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Cancer is a disease characterised by uncontrolled growth of abnormal cells. As its progression relies on growth and replication, it can spread to multiple organs. One defining feature of cancer is the creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and metastasise to other organs.

The transformation of normal cells into malignant tumours is a multistep process, during which genetic mutations accumulate. Hanahan and Weinberg have described ten key changes that can occur during the transformation of a normal cell to a tumour cell; these features are considered hallmarks of cancer.

Validating Cancer Models

Most of the key techniques for cell culture were established during the 1950’s. The focus at that time was to make the cells proliferate as quickly as possible. This was done by allowing the cells to grow as monolayer cultures on essentially flat glass or plastic surfaces (i.e. in ‘2D’).

For a model to be relevant it must successfully replicate certain in vivo conditions.

Growth Rate

Cells in 2D cultures usually can double their numbers within a few days. Cells in normal tissues, cancers and in 3D cultures usually double their numbers in months.

Architecture and Structure

Cells grown in 2D show no tissue architecture whereas the same cells grown in 3D can spontaneously form structures which resemble their parental tissue. Key to this is that spheroids develop oxygen, nutrient and waste product gradients similar to those seen in tumours.

Function – Uniformity and Reproducibility

For a 3D cancer model to be relevant, it must successfully replicate the functionality demonstrated by the active tumour. 

Reproducibility is inversely proportional to heterogeneity. Patients are heterogeneous. Their tumours are heterogeneous. The cells within a tumour are heterogeneous. It therefore makes no sense to increase this heterogeneity even further by growing the cells in conditions which force them to adapt.

Longevity

Once cells have repaired the damage to their ECM (from 2D passaging), they enter a ‘dynamic equilibrium’ state: a state that resembles a functioning organ. Unperturbed, the cells execute their functions at a steady rate. Treated with a drug (or other biologically active molecules) they respond and when the drug is metabolised (or removed) the cell clusters return to their original dynamic equilibrium. In the ClinoReactors, cell clusters can remain in this dynamic equilibrium for weeks or months and this is an ideal starting point for experimentation.

Biomarkers found using 3D culture

Efficient and timely identification of malignant tumours forms the basis of cancer treatment. Recently, accurately detecting cancer-specific biomarkers have become the pathologist’s chosen tool to study biopsies. To build this toolkit with biomarkers specific to the myriad of cancer types, it is necessary to conduct gene expression profiling of the appropriate tissue. One way to do this is to employ 3D culture to study tumour extracts and cancer cell lines.

Example 3D cancer models developed using the ClinoStar: