A new study conducted by researchers from Johns Hopkins University Round Cancer, shows that two different proteins work separately and together to feed a small pool of stem cells that help the bladder cancer to resist chemotherapy. The discovery, published online in Cancer Research, could lead to new targets for the fight against this deadly disease, and possibly other cancers.
Urothelial carcinoma of the bladder (MSN) is the most common cancer of the urinary tract. In the United States, tens of thousands of patients each year are diagnosed with the disease, which annually kills more than 100,000 people worldwide.
One of the reasons why this disease is so deadly - is the tendency of these tumors to develop resistance to drugs, says study leader Mohammad Hawk, MD, Institute of Philosophy and cancer of the bladder them. Johns Hopkins Greenberg. Recent studies show that the resistance is caused by a small pool of cancer stem cells (RGCs) in these tumors, which are not killed by chemotherapy leading to tumor growth and spread, even after the initial success of the treatment of bladder cancer.
While removal of these RCC is crucial to the fight against bladder cancer, said Hawk, little is known about the mechanisms that underlie how tumor support stem cell population. To explore this, Hawk and his team, including members from the Institute network of cancer Allegheny Network Network, investigated the role of various proteins that have been identified as being associated with the unique features of cancer in RSK: Yes-associated protein1 (YAP1) and cyclooxygenase 2 ( TSOG2).
Working with an RDI of tissue samples urothelial carcinoma human bladder in petri dishes, researchers used a medicine known as celecoxib or genetic techniques to reduce the amount TSOG2 which produced these cells. Their results showed that when the expression TSOG2 decreased, the amount of protein SOX2-a, which is shown as the other experiments, it was crucial for the RAC's ability for self-renewal, migrate and invade surrounding tissue - decreased slightly. Similarly, inhibition YAP1 via drug known as verteporfin or by genetic methods led to a moderate reduction SOX2.
However, when the researchers inhibited production as TSOG2 and YAP1 simultaneously, dramatically inhibited the expression of SOX2, which led to a serious decrease in the ability of these cells to grow into tumors. The data obtained show that TSOG2 YAP1 and work both independently and together to regulate the activity of RAC through SOX2.
"Thus, sharing TSOG2 YAP1 and it may be necessary to eradicate the RSK" - says Hawk.
Indeed, using another model, in which the RSK from tissue samples of urothelial carcinoma of human bladder were grafted into mice and allowed to grow into tumors, the researchers found that inhibition or COX2, or YAP1 drugs enhances tumor response to gemcitabine and cisplatin combination chemotherapy, which often used to treat bladder cancer. But use of both inhibitory drug together with combination chemotherapy has led to an even more dramatic response, resulting in animal tumors regressed continuously during the treatment cycle.
Further experiments suggested that the promotion of RAC overexpress COX2 and YAP1, has led to the fact that cells become resistant to drugs that target protein associated with cancers, known as the epidermal growth factor receptor (EGFR). When researchers treated mice grafted with tumor drug known as erlotinib that targets EGFR, together with combination chemotherapy and inhibitors of COX2 and YAP1, they found most dramatic tumor regression at all, even in aggressive sub bladder cancer, known as basal-type.
These results show that COX2 and YAP1 work individually and together to regulate the RSK in bladder tumor. Impact on both proteins simultaneously may help improve the response of tumors to standard regimens and avoid resistance to chemotherapy.
"Since drugs that inhibit these proteins have already been approved by the FDA for the treatment of other diseases, - adds Hock - this creates the basis for an easy transition to clinical trials."
Source: Cancer Research