Sexual Dimorphism in Colon Cancer

Abstract

A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18-44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.

Keywords: GPER; Kv channels; Wnt/β-catenin; colon cancer; estrogen; sexual dimorphism.

Figure 1

Estimated age-standardized incidence rates worldwide of colorectal cancer in 2018. Men (in red) display higher incidence rates than age-matched women (in green) in each region. ASR, Age-standardised rate. Data from the Global Cancer Observatory https://gco.iarc.fr/today/home (5).

Figure 2

Age-standardised colorectal cancer incidence rates of men and women in USA, UK and China. Colon cancer incidence rates by age show men have higher incidence rates than females from 45 years of age Colon cancer is shown in red for men and green for women. Data from Ci5plus in the International Agency for Research on Cancer (6). https://ci5.iarc.fr/CI5plus/Pages/graph1_sel.aspx.

Figure 3

CRC incidence rates over time show sexual dimorphism and have been relatively stable during the 25 years examined. Examples from United States, United Kingdom, and China colon cancer registries are shown in red for men and green for women. Data acquired from Ci5plus in the International Agency for Research on Cancer (6) https://ci5.iarc.fr/CI5plus/Pages/graph4_sel.aspx.

Figure 4

Estimated age-standardized mortality rate worldwide of colorectal cancer in 2018. Men (in red) exhibit higher mortality rates than female (in green) in every region. ASR, Age-standardised rate. Data from the Global Cancer Observatory (5).

Figure 5

GPER mediates opposing functions of estrogen in CRC cells, depending on oxygen levels. GPER agonists suppress cell proliferation and migration under normoxic conditions, but stimulate proliferation under hypoxic conditions. Estrogen synergises with hypoxia by repressing ATM expression via GPER, and combined with the activation of HIF1A and VEGFA, potentiates the hypoxia-induced cell proliferation and migration.

Figure 6

Sexual dimorphism of HIF1A and VEGFA expression in CRC survival. CRC patient survival analysis carried out using the R2 data visualisation platform from the Amsterdam Medical Centre R2: Genomics Analysis and Visualization Platform (http://r2.amc.nl) publically available datasets gse14333 + gse17538. The upper quartile of HIF1A gene expression was used to separate between high and low expression. P-values were calculated using a logrank test. Sufficient survival data was not available to calculate overall survival. (A) Relapse free survival in females only when associated with HIF1A expression, last quartile expression of HIF1A was associated with worse relapse-free survival in the female population (p = 0.047). (B) Relapse-free survival in males only when associated with HIF1A expression, last quartile expression of HIF1A was not associated with relapse free survival in the male population (p = 0.721). (C) Relapse-free survival in females only when associated with VEGFA expression, last quartile expression of VEGFA was associated with worse relapse-free survival in the female population (p = 1.1 e-3). (D) Relapse-free survival in males only when associated with VEGFA expression, last quartile expression of VEGFA was associated with worse relapse-free survival in the male population (p = 0.01).

Figure 7

Regulation of epithelial mesenchymal transition via β-catenin:KCNQ1 interactions in CRC cells. In well-differentiated CRC cell lines, KCNQ1 stabilizes β-catenin with E-cadherin at adherens junctions to maintain a polarised epithelial phenotype. KCNQ1 expression also modulates the β-catenin phosphorylation state. KCNQ1 promotes Ser33 β-catenin phosphorylation, which reduces β-catenin stability by enhancing its proteosomal degradation. In poorly differentiated CRC cells in which Wnt/β-catenin activation is high, KCNQ1 expression is repressed by the β-catenin/TCF4 transcription factor. The low expression of KCNQ1 increases β-catenin phosphorylation at residues Tyr654 and Ser675, which activate nuclear translocation of activated β-catenin to stimulate the expression of proliferative genes and promote EMT and loss of cell polarity. In addition, phosphorylation at Tyr654 reduces β-catenin binding to E-cadherin and P-Ser675 protects β-catenin from proteosomal degradation [from (199)].

Figure 8

Sexual dimorphism in the correlation between KCNQ1:KCNE3 and CRC patient relapse-free survival. Sex-differentiated analysis of human primary CRC tumor patient databases (accession number: GSE39582) showed a positive correlation between KCNQ1 and KCNE3 expression and disease-free survival in female patients only with no correlation observed in male patients. Survival analysis carried out using the R2 data visualisation platform from the Amsterdam Medical Centre R2: Genomics Analysis and Visualization Platform (http://r2.amc.nl) publically available datasets gse39582. Median gene expression values was used to separate between high and low expression. P-values were calculated based on a logrank test. Sufficient data was not available to calculate overall survival.

Figure 9

Sexual dimorphism targets of estrogen signaling, receptors and genes underpinning sex differences in the development of CRC. Estrogen, receptors and genes modulate ion channels, metabolism, innate and adaptive immunity, and oncogene expression to activate non-genomic and genomic responses underpinning CRC development from neoplastic transformation, adenomas, carcinoma to tumor.