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Evaluation of a Novel Organ-Preserving Bladder Cancer Treatment

/ by Lifeline® Cell Technology

Bladder Health Awareness Month

Bladder health conditions affect millions of men and women worldwide, yet symptoms often go unrecognized or unaddressed due to stigma or lack of awareness. In some cases, these symptoms may indicate more serious conditions, including bladder cancer (BCa), which is the 10th most common cancer worldwide.

Bladder Health Awareness Month highlights the importance of education, early detection, and timely treatment. While surgery remains the standard of care for bladder cancer treatment, the approach can have significant implications for quality of life particularly in late-stage cancer, highlighting the need to investigate effective bladder-preserving treatment strategies.

Photodynamic therapy (PDT) and radiotherapy using ionizing radiation (IR) are two approaches being investigated for their potential in organ-preserving bladder cancer treatment. Understanding whether combining these therapies can improve antitumor responses and specificity requires experimental models that closely reflect human bladder biology.

In our featured publication, researchers used human bladder-like organoids, which are physiologically relevant, three-dimensional (3D) in vitro models, to evaluate the antitumor effects of a combination therapy (IR+PDT), as a bladder-preserving therapeutic strategy.

Enhanced Cytotoxicity and Tumor Selectivity with Combined PDT and IR Therapy

Radiotherapy using IR induces DNA damage, including single- and double-strand breaks, leading to tumor cell death. In contrast, photodynamic therapy (PDT) uses light to activate a photosensitizer (PS) in the presence of oxygen, generating reactive oxygen species (ROS) that damage cellular components and trigger cell death. Combining these approaches may work together to enhance tumor-specific activity.

To investigate the therapeutic potential of combined IR and PDT for bladder cancer,  Reinhold et al. generated three-dimensional bladder-like organoids using bladder cancer cell lines, Lifeline® Cell Technology primary human bladder fibroblasts (hBF), and human bladder smooth muscle cells (hBSMC). The organoids were generated using the ultra-low attachment (ULA) microplate method. Bladder fibroblasts were cultured in Lifeline® FibroLife® S2 Medium, while bladder smooth muscle cells were cultured in Lifeline® VascuLife® SMC Medium.

The researchers exposed bladder-like organoids to IR (9 Gy), PDT using the near-infrared photosensitizer tetrahydroporphyrin-tetratosylate (THPTS; 25 or 50 μM, 20 J/cm²), or a combination of both treatments. After treatment, the organoids were cultured for additional 24, 48, 72 and 96 h. Treatment-induced cytotoxicity was determined using microscopy, cell-based assays and histology. The mechanism of cell death was analyzed by applying specific inhibitors followed by immunofluorescence or qPCR analyses of cell death markers. A matrix-based co-culture model was used to study T cell migration into the environment of treated organoids.

Treatment with PDT or IR reduced metabolic activity and organoid diameter and disrupted organoid integrity, with responses varying according to tumor grade. High-grade bladder cancer organoids generally exhibited greater sensitivity to treatment. Combination IR + PDT enhanced cytotoxicity compared with either treatment alone, producing additive or synergistic effects depending on the experimental conditions.

Combination IR + PDT was found to activate multiple cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, and necrosis. The combination also demonstrated tumor-selective effects in the organoid models, significantly reducing the thickness of the tumor cell layers in BCa organoids compared to non-malignant organoids non-malignant bladder organoids, generated from the immortalized uroepithelial cell line HBLAK. In comparison, the standard of care chemotherapeutic agent doxorubicin was highly non-selective and induced cell death in both malignant and nonmalignant organoid models.

Finally, the researchers also investigated the immunogenic effects of combined treatment using a co-culture model containing bladder cancer organoids and T cells. Treatment-associated release of damage-associated molecular patterns (DAMPs) was accompanied by increased T-cell migration into the organoid microenvironment, suggesting the immunogenic potential of combination IR + PDT to activate antitumor immune responses.

Together, these findings highlight the potential of combined IR and PDT as a bladder-preserving therapeutic strategy that enhances tumor cell killing while potentially stimulating antitumor immune activity. Although further research is needed to establish its safety and clinical efficacy, the study also demonstrates the value of human-relevant, multicellular bladder organoid models for evaluating emerging cancer treatments.

Lifeline Cell Technology Bladder Cells and Media

Lifeline offers a comprehensive portfolio of primary human bladder cells and specialized culture media to support in vitro urological research. These products provide researchers with tools to develop human-relevant experimental models, including multicellular systems such as the bladder-like organoids featured in this publication.

Explore our blog to see how our cells and culture media are advancing biomedical research worldwide. If you have used our products in your publication, we’d love to feature your work here!

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