Statistically, men are nearly four times more likely to be diagnosed with bladder cancer than women. But why is this? In the UK alone, bladder cancer is the seventh most common cancer in men, but only ranks seventeenth in women. This discrepancy has long been attributed to lifestyle factors like smoking or occupational exposure to carcinogens.
However, a recent review in Oncogenesis* looked at a number of biological differences between the sexes that could underlie the higher incidence of bladder cancer in men compared to women.
*Doshi, Athans and Woloszynska, Biological differences underlying sex and gender disparities in bladder cancer: current synopsis and future directions. Oncogenesis, 2023;12:44
https://pubmed.ncbi.nlm.nih.gov/37666817
The Role of Androgen Receptors and Immune Evasion
At the heart of this mystery lies the influence of androgens and their receptors. One key mechanism involves the expression of CD24, a surface marker known for its immunosuppressive qualities. When expressed on tumour cells, CD24 helps them evade immune system detection by essentially “hiding” from immune surveillance. Androgen receptors are believed to promote the upregulation of CD24, thereby facilitating this immune evasion. The implication is that men, with higher levels of circulating androgens than women, may have a more immunosuppressive and tumour-promoting microenvironment.
Compared to normal bladder cells, bladder cancer cells have been found to recruit more beta cells, which promote androgen-receptor signalling pathways. In turn, these further promote the expression of genes associated with metastasis. This creates a feedback loop in which increased androgen receptor activity leads to greater immunosuppression and enhanced metastatic potential through gene expression that supports cell migration and invasion. This loop not only gives cancer a head start in establishing itself in the bladder tissue but also enables it to spread more aggressively in men compared to women.
Gender Differences in Immune Responses to Carcinogens
Bladder cancer is notably associated with exposure to harmful chemicals, particularly aromatic amines found in tobacco smoke and certain industrial environments. It is the second-highest preventable risk factor for bladder cancer globally, right after smoking.
In epithelial squamous cell carcinoma mouse models, male mice show a higher rate of mitosis and proliferation of cancer cells than females when exposed to a carcinogen. The males’ tumours are less differentiated and more advanced in stage than those found in female mice. This suggests that males are biologically more prone to developing aggressive tumours under carcinogenic stress.
What’s interesting is that these differences persist even when other variables are controlled. The implication is that female immune systems may offer a degree of protection – perhaps through more robust immune surveillance, a higher baseline of immune cell activity, or differing hormonal influences that suppress tumour growth. These protective mechanisms could be key to understanding why women develop bladder cancer at lower rates, despite potential equal exposure to risk factors like smoking or environmental toxins.
Lifestyle Factors Don’t Tell the Whole Story
For decades, the prevailing wisdom attributed the higher incidence of bladder cancer in men to lifestyle choices. After all, men have historically had higher smoking rates and were more likely to work in industries with chemical exposure. But modern data complicates this narrative. Even after adjusting for smoking status, men continue to experience disproportionately high rates of bladder cancer. This suggests that while lifestyle certainly plays a role, it doesn’t fully account for the disparity.
Nearly 8,000 new cases are diagnosed in men each year – and rates are 23% higher in the most deprived quintile compared with the least.
Genetics and Epigenetics
Men and women exhibit distinct mutations and gene expression profiles in bladder tumour tissues. These differences influence not only how the cancer develops but also how it progresses and responds to treatment.
For instance, some studies suggest that male tumours are more likely to express genes associated with immune escape and metastasis, while female tumours might be more immunogenic – eliciting a stronger immune response. Epigenetic alterations, which involve changes in gene activity without altering the DNA sequence, also differ by sex. These changes can be influenced by hormone levels, immune function, and environmental exposures, further widening the biological gap between male and female cancer development.
Current Trends and Hopeful Signs
Despite the grim statistics, there’s a silver lining: bladder cancer rates in men have declined by approximately 16% since the early 2000s. This positive trend is likely due to a combination of reduced smoking rates, improved occupational safety, better awareness, and early detection. However, the rate of decline is not uniform across demographics, and men still bear the brunt of the burden.
The answer for improved bladder cancer treatment and prevention could lie in personalised medicine, in which treatment is based on individual genetic and hormonal profiles – especially if sex-specific therapies are developed.
