

4. Godongwana M, De Wet-Billings N, Milovanovic M. The comorbidity of HIV, hypertension and diabetes: a qualitative study exploring the challenges faced by healthcare providers and patients in selected urban and rural health facilities where the ICDM model is implemented in South Africa. BMC health services research.2021;21(1):647. doi:10.1186/s12913-021-06670-3.

5. Cuadros DF, Li J, Musuka G, Awad SF. Spatial epidemiology of diabetes: Methods and insights. World journal of diabetes. 2021;12(7):1042–1056. doi:10.4239/wjd.v12.i7.1042.

6. Scherübl H. Typ-2-Diabetes-mellitus und Krebsrisiko [Type-2-diabetes and cancer risk]. Dtsch Med Wochenschr. 2021;146(18):1218-1225. doi:10.1055/a-1529-4521.

7. Ramteke P, Deb A, Shepal V, Bhat MK. Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality. Cancers.2019;11(9):1402. doi:10.3390/cancers11091402.

8. Zylla D, Gilmore G, Eklund J, Richter S, Carlson A. Impact of diabetes and hyperglycemia on health care utilization, infection risk, and survival in patients with cancer receiving glucocorticoids with chemotherapy. J Diabetes Complicat.2019;33(4):335–339. doi:10.1016/j.jdiacomp.2018.12.012.

9. Supabphol S, Seubwai W, Wongkham S, Saengboonmee C. High glucose: an emerging association between diabetes mellitus and cancer progression. J Mol Med (Berl).2021;99(9):1175-1193. doi:10.1007/s00109-021-02096-w.

10. Treshchalina E.M., Zhukova O.S., Gerasimova G.K., Andronova N.V., Garin A.M. Metodicheskie rekomendatsii po doklinicheskomu izucheniyu protivoopukholevoi aktivnosti lekarstvennykh sredstv. Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv. Ch. 1. M.: Grif i K. 2012.- с. 642–657. (in Russ.)

11. Goodwin PJ. Diabetes and Cancer: Unraveling the Complexity. J Natl Cancer Inst. 2021; 113(4):347-348. doi:10.1093/jnci/djaa142.

12. Zhou Y, Zhao R, Lyu Y, Shi H, Ye W, Tan Y, Li R, Xu Y. Serum and Amniotic Fluid Metabolic Profile Changes in Response to Gestational Diabetes Mellitus and the Association with Maternal-Fetal Outcomes. Nutrients.2021;13(10):3644. doi:10.3390/nu13103644.

13. Masi M, Racchi M, Travelli C, Corsini E, Buoso E. Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers. Cells.2021;10(11):2999. doi: 10.3390/cells10112999.

14. Contaldo M, Boccellino M, Zannini G, Romano A, Sciarra A, Sacco A, Settembre G, Coppola M, Di Carlo A, D'Angelo L, Inchingolo F, Feola A, Di Domenico M. Sex Hormones and Inflammation Role in Oral Cancer Progression: A Molecular and Biological Point of View. Journal of oncology. 2020:9587971. doi:10.1155/2020/9587971.

15. Boccellino M, Di Stasio D, Dipalma G. Steroids and growth factors in oral squamous cell carcinoma: useful source of dental-derived stem cells to develop a steroidogenic model in new clinical strategies. European Review for Medical and Pharmacological Sciences. 2019;23(20):8730–8740. doi:10.26355/eurrev_201910_19267.

16. Isa MA, Majumdar RS, Haider S. In silico identification of potential inhibitors against shikimate dehydrogenase through virtual screening and toxicity studies for the treatment of tuberculosis. Int. Microbiol.2019;22:7–17. doi:10.1007/s10123-018-0021-2.

17. He D, Huang JH, Zhang ZY, Du Q, Peng WJ, Yu R, Zhang SF, Zhang SH, Qin YH. A network pharmacology-based strategy for predicting active ingredients and potential targets of Liu Wei Di Huang pill in treating type 2 diabetes mellitus. Drug Des. Dev. Ther. 2019;13:3989-4005. doi: 10.2147/DDDT.S216644.

18. Piao L, Chen Z, Li Q, Liu R, Song W, Kong R, Chang S. Molecular dynamics simulations of wild type and mutants of SAPAP in complexed with Shank3. Int. J. Mol. Sci. 2019;20:224. doi:10.3390/ijms20010224.

19. Ide H, Miyamoto H. The role of steroid hormone receptors in urothelial tumorigenesis. Cancers.2020;12:2155. doi:10.3390/cancers12082155.

20. Navarro G, Allard C, Xu W, Mauvais-Jarvis F. The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity (Silver Spring, Md.).2015;23(4):713–719. doi:10.1002/oby.21033.

21. Sharma P. Biology and Management of Patients With Triple-Negative Breast Cancer. Oncologist.2016;21(9):1050-62. doi:10.1634/theoncologist.2016-0067.

22. Bianchini G, De Angelis C, Licata L, Gianni L. Treatment landscape of triple-negative breast cancer - expanded options, evolving needs. Nat Rev Clin Oncol. 2022;19(2):91-113. doi:10.1038/s41571-021-00565-2.