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3D cancer model reveals how a static magnetic field can enhance radiotherapy

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3D model of pancreatic cancer

Pancreatic cancer is a notoriously lethal disease, with a five-year survival rate of about 9%. As surgery is only appropriate for 8–20% of patients, chemotherapy is the most common treatment, with radiation therapy still sparsely used and mainly as an adjuvant option.

Clinical trials examining radiation treatments of pancreatic cancer have produced conflicting results, promoting a debate on the best guidelines to apply and potential benefits. Pancreatic cancer is notoriously resistant to chemotherapy and radiotherapy due to an extremely complex tumour microenvironment (TME, the tissues surrounding a cancerous lesion) characterized by the presence of diverse cell populations and strong hypoxia gradients.

Newer advanced radiotherapy modalities, such as MR-guided radiotherapy which employs MRI to guide the delivery of the radiation dose, can provide some benefit by supplying accurate information about the TME. This could then be used to optimize the treatment. To date, however, there is limited knowledge regarding the interaction between radiation and the static magnetic field from an MR-guided radiotherapy system, and how this may impact the response of cancer cells.

To study complex TMEs like those associated with pancreatic cancer, a UK-based research team has developed a 3D polymeric highly macro-porous scaffold model. The researchers, from the University of Surrey, University College London and the National Physical Laboratory (NPL), created the multicellular non-animal model to evaluate the impact of a static magnetic field on the response of pancreatic cancer cells to MR-guided radiotherapy.

Pancreatic ductal adenocarcinoma has a complex and highly immunosuppressive TME containing many different cell types, including pancreatic stellate cells that, once activated by cancer cells, create dense desmoplasia (excessive connective tissue). This desmoplasia, along with chaotic cancer cell growth, causes the collapse of blood vessels and the formation of aberrant, disorganized vessel networks, hindering chemotherapy delivery and creating large hypoxic expanses that impair radiotherapy efficiency.

The 3D model, described in the British Journal of Radiology, incorporates pancreatic cancer cells, human microvascular endothelial cells and pancreatic stellate cells. It consists of an outer collagen-coated compartment for growth of stellate and endothelial cells, and an inner fibronectin-coated compartment for growth of the cancer cells. This architecture supports growth and proliferation of different TME cells, enabling cells to migrate from one compartment to another during an extended observational period of 37 days. Importantly, the model is able to replicate the hypoxic regions of the TME.

Principal investigator Giuseppe Schettino and colleagues used their 3D scaffold model to investigate the response of pancreatic cancer cells to radiation in combination with a static magnetic field. They irradiated samples exposed to hypoxia (1% O2) or normoxia (21% O2) with 6 MV photons in the presence or absence of a 1.5 T field, using dedicated equipment at NPL. They then monitored cell viability and cell apoptosis one and seven days after irradiation.

The results revealed a systematic trend of hypoxia-associated radioprotection in pancreatic cancer cells in the 3D scaffolds, with increased tumour cell viability and decreased cell apoptosis seen in both short-term and long-term analyses. Specifically, irradiation of scaffolds in normoxia led to a significant decrease in live cells, while those treated with radiation in hypoxia showed no significant decrease. The team notes that this is in line with previous findings of radioprotection under in vitro hypoxia.

Cancer cell viability after radiation treatment

The researchers report that, in both hypoxia and normoxia, they observed a small enhancement of the effect of radiation in the presence of the static magnetic field. Exposure to the magnetic field alone did not induce any toxicity. They now plan to investigate the mechanisms responsible for such radiation enhancement in future studies.

“It is important to have good models on which to test new therapeutic approaches for difficult-to-treat cancers, such as image-guided radiotherapy, which employs strong magnetic fields,” says Schettino. “Before clinically adopting new approaches, they need to be well evaluated and understood at the pre-clinical level, which usually requires use of animal models that don’t always well represent humans. Our non-animal model can assess the potential impact of the magnetic field on the radiation response.”

“Our work is aimed at improving cancer radiotherapy through a more biologically optimized approach,” he tells Physics World. “We need to analyse how interaction between the magnetic field, the radiation beam, and cellular and molecular processes could alter the response of both normal and cancerous tissues, and therefore the efficacy of the radiotherapy. Estimating such an effect, or lack of effect, is helpful in designing and planning new clinical trials.”

Schettino advises that the NPL is interested in using the multicellular scaffold model with proton beams and potentially also FLASH beams.

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