‘Fiery’ cell death during chemotherapy may help bladder cancer cells fight back

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 chemoresistant cancer 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,” said Keith Syson Chan, Ph.D., the Neal Cancer Center Distinguished Chair in the Dr. Mary and Ron Neal Cancer Center at Houston Methodist and a 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.