In Lithuania, endometrial (uterine lining) cancer is diagnosed more often than in many other European countries. Based on incidence rates, the country ranks among the highest in the region, while neighbouring countries show significantly lower figures. What explains this difference?
Researchers at the Vilnius University Life Sciences Center, led by Dr. Aušra Sasnauskienė, are seeking answers. Using patient-derived tissues, they develop model systems of this cancer that allow them to observe the earliest cellular changes and identify the molecular signals that drive normal endometrial cells to become cancerous.
The scientists aim to determine whether specific genetic alterations and signalling pathways could explain the higher prevalence of this disease in Lithuania. However, to answer these questions, it is essential first to examine the tissue itself – one of the most dynamic in the human body.
What is the endometrium, and why is it vulnerable?
The inner lining of the uterus is called the endometrium. It is one of the fastest-renewing tissues in the human body, regenerating every month. During each cycle, cells rapidly divide as the lining thickens; if fertilisation does not occur, this layer is shed, removing old cells. A completely new layer is then formed, and the process begins again. This constant renewal is regulated by hormones, primarily oestrogen and progesterone.
Oestrogens stimulate cell growth and division, while progesterone promotes cell maturation and prepares the uterus for possible pregnancy. Such continuous turnover requires precise regulation of molecules involved in cell growth and division. However, intensive DNA synthesis increases the risk of mutations. Most of these are quickly repaired and pose no harm, but sometimes these protective mechanisms fail. Cells may then begin to behave abnormally, accumulating genetic changes that lead to uncontrolled growth and reduced responsiveness to regulatory signals. Over time, such altered cells can give rise to tumours.
The role of hormones: balance between oestrogen and progesterone
Most cases of endometrial cancer (around 70–80%) are linked to excess oestrogen and are therefore hormone-dependent. But why can hormones promote harmful changes?
Oestrogens – including estradiol, estrone and estriol – are key female sex hormones, mainly produced in the ovaries, but also in the adrenal glands and adipose tissue. They regulate reproductive functions and influence gene expression by binding to specific receptors in or on cells.
Progesterone, produced by the corpus luteum and placenta (and to a lesser extent by the adrenal glands), also regulates gene expression. It promotes cell maturation, prepares the endometrium for pregnancy, and counteracts the estrogen-induced signals that promote cell division.
When does a hormonal imbalance occur?
Hormonal imbalance can arise for several reasons, one of the most important being age. Endometrial cancer is most often diagnosed in postmenopausal women. Oestrogen levels increase from the onset of menstruation and decline during menopause (typically between ages 45 and 55). Long-term exposure to oestrogen increases cancer risk, especially when it is not balanced by progesterone.
Obesity is one of the most significant risk factors. A higher body mass index (BMI) is associated with increased risk, partly because adipose tissue produces oestrogens and enzymes such as aromatase, which convert androgens into oestrogens. This leads to stronger signals promoting cell growth, while progesterone levels may be insufficient to counteract them.
Other risk factors
Additional risk factors are related to reproductive history. Early onset of menstruation or late menopause increases risk due to prolonged exposure to oestrogen. Nulliparity (never having been pregnant) also raises risk, while multiple pregnancies reduce it.
Certain conditions, such as endometrial hyperplasia and polycystic ovary syndrome, are linked to increased risk. Type 2 diabetes and hypertension are also contributing factors. In diabetes, elevated insulin levels and inflammation-related factors may activate oestrogen receptors, further promoting cell proliferation.
Heredity and genetic factors
Only a small proportion (around 5%) of endometrial cancer cases are hereditary. Some genetic mutations, particularly those in genes involved in DNA repair, can be inherited. Others affect genes controlling cell growth and division.
Nevertheless, differences in incidence between neighbouring countries suggest that population-specific genetic or molecular factors may also play a role. For example, in 2022, Lithuania reported 21.8 new cases per 100,000 people, compared to 16.2 in Latvia and a European average of 15.5.
Lithuania ranks second in Europe for endometrial cancer incidence, following Belarus, and fifth worldwide. These figures raise important questions about underlying causes, including possible population-specific genetic variations.
Lithuanian researchers search for answers
Scientists at the Vilnius University Life Sciences Center have launched studies to characterise the molecular features of endometrial cancer cells. One such project, “Development of endometrial cancer model systems for the investigation of the Notch signalling pathway” (project leader Dr Vilmantė Žitkutė), is supported by the Vilnius University Research Promotion Fund.
The goal is to derive cell lines from patient tumour tissues and use them to investigate genomic changes and signalling pathways involved in cancer development. Particular attention is given to the Notch signalling pathway, which is known to play a role in other cancers and may be linked to chemotherapy resistance.
The developed cell lines will also support future studies of additional pathways, helping to build a clearer understanding of why endometrial cancer is more prevalent in Lithuania, and how it can be detected and treated more effectively.