Which are the best pre-clinical models for cancer research?

Research in oncology, as well as in other biomedical-related disciplines, forcedly includes a step of pre-clinical testing before being translated to the patients. However, often clinical testing is not successful because of the poor reliability of the pre-clinical models that do not adequately recapitulate the original tumor.

 

Basically, this means that a drug giving promising results after in vitro studies, it is often selected based on the efficient targeting of traits that instead of being proper of the original tumor, are induced by the experimental settings, such as the culturing conditions of the cells that alter those aspects making cells sensitive to a specific drug in vitro, while resistant in vivo. Therefore, when the same drug is tested in clinical trials, it frequently does not work.

 

Hence, identifying pre-clinical tumor models that retain the characteristics of the tissue they belong to is imperative to perform reliable pre-clinical tests and avoid to waste time (and money) with non-functional, mistakenly selected drugs.

 

Pre-clinical models. Pre-clinical tumor models typically include cell lines, meaning cells that are genetically modified to proliferate indefinitely; 2D and 3D cultures of primary cells, meaning cells isolated from patients and kept in culture for a definite time; and xenografts, which are primary cells isolated from patients and re-transplanted in a mouse, enabling to study their features and behavior in an in vivo environment closely resembling the patients’.

 

A recent study addresses the issue of identifying the best cancer model, which means the one more closely mimicking the primary tumor, particularly in regard of epigenetic features.

 

What is epigenetics? Epigenetics technically refers to the ensemble of changes in gene expression that are not related to the DNA sequence itself. Epigenetic mechanisms modulating gene expression include the so-called Post Translational Modifications (PTM), which involve the addition of chemical groups to proteins called Histones (Histones have the role of organizing the DNA and packing it inside the cell nucleus). PTM depend on the activity of enzymes named HME (Histone Modifying Enzymes) that act by adding chemical groups such as methyl and acethyl groups.

 

PTM in cancer. PTM levels are deregulated in different tumor types; particularly, HME (enzymes responsible for PTM) mutations, altered expression or localization inside the cell have been reported in many different tumors, and different patterns of PTM have been related to patients’ prognosis, overall supporting a key role for epigenetics in cancer progression. Indeed, few drugs targeting HME are currently in clinical trial for the treatment of solid tumors, and some are already used for hematological tumors.

 

Therefore, investigating PTM represents an useful way to identify (and eventually exploit) crucial mechanisms of cancer progression, and having proper models to do so is necessary.

 

PTM in tumor models. A systematic analysis of the PTM in different models (cell lines, primary cells and xenografts) and cancer types, by means of proteomic approaches*, showed that PTM patterns vary significantly in cell lines compared to primary tumors, as well as in primary cells (especially when cultured for long periods) vs the primary tumor, highlighting the effects of culture conditions and time of culturing. Oppositely, the xenografts resulted to be the most similar to the original tumor, exhibiting similar PTM patterns.

 

Thus, xenografts represent the most reliable system for pre-clinical research aimed at unraveling the epigenetic mechanisms of the malignant transformation and, eventually, therapeutically correct them.

   

*What is a proteomic approach? Proteomics is the study of proteins from any point of view, the systematic analysis of protein expression, structure, function, spatial distribution and dynamics.

 

Analyzing a condition/mechanism by a proteomic approach means using a number of specific techniques to characterize the aforementioned aspects of proteins of interest. Proteomic studies include i) isolation of proteins of interest to analyze, ii) mass spectrometry (and related techniques) to acquire the data on each protein, and iii) bioinformatics to analyze the data (see Methods section for more details: https://science-whatelse.jimdo.com/methods/ ).

   

Reference:

Extensive and systematic rewiring of histone post-translational modifications in cancer model systems. Roberta Noberini, Daniela Osti, Claudia Miccolo, Cristina Richichi, Michela Lupia, Giacomo Corleone, Sung-Pil Hong, Piergiuseppe Colombo, Bianca Pollo, Lorenzo Fornasari, Giancarlo Pruneri, Luca Magnani, Ugo Cavallaro, Susanna Chiocca, Saverio Minucci, Giuliana Pelicci and Tiziana Bonaldi. Nucleic Acid Research, March 2018.