Thus, preclinical models that faithfully mimic peritoneal metastasis are needed to assess the efficacy of new therapies. To this end, Olivier De Wever and his team at Ghent University have developed a novel 3D model that combines 3D printing, multicellular cell culture and in vivo implantation. This model improved the replication of the peritoneal metastasis compared with current models (Biomaterials 158 95).

Printing a tumour model
One of the limitations of current models is imitating the dimensions and mechanical properties of the tumour. However, with the new technologies of 3D printing, and subsequent surface modifications such as collagen coating and UV treatment, the properties of the produced scaffold model can be tuned as required. In particular, the researchers employed 3D printing of polylactic acid (PLA) and treatments with plasma, gelatin and UV to modify the surface.

Using this process, they created a scaffold with the appropriate size, porosity, and mechanical and biochemical properties to replicate metastasis conditions and promote a population of relevant cancer and interacting cells. This resulted in a more clinically relevant model than achieved in previous studies.

Replicating tumour complexity
Solid tumours include different cell populations that interact among themselves. Such interactions play a crucial role in the fate of the tumour. Thus, they must be present to achieve a relevant model. In this study, the researchers combined cancer-associated fibroblasts (CAF) with tumour cell lines. The combination of these cell populations enabled the formation of tumour structures in vitro (spheroids), demonstrating the importance of the presence of CAF in forming a representative tumour model and providing an additional advantage over previous models.

To further assess whether these modelled constructs can reproduce metastasis conditions in vivo and serve as a representative model, the researchers implanted them in the peritoneal cavity of mice. After 11 weeks, they observed that the implanted models presented a heterogeneous cell population, including the seeded CAF and proliferating cancer cells, as well as host cells such as immune, adipose and epithelial cells.

Interestingly, these constructs also promoted the formation of blood vessels. This is thought to be dependent on the CAF-cancer cell interaction, which is able to produce specific signals that promote neovascularization. In addition, comparing the implanted constructs, a traditional metastasis model and a patient-extracted tumour revealed that the immune response and histological organization of the construct was similar to that found in the patient tumour, in contrast to the traditional model.

A step closer
Overall, the research team succeeded in developing a more representative preclinical model of peritoneal metastasis, by replicating more closely characteristics such as size, heterogeneous cell population, blood vessel formation, immune response and histological resemblance to human tumours. This study represents a step forward in the development of preclinical models to assess drug efficacy and penetrability, a major limitation in the field of peritoneal metastases. Furthermore, it provides a basis to advance screening technologies for the development of new therapies.