Chemotherapy may trigger inflammatory response that fuels bladder cancer resistance

Chemotherapy used to target and kill bladder cancer cells may trigger an inflammatory response that ultimately may make the cancer more resistant to treatment, according to new research from scientists at Houston Methodist.

The findings are highlighted in "Caspase-1–dependent pyroptosis converts αSMA+CAFs into collagen-III high iCAFs to fuel chemoresistantcancer stem cells," which was recently published in Science Advances. The researchers examined why chemotherapy is not exerting its desired effects in the treatment of bladder cancer. The study also found that blocking this inflammatory process with the drug belnacasan can overcome chemoresistance in preclinical mouse models.

Specifically, the study looked at how chemotherapy-induced tumor cell death – known as pyroptosis or "fiery death" – affects neighboring fibroblasts, a type of support cell within the bladder cancer. Instead of destroying these support cells, the chemotherapy treatment caused some of them to produce collagen, which can help cancer stem cells survive and become more resistant to chemotherapy.

"Our findings surprisingly revealed that not all forms of cell deaths are helpful in fighting cancer," said Hongbo Beth Gao, Ph.D., a research associate at Houston Methodist and a co-corresponding author. 

In a sense, the 'fiery' or inflammatory death of these cancer cells from the chemotherapy actually made things worse, not better."

Keith Syson Chan, Ph.D., the Neal Cancer Center Distinguished Chair in the Dr. Mary and Ron Neal Cancer Center at Houston Methodist and co-corresponding author

The researchers used mice and patient samples, gene analysis and lab experiments. They found that proactively administering drug therapy to block this "fiery" or inflammatory cell death – and the resulting collagen production – may improve patient treatment outcomes.

"Combination treatment with belnacasan, to stop this type of 'fiery' cell death can improve chemotherapy response," Gao said.

While future work is needed to examine the effects of this treatment across different types of cancer, the researchers said this therapy has also shown promise in the treatment of breast cancer. They hope their work will ultimately lead to improved treatment for a variety of cancers.

Gao and Chan's collaborators included Stephen Q. R. Wong, Ethan Subel, Yung Hsing Huang, Zachary Melchiode, Ziad El-Zaatari, Steven Shen, Raj Satkunasivam, Fotis Nikolos and Armine Kasabyan from the Department of Urology, Houston Methodist Neal Cancer Center and the Houston Methodist Research Institute; Yu-Cheng Lee from Taipei Medical University; Kazukuni Hayashi from Stanford University; Mark Ellie Alonzo and Xen Ping Hoi from the Department of Urology, Houston Methodist Neal Cancer Center, the Houston Methodist Research Institute and Cedars-Sinai Medical Center; Mustafa Karabicici, Cedars-Sinai Medical Center; and Qianxing Mo from H. Lee Moffitt Cancer Center.

The National Cancer Institute (grants R01cA175397, R01cA175397- S, U54cA274375 and R01cA255609) and Cancer Prevention and Research Institute of Texas (cPRit- RR230010, F31cA247257 and F31cA278582) provided financial support for this research.