Peculiarities of influence made by diabetes mellitus as comorbid pathology on the system of sex hormones and their receptors in tumors of different histological origin

1 – National Medical Research Centre for Oncology, Rostov-on-Don, Russia, 2 – Rostov State Medical University, Rostov-on-Don, Russia

Improving the survival of cancer patients contributes to a growing number of patients with chronic comorbidities, including diabetes mellitus (DM). Moreover, higher risk of cancer development in patients with DM and poor prognosis determine the importance of studying the mechanisms mediating the effect of altered glucose metabolism made on the growth and metastasis of malignant tumors [3,4]. The polyetiology of both pathologies and the presence of research studies that do not confirm a direct relationship between DM and the development of malignant neoplasms indicate the complex nature of their relationship with the possible context-dependent regulation of many cellular processes associated with carcinogenesis and the development of DM [1,2]. An important role in the processes of the regulation is played by an imbalance in the system of sex hormones.

The aim of our investigations was to study the features of the influence made by DM as comorbid pathology on the course of the tumor process and the concentrations of the sex hormones and their receptors in the tumor tissue of different histological origin and the perifocal zone in different species of experimental animals.

Material and methods. Females of the white non-linear rats (n=36) and the BALB/c Nude mice (n=28) were used. The reference groups included the animals with an independent growth of an inoculated tumor (Guerin's carcinoma (GC) in the rats, and the Lewis lung carcinoma (LLC) in the mice), and the main groups covered the rodents with the tumor growth with presence of DM induced by alloxan injection. In some animals, survival and dynamics of the tumor volume were studied. In the other animals after euthanasia in the pre-terminal state (rats on the 10th day after CG inoculation, mice on the 19th day after LLC inoculation) in the tumor and its perifocal zone, the concentrations of estradiol, testosterone, progesterone, estrogen receptors, progesterone and androgens were determined by ELISA (Casabio, China).

Results . The rats in the main group had GC with a tumor volume 1.5 times (p<0.05) smaller than in the reference group and multiple metastatic lesions of the internal organs that led to a reduction in their survival by a factor of 1.7 (p<0.05). In contrast, in the mice of the main group, an increase in the LLC volume was recorded by up to 13.7 times (p <0.001), metastases were not detected, and the survival was 1.5 times shorter (p <0.05) than in the reference group. GC and LLC developed in presence of DM demonstrated higher concentrations of estradiol, testosterone and progesterone than the tumors in the reference groups: they were on average 2.4-2.6 times higher (p<0.02). At the same time, the receptor concentration in GC was on average 3.6 times higher (p <0.01), and in LLC it was on average 1.8 times lower (p <0.05) than in the tumors in the corresponding reference groups. The perifocal zone of GC demonstrated very high concentrations of estradiol and androgen receptors: they were recorded to be 9.5 and 3.9 times higher (p <0.01), respectively, than it was the case in the reference group. In the perifocal zone of LLC, on the contrary, there were lower levels of estradiol, testosterone and receptors, respectively, by 2.3, 5 and on average 1.8 times (p<0.05–p<0.01) than in the reference group. In different models of the tumor growth in presence of DM, the tendency of changes in the concentrations of sex hormones and their receptors in the perifocal zone of the tumors had its own features. In the peritumoral area of disseminated GC (main group) higher levels of testosterone and estradiol were revealed: they were 1.6 and 2.7 times higher, respectively (p <0.05) than in the tumor tissue, in contrast to the respective indicators in the reference group. In the main group of mice with LLC, in contrast to the indicators in the reference group, there were lower concentrations of estradiol and testosterone in the perifocal zone as compared to the levels in the tumor tissue: they were 1.5 and 3.5 times lower, respectively (p<0, 05). At the same time, in both models, higher concentrations of hormonal receptors in the perifocal zone of the tumors remained, similar to what we observed in the independent growth of Guerin's carcinoma and LLC (the reference group).

Conclusion . The obtained evidence data revealed an essential role of DM as comorbid pathology in the activation of the growth and intensification of tumor metastasizing, the formation of its aggressive phenotype, and a reduction in the survival of the animals. The study of tumors of similar histological structure, but of different origin (uterine epithelium, lung epithelium), developing in different physiological contexts, contributed to the proper assessment of the impact made by DM, accompanying the malignant growth, on changes in the hormonal status of the tumor tissue and the perifocal zone, which was involved in the molecular relationship between DM and progression of the tumor process.