Epidemiology, molecular typing, microbiome-immune interactions and treatment strategies of endometrial cancer: a review

Abstract

This review focuses on the field of endometrial cancer. Since 2020, there have been 417,367 new cases of endometrial cancer diagnosed globally and 97,370 deaths reported. Endometrial cancer ranks second in terms of incidence among female genital malignancies and third in terms of mortality among gynecological cancers. The stage, grade, and histological subtype of endometrial cancer were closely correlated with the risk of recurrence and prognosis for survival. Meanwhile, endometrial cancer exhibits significant biological heterogeneity. The complex interactions among the reproductive tract, host cells, and the microbial environment may harbor novel disease mechanisms. In this review, we provide an overview of the epidemiological characteristics, major risk factors, histological and molecular subtypes of endometrial cancer, as well as explore the associations between the female reproductive tract microbiome, immunity, and cancer progression. We also identify the specific roles of different cytokines in the pathophysiology of endometrial cancer. By integrating findings from diverse research fields, this comprehensive review offers an in-depth understanding of the multidimensional nature of endometrial cancer and highlights the significant potential and promising avenues that microbiological factors present for advancing future cancer research and guiding the development of innovative therapeutic strategies.

Keywords: dysbiosis; endometrial cancer; immune response; inflammation; reproductive tract microbiome.

Figure 1

Polycystic ovary syndrome is associated with an increased risk of endometrial cancer in women. Patients with polycystic ovary syndrome often have abnormal levels of estrogen. Their follicles are difficult to mature and ovulate, resulting in the accumulation of small follicles in the ovaries and excessive secretion of estrogen. The absence of a luteinizing hormone peak hinders the formation of corpus luteum, leading to an imbalance in estrogen and progesterone secretion. The endometrium undergoes prolonged stimulation by elevated levels of estrogen, leading to sustained proliferation. Without the antagonism of progesterone, the endometrium fails to undergo the normal periodic exfoliation and instead continues to thicken, which may develop into atypical hyperplasia and increase the risk of EC.

Figure 2

Immune mechanism of endometrial microbiome in the development of endometrial cancer. Dysregulation of the microbial community in the host’s endometrium results in an increase in pathogenic bacteria, which may subsequently induce the release of pro-inflammatory cytokines or toxins. Metabolic products from these pathogens, such as short-chain fatty acids (SCFAs), have the potential to activate the immune system, thereby inducing the release of pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, IL-17, and IL-1α. These pro-inflammatory factors trigger local or systemic inflammatory responses. Prolonged exposure to a pro-inflammatory state within the host’s internal environment can lead to cellular damage. Chronic inflammation and cell proliferation may contribute to abnormal changes and carcinogenesis in endometrial cells. An uncontrolled proliferation of cells ultimately results in abnormal hyperplasia, which may progress into endometrial cancer. Therefore, maintaining microbial homeostasis and preventing the invasion of pathogens are crucial for preserving host health and impeding the onset and progression of cancer. Investigating the relationship between the microbiome and endometrial cancer holds paramount significance in elucidating the pathogenesis of gynecological cancers, particularly endometrial cancer, as well as in developing novel preventive and therapeutic strategies.

Figure 3

The role of different cytokines in the pathophysiology of endometrial cancer. Diverse cytokines can not only influence cell proliferation and differentiation but also modulate the immune system and inflammatory response, thereby impacting the development of endometrial cancer (1). Interleukin-1β, interleukin-6 and interleukin-8 can trigger inflammation, promote the progression of chronic inflammation, activate signaling pathways, stimulate cell proliferation and immune cell recruitment, and promote the secretion of matrix metalloproteinases to accelerate cancer cell invasion and metastasis (2).The binding of Chemokines to receptor proteins can form signaling axes, which can activate signaling pathways, enhance tumor cell migration, invasion, and angiogenesis, regulate the tumor microenvironment, and participate in the onset of endometrial cancer (3). Bacteria and their metabolites can act as exogenous stimuli, recognized and bound by receptors on cells, transmitting signals to the nucleus to promote the transcription of specific cytokines, thereby influencing the occurrence and development of endometrial cancer.