Sexual dimorphism in colorectal cancer: molecular mechanisms and treatment strategies

Abstract

Introduction: Sexual dimorphism significantly influences cancer incidence and prognosis. Notably, females exhibit a lower risk and favorable prognosis for non-reproductive cancers compared to males, a pattern observable beyond the scope of risk behaviors such as alcohol consumption and smoking. Colorectal cancer, ranking third in global prevalence and second in mortality, disproportionately affects men. Sex steroid hormones, particularly estrogens and androgens, play crucial roles in cancer progression, considering epidemiological in vivo and in vitro, in general estrogens imparting a protective effect in females and androgens correlating with an increasing risk of colorectal cancer development.

Main body: The hormonal impact on immune response is mediated by receptor interactions, resulting in heightened inflammation, modulation of NF-kB, and fostering an environment conducive to cancer progression and metastasis. These molecules also influence the enteric nervous system, that is a pivotal in neuromodulator release and intestinal neuron stimulation, also contributes to cancer development, as evidenced by nerve infiltration into tumors. Microbiota diversity further intersects with immune, hormonal, and neural mechanisms, influencing colorectal cancer dynamics. A comprehensive understanding of hormonal influences on colorectal cancer progression, coupled with the complex interplay between immune responses, microbiota diversity and neurotransmitter imbalances, underpins the development of more targeted and effective therapies.

Conclusions: Estrogens mitigate colorectal cancer risk by modulating anti-tumor immune responses, enhancing microbial diversity, and curbing the pro-tumor actions of the sympathetic and enteric nervous systems. Conversely, androgens escalate tumor growth by dampening anti-tumor immune activity, reducing microbial diversity, and facilitating the release of tumor-promoting factors by the nervous system. These findings hold significant potential for the strategic purposing of drugs to fine-tune the extensive impacts of sex hormones within the tumor microenvironment, promising advancements in colorectal cancer therapies.

Keywords: Androgen receptor; Colon cancer; Estrogen receptor; Neuroimmunoendocrine network; Sex steroids; Sexual dimorphism.

Fig. 1

Pathogenesis of colorectal cancer associated with ulcerative colitis (early stages of CRC). Innate cells and adaptative immune cells increase their production of soluble factors which can trigger a chronic inflammation process. If this state is maintained, the possibility of developing cancer is greater due to an increase in the mutation rate and the loss of intestinal homeostasis. One of the pathway involved in this process is NF-kB that contributes increasing the proliferation of intestinal cells, modulating the production of proinflammatory cytokines and stimulating the expression of receptors such as TLRs and MCH II (A). On another hand, in advance stages of cancer, immune cells change to an immunosuppressor phenotype. Both tumor and immune cells secrete factors that hinder the effective elimination of transformed cells (B). abbreviations: ROS, reactive species of oxygen. COX2, cyclooxygenase 2. NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells. IL-(6,10, 1β), Interleukin. TGF-β, Transforming growth factor beta. TNF-α, tumor necrosis factor alpha. MHC, Major Histocompatibility Complex. TLR, Toll-like receptors. VEGF, Vascular endothelial growth factor. MMPs, metalloproteinases. This figure was created with BioRender.com

Fig. 2

General action mechanism of sex steroids. These molecules can exert their effects on cells through binding to cytoplasmic receptors (genomic effect). These receptors translocate to the nucleus and binds to EREs or AREs. The other mechanism is through membrane receptors (non-genomic effect) that activates signaling cascades such as PI3K/AKT, MAPKs and ERK. Both mechanisms modulate process involved on inflammation such as survival, cytokine production, chemokine segregation. The effect of estrogens depends principally on the dose and the type of receptor expressed (alpha or beta) (A). On another hand, in general, androgens exert and immunosuppressor phenotype (B). abbreviations: PI3K: phosphoinositide 3-kinases. MAPKs: mitogen-activated protein kinases. EREs: estrogen response elements. AREs: androgen response elements. ERK: extracellular signal-regulated kinase. AKT: alpha serine/threonine-protein kinase. SRC: proto-oncogene tyrosine-protein kinase. E2: estradiol. T: testosterone. This figure was created with BioRender.com

Fig. 3

Mechanism of action of nervous innervation in the colon and tumor progression. CRC patients exhibit increased infiltration of nerve fibers directly associated with the stage of disease. Nerve fibers secrete neurotransmitter that influence increase inflammation, proliferation and invasion that promotes the development of tumors. These effects are carried out by the segregation of neurotransmitters such as NE, 5-HT and Ach that interact with their receptors in immune and tumor cells. NE: norepinephrine. 5-HT: serotonin. Ach: acetylcholine. MMPs: metalloproteinases. VEGF: vascular endothelial growth factor. This figure was created with BioRender.com

Fig. 4

Regulation of sex steroids to neuroinmmunedocrine network. E2 potentially inhibits tumoral progression by several mechanisms. First, this hormone avoids chronic inflammation; affects the enteric system. Primarily, it stimulates neurogenesis and maintains tissue architecture. Also, increase the diversity of bacteria which protects against the development of tumors. Finally, E2 reduce the proliferation of tumor cells directly through their interaction with ER-β (A). Possible regulatory effects of androgens on the neuroendocrine network and repercussions for tumor growth. Contrarily, androgens play an immunosuppressive role that potentially help tumor cells to evade immune response. These molecules stimulate the release of catecholamines, 5-HT and Ach that promotes tumor growth and invasion. Additionally, androgens reduce the diversity of bacteria in the microbiota. Finally, stimulate apoptosis and migration of tumor cells directly (B). T: testosterone. E2: estradiol. This figure was created with BioRender.com