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.

Sex differences in tumor characteristics, treatment, and outcomes of gastric and esophageal cancer surgery: nationwide cohort data from the Dutch Upper GI Cancer Audit

“…For both gastric and esophageal adenocarcinomas, behavioral risk factors, such as obesity or exposure to carcinogens like tobacco smoking, do not entirely explain the sex disparity in incidence seen across multiple populations [3][4][5], thus strongly suggesting sex differences in susceptibility and/or biology for this type of cancer. In fact, increasing evidence suggests a sexual dimorphism in cancer biology, and sex-biased molecular signatures have been observed across multiple tumor types [6][7][8][9][10].…”

Association Between the Sulfur Microbial Diet and Risk of Colorectal Cancer

“…6 However, because there are potential sex-based differences in nutrient metabolism 7 and CRC risk, 8 a study leveraging a more diverse population is needed to confirm these findings. Cohort studies 9,10 and reviews 8,11 have reported that, compared with men, women have a lower overall incidence of CRC but a higher risk of proximal colon cancer, which tends to be more advanced and less differentiated than distal colon cancer. 8,10,12 In addition, there are potential sex differences in the gut microbiome in response to diet.…”

Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study

“…Our previous study identified that multiple LysoPCs and LysoPEs were upregulated in female patients with RCC (stage I) only, suggesting that the higher level of lysophospholipids in women with RCC would promote fatty acid supply that is essential for cancer cell growth at early stages 21 . It has also been discussed that sex-specific estrogen regulation may inhibit CRC cell survival by suppressed triglyceride biosynthesis, a vital lipid marker related to CRC progression 17 .…”

“…In addition, sex-related differences in CRC prognosis have become increasingly important in cancer research 16,17 . Female patients have a higher prevalence of right-sided colon cancer (RCC), which is associated with poorer overall survival (OS) 18,19 .…”