Bladder cancer is a common malignancy in women and is the fourth most common malignancy in men . Men's risk is 3-4 times that of women. In 2020, the American Cancer Society estimates that there will have been approximately 81,400 new cases of bladder cancer (about 62,100 in men and 19,300 in women) and 17,980 deaths from bladder cancer (about 13,050 in men and 4,930 in women) in the U.S. The rates of new bladder cancers and deaths linked to bladder cancer and have been dropping slightly in women in recent years. In men, incidence rates have been decreasing, but death rates have been stable. So what is bladder cancer? And how to prevent yourself from it? Continuing to read this article…
1. What is Bladder Cancer?
Bladder cancer refers to a malignant tumor that occurs on the cells of bladder. The bladder is a hollow muscular organ in your lower abdomen that stores urine (Figure 1). Bladder cancer most often begins in the cells (also called urothelial cells) that line the inside of your bladder. It is the most common malignant tumor of the urinary system and one of the ten most common tumors throughout the body. Its incidence is second only to prostate cancer in the West. Bladder cancer can occur at any age, even in children. The incidence rate increases with age, with a high incidence age of 50 to 70 years.
Figure 1. Male urinary system
In 2004, the pathological types of bladder cancer in the histological classification of urinary system tumors in the WHO "Urinary System and Male Reproductive Organ Tumor Pathology and Genetics" include bladder urothelial carcinoma, bladder squamous cell carcinoma, bladder adenocarcinoma, and other rare (including bladder clear cell carcinoma, bladder small cell carcinoma and bladder carcinoid). The most common one is bladder urothelial cancer, which accounts for more than 90% of the total number of bladder cancer patients. The commonly referred to as bladder cancer refers to bladder urothelial cancer (formerly called bladder transitional cell carcinoma).
2. What are The Symptoms of Bladder Cancer?
No matter what's your age, it's good to know the possible symptoms of bladder cancer. Although they aren't enough to diagnose the disease, they can be clues for you and your doctor so that you can find the problem as soon as possible. Treatment works best early on, when a tumor is small and hasn't spread. These symptoms are important to see your doctor so they can take a closer look at your health and take action. Bladder cancer symptoms may include blood in urine (hematuria), frequent urination, painful urination and back pain.
Among of them, blood in urine is the main symptom of bladder cancer. About 90% of patients with bladder cancer have hematuria in the initial clinical manifestations, usually painless, intermittent, gross hematuria, and sometimes microscopic hematuria. Hematuria may only occur once or last for 1 day to several days, and can be relieved or stopped by itself. It often gives the patient with the hematuria the illusion of healing after taking the medicine.
3. What are The Stages of Bladder Cancer?
Before learning the stages of bladder cancer, we need to know the structure of bladder. The bladder consists of three layers of tissue (Figure 2). The innermost layer of the bladder (called mucosa or urothelium), which comes in contact with the urine stored inside the bladder. The middle layer is a thin lining (known as the "lamina propria") and forms the boundary between the inner "mucosa" and the outer muscular layer. This layer has a network of blood vessels and nerves and is an important landmark of the staging of bladder cancer. The outer layer of the bladder (the "muscularis") comprises of the "detrusor" muscle. This is the thickest layer of the bladder wall.
Figure 2. Types and stages of bladder cancer.
*This figure is derived from the publication on Nat Rev Dis Primers. 
As the Figure 2 shows, bladder cancer generally originates from the urothelium of the bladder and is referred to as urothelial carcinoma, which is the most common type of bladder cancer. Papillary tumors that are limited to mucosa or have invaded the lamina propria are classified as Ta and T1, respectively. Carcinoma in situ (Tis) is a flat, poorly differentiated tumor confined to mucosa. Stage 2 is that tumors have invaded the muscle layer either superficially (T2a) or deeply (T2b). T3 tumors have invaded beyond the muscularis propria into perivesical fat (T3a invasion is microscopic, T3b is macroscopic). T4a tumours have invaded the prostate, uterus, vagina and/or bowel, whereas T4b tumours have invaded the pelvic or abdominal walls .
4. Mechanisms of Bladder Cancer?
Current studies have shown that bladder cancer, like many other cancers, is due to a variety of carcinogenic factors acting on normal cells for a long time, leading to the activation of proto-oncogenes, and failure to repair damaged DNA in time during the replication and transcription process, affecting the cell cycle and causing unlimited replication and proliferation of cancer cells.
In terms of mechanisms of bladder cancer, metabolism of bladder cancer represents a key issue for cancer research . Several metabolic altered pathways are involved in bladder tumorigenesis. In this section, we list the main metabolic pathways involved in the pathogenesis of bladder cancer.
Tumor cells, including urothelial cancer cells, rely on a peculiar shift to aerobic glycolysis-dependent metabolism (the Warburg-effect) as the main energy source to sustain their uncontrolled growth and proliferation. And the high glycolytic flux usually depends on the overexpression of glycolysis-related genes, including SRC-3, GLUT1, GLUT3, LDHA, LDHB, HK1, HK2, PKM, and HIF-1a, leading to an overproduction of pyruvate, alanine and lactate.
Concurrently, bladder cancer metabolism also displays an increased expression of genes G6PD and FASN, and companies with a decrease of AMPK and Krebs cycle activities. G6PD is favored in the pentose phosphate pathway, and FASN is favored in the fatty-acid synthesis. Moreover, the PTEN/PI3K/AKT/mTOR pathway, as central regulator of aerobic glycolysis, is hyper-activated in bladder cancer, contributing to cancer metabolic switch and tumor cell proliferation. Besides glycolysis, glycogen metabolism pathway also plays a robust role in bladder cancer development.
5. What are The Risk Factors for Bladder Cancer?
The etiology of bladder cancer is currently unclear. There are both internal factors and external environmental factors. The two more clear risk factors for disease are smoking and occupational exposure to aromatic amine chemicals.
Smoking is currently the most certain risk factor for bladder cancer. 30% to 50% of bladder cancer is caused by smoking. Comparing to people without smoking, smoking can increase the risk of bladder cancer by 2 to 6 times. With the prolongation of smoking, the incidence of bladder cancer also significantly increased.
Another important disease risk factor is related to a series of occupations or occupational exposure. It has been confirmed that aniline, diaminobiphenyl, 2-naphthylamine, and 1-naphthylamine are all carcinogens of bladder cancer. People with long-term exposure to these chemicals are more likely to develop bladder cancer. Patients with bladder cancer caused by occupational factors account for 25% of the total number of bladder cancer patients. Industries related to bladder cancer include aluminum products, coal tar, asphalt, dyes, rubber, and coal gasification.
In addition, according to a report issued by the International Agency for Research on Cancer (IARC) on October 17, 2013, air pollution is also one of the human carcinogens, and its carcinogenic risk is classified as the first category. The report pointed out that there is sufficient evidence that air pollution not only has a causal relationship with lung cancer, but also increases the risk of bladder cancer. So far, haze is also one of the clear carcinogenic factors.
6. What are The Treatments for Bladder Cancer?
Urothelial carcinoma of the bladder is divided into non-muscle invasive urothelial carcinoma and muscle invasive urothelial carcinoma. Patients with non-muscular invasive urothelial carcinoma usually use transurethral resection of the bladder tumor, followed by bladder perfusion to prevent recurrence.
Patients with muscular invasive urothelial carcinoma, bladder squamous cell carcinoma, and adenocarcinoma are mostly treated with total cystectomy, and some patients can be treated with partial cystectomy. Patients with muscular invasive urothelial carcinoma can also be treated with neoadjuvant chemotherapy and surgery first. Metastatic bladder cancer is dominated by chemotherapy. Commonly used chemotherapy regimens include M-VAP (methotrexate + vinblastine + adriamycin + cisplatin), GC (gemcitabine + cisplatin) and MVP (methotrexate + The vinblastine + cisplatin) regimen, the effective rate of chemotherapy is 40% to 65%.
7. What Treatments are needed to Better Prevent Recurrence after Surgery?
Bladder cancer has the characteristics of multifocality and implantation, so the recurrence rate after surgery is high. Therefore, after bladder cancer surgery, adjuvant treatment is usually needed. So, what treatments are needed after bladder cancer surgery?
As mentioned previously, patients with non-muscular invasive urothelial carcinoma will be treated with bladder perfusion therapy. Bladder perfusion therapy is to inject anticancer drugs into the bladder to kill tumor cells remaining after surgery. There are two main types of drugs for bladder perfusion therapy, one is chemotherapeutics and the other is immunotherapy, and chemotherapy drugs are currently more commonly used. The chemotherapeutics used for bladder cancer include birubicin, epirubicin, adriamycin and mitomycin. For most bladder cancers, bladder infusion chemotherapy can significantly reduce the risk of tumor recurrence after surgery.
In addition to bladder perfusion therapy, regular cystoscopy is also very important. In low-risk patients, there was no recurrence after the cystoscopy was rechecked 3 months after the operation. The next cystoscopy can be checked 1 year after the operation. Then once a year for 5 years. But, high-risk patients need to review the cystoscopy every 3 months for 2 years after the operation, and every 6 months from the 3rd year, and once a year after the 5th year.
8. How to prevent yourself from Bladder Cancer?
Although there's no guaranteed way to prevent bladder cancer, you can take the following steps to help reduce your risk.
Increase drinking water: Researchers from Harvard University in the United States conducted a 10 year follow-up study on nearly 50,000 American men between the ages of 40 and 75, and found that men who drink 6 large glasses of plain water a day have a lower risk of bladder cancer than those who drink only 1 cup. It may be that the liquid will excrete carcinogens from the body before they can affect the bladder. Thereby reducing the chance of attaching to the bladder wall. Note that, in order to minimize the intake of the chemical components in the water, the water must be boiled.
Quit smoking and alcohol: Studies have shown that cigarettes contain nicotine, tar, tobacco-specific nitrosamines and other toxic carcinogens. People who smoke a lot have a higher concentration of carcinogens in the urine. If the daily smoking index reaches 600 (number of cigarettes smoked per day × number of years of smoking), it has reached the risk of bladder cancer. Therefore, early quitting smoking and drinking can minimize the risk of bladder cancer.
Adhere to scientific eating habits and eat more fresh vegetables and fruits: Eat as little meat as possible, because meat can produce substances similar to aniline and benzidine during the process of metabolism in the body. An investigation found that workers exposed to chemical raw materials such as aniline and benzidine suffer more from bladder cancer.
 Andrew T. Lenis, Patrick M. Lec, Karim Chamie. Bladder Cancer A Review [J]. JAMA. 2020, 324 (19).
 Oner Sanli, Jakub Dobruch, Margaret A. Knowles, et al. Bladder Cancer [J]. Nat Rev Dis Primers. 2017.
 Knowles, M. A. & Hurst, C. D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat. Rev. Cancer. 2015, 15, 25–41.
 Francesco Massari, Chiara Ciccarese, Matteo Santoni, et al. Metabolic phenotype of bladder cancer [J]. Cancer Treatment Reviews. 2016, 45: 46–57.
CUSABIO team. Bladder Cancer, A Malignancy that Favors Men. https://www.cusabio.com/c-21003.html