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Multicellular tumour spheroids: 3D models for tumour research

Multicellular tumour spheroids, MCTS or MTS for short, have been the focus of studies by researchers since the early 1970s. MCTS are spheroid tumour cell aggregates that offer an excellent in vitro system for investigating the properties of solid tumours and their responses to therapy, thereby opening up new strategies for the establishment of new therapeutic approaches.

MCTS as "hanging drops" on the lid of a Petri dish. © Samantha Nolan, BIOPRO

Although MCTS are not at all widely known, they have long been an important research tool in modern cancer research laboratories. MCTS, like their in vivo solid tumour counterparts, are cellular aggregates consisting of several thousand tumour cells at different stages. The outer layer consists of proliferating cells, which are also responsible for tumour growth in living organisms. The middle layer consists of dormant cells, and the inner layer consists of a so-called central necrosis, cells that have died from acute nutrient deficiency. Solid tumours and metastases have a similar composition. The tumour cells are cultivated as "hanging drops" on the lids of microtitre plates or Petri dishes.

MCTS are more realistic tumour models than models of adherent cells, which is a classical tumour cell culture method involving cell culture flasks. Adherent tumour cells form a two-dimensional layer in the flask that represents conditions that do not occur in the same way in vivo. Three-dimensional tumours and metastases are characterised by differing gradients from the outside to the inside, which lead to nutrient and oxygen deficiency inside the tumour. In order to survive such deficiencies, tumours induce angiogenesis, i.e. the creation of new blood vessels. This is why many therapies target tumour angiogenesis with the aim of starving the tumour and stopping its growth.

MCTS help reduce the number of animal experiments

Researcher at the University of Stuttgart investigating MCTS © Samantha Nolan, BIOPRO

Despite all their advantages, it is not possible to use MCTS to replace animal experiments. MCTS provide an excellent in vitro model that mimics tumour growth much better than 2D models. In the laboratory, researchers are unable to mimic all the processes occurring in complex organisms. In vivo, there are many other factors affecting tumour growth that cannot be mimicked in vitro. Besides angiogenesis, these factors include cell-cell contacts and the interaction with surrounding normal tissue, e.g., fibroblasts. Nevertheless, the researchers hope that the multicellular spheroid model will help them contribute to establishing new therapeutic options. MCTS are excellently suited for studying many processes related to tumour growth, including signal transduction, different gene expression inside and outside the tumour, metabolism and differentiation.

MCTS can be used to investigate pharmaceutically active substances such as antibodies, cytokines, immunotoxins and others and help exclude those substances that are unsuitable as anticancer drugs more quickly than with other methods. This is made possible because 3D models and tumours are both characterised by permeability differences, which prevents molecules that are too big from reaching all cells. In classical models involving adherent cells, all drugs reach their targeted destination and exert their effects. However, molecules that are too large to penetrate several cell layers are barely effective in the treatment of tumours. Too many tumour cells will survive and continue to grow after treatment. In many cases, the tumour cells that survive this kind of treatment become resistant and it then becomes difficult to destroy them.

Systems biology is key

Within the project "FORSYS Partner: A Systems Biology Approach towards Predictive Cancer Therapy", researchers at the Institute of Cell Biology and Immunology at the University of Stuttgart are focusing on research involving MCTS. The main aim of the project is to investigate in greater detail the transport of protein-based drugs to their destination inside tumours or inside the whole organism. The project involves ten groups of researchers, the majority of whom is based in Baden-Württemberg.

FORSYS Partner complements the "Research Units in Systems Biology - FORSYS" funded by the German Federal Ministry of Education and Research (BMBF). FORSYS has four research units in Freiburg, Golm, Heidelberg and Magdeburg.

Literature:
G. Fracasso, M.Colombatti; Critical Reviews in Oncology/Hematology 36 (2000) 159- 178
Kelm et al.; Biotechnology and Bioengineering, Vol. 83, NO.2, July 20, 2003
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/multicellular-tumour-spheroids-3d-models-for-tumour-research