Changes in the histological structure of Guerin's carcinoma in the model of tumor development on the background of diabetes mellitus

Purpose of the study. To create a model of tumor growth in the uterus in the context of diabetes mellitus (DM) and to study its morphological features.

Materials and methods. The model was created using female non-linear white rats weighing 180–220 g (n = 15). Alloxan was prelim inarily injected at a dose of 150 mg/kg of weight intraperitoneally once (inducing DM). Twenty-four hours after injection, rats were anesthetized with xylazine-zolazepam, and a suspension of Guerin's carcinoma cells was transplanted into the uterine horn. Blood glucose levels, body weight, and trunk circumference were measured for two weeks. Fourteen days after transplantation, the rats were euthanized via CO₂ inhalation. The tumor affected abdominal cavity organs and uterus were then dissected, and histological sections (5–7 μm) were prepared and stained with hematoxylin and eosin staining, with a following microscopic examination.

Results. At the time of tumor transplantation, the mean glucose level was 4.6 ± 0.4 mMol/L, 24 hours later it had increased to 25.4 ± 1.2 mMol/L, and it remained at this level until euthanasia. In the abdominal cavity, macroscopically, massive multinodular osseous tumor lesions of the uterus, mesentery, and internal organs were observed. Microscopically, numerous densely located cells with polymorphic hyperchromic nuclei and figures of pathological mitosis were observed, accompanied by significant vacuolization of cells that deviated from the typical characteristics of Guerin's carcinoma. Additionally, a mass of mucous elements was observed along the borders of nodules, suggestive of fringing. In the uterine tubes fused with tumor nodules, excessive mucus secretion, destruction of epithelium, and expansion of the interclavicular space were noted.

Conclusion. The constructed model of orthotopic growth of Guerin's carcinoma in the rat uterus following the induction of DM by alloxan demonstrated that in a hyperglycemic environment, morphological alterations occur in both the tumor, reflecting its transition to a more aggressive mucinous low-differentiated form, and in the uterus with substantial damage to the uterine tube. Such alterations may intensify the proclivity of tumorigenesis in the uterus in the context of DM.

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209–249. https://doi.org/10.3322/caac.21660

2. The state of oncological care for the Russian population in 2023. Edited by Kaprin AD, Starinsky VV, Shakhzadova AO. Мoscow: P.Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre, Ministry of Healthof the Russian Federation; 2024, 262 p. (In Russ.). Available at: https://oncology-association.ru/wp-content/uploads/2024/06/sop-2023-elektronnaya-versiya.pdf Accessed: 13.02.2025.

3. Zhang ZH, Su PY, Hao JH, Sun YH. The role of preexisting diabetes mellitus on incidence and mortality of endometrial cancer: a meta-analysis of prospective cohort studies. Int J Gynecol Cancer. 2013 Feb;23(2):294–303. https://doi.org/10.1097/igc.0b013e31827b8430

4. Lai Y, Sun C. Association of abnormal glucose metabolism and insulin resistance in patients with atypical and typical endometrial cancer. Oncol Lett. 2018 Feb;15(2):2173–2178. https://doi.org/10.3892/ol.2017.7590

5. Byrne FL, Martin AR, Kosasih M, Caruana BT, Farrell R. The Role of Hyperglycemia in Endometrial Cancer Pathogenesis. Cancers (Basel). 2020 May 8;12(5):1191. https://doi.org/10.3390/cancers12051191

6. Zabuliene L, Kaceniene A, Steponaviciene L, Linkeviciute-Ulinskiene D, Stukas R, Arlauskas R, et al. Risk of Endometrial Cancer in Women with Diabetes: A Population-Based Retrospective Cohort Study. J Clin Med. 2021 Aug 4;10(16):3453. https://doi.org/10.3390/jcm10163453

7. Constantine GD, Kessler G, Graham S, Goldstein SR. Increased Incidence of Endometrial Cancer Following the Women's Health Initiative: An Assessment of Risk Factors. J Womens Health (Larchmt). 2019 Feb;28(2):237–243. https://doi.org/10.1089/jwh.2018.6956

8. Wu D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature. 2018 Jul;559(7715):637–641. https://doi.org/10.1038/s41586-018-0350-5

9. McVicker L, Cardwell CR, Edge L, McCluggage WG, Quinn D, Wylie J, McMenamin ÚC. Survival outcomes in endometrial cancer patients according to diabetes: a systematic review and meta-analysis. BMC Cancer. 2022 Apr 20;22(1):427. https://doi.org/10.1186/s12885-022-09510-7

10. Frantsiyants EM, Bandovkina VA, Kaplieva IV, Surikova EI, Neskubina IV, Pogorelova YuA, et al. Changes in pathophysiology of tumor growth and functional activity of the hypothalamic-pituitary-thyroid axis in rats of both sexes with the development of Guerin's carcinoma on the background of hypothyroidism. South Russian Journal of Cancer. 2022;3(4):26–39. DOI: https://doi.org/10.37748/2686-9039-2022-3-4-3

11. Vollmer G. Endometrial cancer: experimental models useful for studies on molecular aspects of endometrial cancer and carcinogenesis. Endocr Relat Cancer. 2003 Mar;10(1):23–42. https://doi.org/10.1677/erc.0.0100023

12. Cherkashina DV, Lebedinskij AS, Petrenko JuA, Shtemenko NI, Petrenko AYu. Inhibition of the growth of Guerin's carcinoma in rats after management of human adipose tissue mesenchymal stromal cells and bioregulators of stem and progenitor cells. Journal Academy of Medical Sciences of Ukraine. 2010;16(3):492–506. (In Russ.).

13. Zhang W, Fan W, Rachagani S, Zhou Z, Lele SM, Batra SK, Garrison JC. Comparative Study of Subcutaneous and Orthotopic Mouse Models of Prostate Cancer: Vascular Perfusion, Vasculature Density, Hypoxic Burden and BB2r-Targeting Efficacy. Sci Rep. 2019 Jul 31;9(1):11117. https://doi.org/10.1038/s41598-019-47308-z

14. Kadomcev DV, Pasechnikova EA, Golubev VG. Zoletyl-xylazine anesthesia in experiments in rats. International Journal of Applied and Fundamental Research. 2015;5-1:56–57. (In Russ.).

15. Borodin YuI, Malygin MV, Astashov VV, Marinkin IO, Larionov PM, Michurin IE, et al. A method for modeling a tumor of the uterine body to study its regional lymphatic bed. Russian Federation Patent RU 2220459C1. 2003 Dec 27. (In Russ.).

16. Sidorkiewicz I, Jóźwik M, Niemira M, Krętowski A. Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA. Cancers (Basel). 2020 Sep 8;12(9):2559. https://doi.org/10.3390/cancers12092559

17. Ma J, Yao Z, Ma L, Zhu Q, Zhang J, Li L, Liu C. Glucose metabolism reprogramming in gynecologic malignant tumors. J Cancer. 2024 Mar 17;15(9):2627–2645. https://doi.org/10.7150/jca.91131

18. Byrne FL, Poon IK, Modesitt SC, Tomsig JL, Chow JD, Healy ME, et al. Metabolic vulnerabilities in endometrial cancer. Cancer Res. 2014 Oct 15;74(20):5832–5845. https://doi.org/10.1158/0008-5472.can-14-0254

19. Levin DA, The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73. https://doi.org/10.1038/nature12113

20. Mujammami M, Rafiullah M, Alfadda AA, Akkour K, Alanazi IO, Masood A, et al. Proteomic Analysis of Endometrial Cancer Tissues from Patients with Type 2 Diabetes Mellitus. Life (Basel). 2022 Mar 28;12(4):491. https://doi.org/10.3390/life12040491

21. Shikhlyarova AI, Kit OI, Frantsiyants EM, Kaplieva IV, Zhukova GV, Neskubina IV, et al. Relationship between comorbid pathology and tumor progression. Morphological portrayal of internal organs in modeling the growth of Guerin's carcinoma under diabetic conditions. Cardiometry. 2022;21:18–26. https://doi.org/10.18137/cardiometry.2022.21.1826

22. Duzguner S, Turkmen O, Kimyon G, Duzguner IN, Karalok A, Basaran D, et al. Mucinous endometrial cancer: Clinical study of the eleven cases. North Clin Istanb. 2019 Jul 3;7(1):60–64. https://doi.org/10.14744/nci.2019.17048

23. Ohira S, Tachibana R, Yasaki S, Tsunemi K, Uchiyama N, Ikeda E, Sano K. Mucinous carcinoma originating from uterine adenomyosis: a case report. J Med Case Rep. 2023 Feb 6;17(1):36. https://doi.org/10.1186/s13256-023-03772-w

24. Bragantini E, Angelico G, Disanto MG, Magri E, Maccio L, Barbareschi M. Gastric (gastrointestinal)-type endometrial adenocarcinoma presenting as a solitary endometrial polyp: a case report and literature review on a novel and potentially aggressive endometrial cancer histotype. Pathologica. 2023 Aug;115(4):227–231. https://doi.org/10.32074/1591-951x-870

25. Galic V, Schiavone MB, Herzog TJ, Holcomb K, Lewin SN, Lu YS, Neugut AI, Hershman DL, Wright JD. Prognostic significance of mucinous differentiation of endometrioid adenocarcinoma of the endometrium. Cancer Invest. 2013 Aug;31(7):500–504. https://doi.org/10.3109/07357907.2013.820321

26. Wong RW, Ralte A, Grondin K, Talia KL, McCluggage WG. Endometrial Gastric (Gastrointestinal)-type Mucinous Lesions: Report of a Series Illustrating the Spectrum of Benign and Malignant Lesions. Am J Surg Pathol. 2020 Mar;44(3):406–419. https://doi.org/10.1097/pas.0000000000001381