Mets Day 747: What causes bladder cancer

Scientists have known for some time of an association between smoking and bladder cancer. But there has been little understanding of how bladder cancer actually gets started, especially because it can mutate so quickly. A just-published study out of Stanford claims to have definitively answered the question, however. The study, titled "Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma", by Shin, et al., was published online in Nature Cell Biology on April 20, 2014. An abstract is available here. I could not find the full version of the article on a free website; fortunately, my daughter who is graduating from medical school next month was able to get the complete article and send it to me. 

In short, the study says that all bladder cancers start from a certain type of stem cell in basal urothelium -- the lining of the bladder. The specific characteristic of the cancer-triggering stem cell is that it expresses a certain type of protein with the real, but incredibly stupid, name of Sonic hedgehog. The researcher chose the name after Sonic the Hedgehog, a character in the Sega video game.  The abbreviation for the Sonic hedgehog protein is Shh. 

The Stanford article details how the researchers isolated the Shh protein and showed that the mutations from Shh-expressing stem cells were solely responsible for all bladder cancers in mice, which closely mimic human bladders. Once those Shh-expressing stem cells start cloning themselves, they rapidly displace all other types of cells in the lining of the bladder. Amazingly, once the cells start forming tumours, they lose their Shh-expressing characteristics. This is why mature bladder cancer tumours do not reflect their origin in Shh-expressing stem cells.

Figure 8 of the study contains a graphic that details the progression from normal cells lining the bladder to bladder cancer tumours. (Figure 8 can be viewed in the abstract by clicking through the figures under the "at a glance" tab.) The concluding paragraph of the article says:

The events of carcinoma initiation and progression are summarized in Fig. 8, and begin with accumulation of mutations in Shh-expressing urothelial basal stem cells, the cancer cell of origin. These mutations allow the progeny of a single cell to sweep through and colonize an extensive portion of the urothelium and form a CIS precursor lesion. Within this lesion, Shh-positive basal cells accumulate further mutations, leading to further clonal expansion and ultimately to trans-formation and invasion of the stromal and muscle layers of the bladder. The latter stages of this process are consistently accompanied by loss or attenuation of Shh expression, and further studies will be required to establish the significance of this loss. One of the key features of our findings is that progression to invasion occurs in the context of a precursor lesion with pre-neoplastic changes that aggressively spreads through most if not all of the urothelium. Resection of invasive carcinomas, even if complete, thus may leave in place urothelial cells that already have taken several early steps along the path to invasive tumour formation, thus potentially accounting for the frequent recurrence and high morbidity of invasive human bladder cancer.

I've never smoked, so there is no obvious explanation of what caused my bladder cancer. But now I know it's because of a mutation in my bladder stem cell gene called Sonic hedgehog.

The article does not suggest how patients with existing metastatic bladder cancer can be cured. Mature bladder cancer tumours, both within the bladder, and metastatic, have a number of mutations and characteristics that make it a very hard cancer to kill. But by identifying the definitive pathway by which bladder cancer starts, this study is an important step forward for diagnosing and treating early bladder cancers, and eventually learning how to prevent the cancer from forming at all.