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Comment

Cancer modelling as fertile ground for new mathematical challenges

Comment on “Improving cancer treatments via dynamical
biophysical models” by M. Kuznetsov, J. Clairambault & V. Volpert
Tommaso Lorenzi
Department of Mathematical Sciences, Politecnico di Torino, Italy

Received 9 December 2021; accepted 17 January 2022

Available online 20 January 2022
Communicated by Jose Fernando Fontanari

Mathematical models support cancer research by providing a framework in which to consolidate the profusion
of experimental and clinical data being generated, offering the possibility to dissect out the diverse mechanisms
that underpin carcinogenesis and the emergence of resistance to anti-cancer therapy, facilitating the formulation of
empirically testable hypotheses, and suggesting new experiments that have the potential to open unexplored directions
of biomedical research [1–3].
When studying multifaceted processes such as those implicated in cancer dynamics, which involve a variety of
interdependent mechanisms that dynamically interact over a wide range of spatio-temporal scales, different mathe-
matical modelling approaches can be adopted [4–7]. The article by Kuznetsov, Clairambault and Volpert [8] provides
a self-contained and systematic review of ordinary differential equation and partial differential equation (PDE) models
for the dynamics of cell populations and the growth of solid tumours, and gives examples of how optimal control of
these models can help to improve anti-cancer treatment.
In particular, the focus of the review is on minimal models that have broad application in several areas of can-
cer research. In contrast to more comprehensive models developed with the aim of integrating as many biological,
biochemical and biophysical facts as possible, these minimal models capture only the key elements of the processes
under study and, as such, involve a smaller number of parameters. This mitigates the difficulties associated with the
estimation of parameter values from experimental and clinical data. Moreover, these models are amenable not only
to numerical simulations but also to analytical approaches, which enable a complete exploration of the model pa-
rameter space. This permits a precise identification of the validity domain of the results obtained and ensures higher
robustness and precision of the conclusions drawn therefrom, which ultimately provides a more in-depth theoretical
understanding of the underlying cellular dynamics.
The analysis and numerical simulation of these models, which may help identifying the determinants of can-
cer development, progression and response to therapy, pose a series of mathematical challenges. Overcoming these
challenges entails harnessing a wide range of methods and techniques from across different research areas of mathe-
matics. This is particularly well illustrated by the florilegium of PDE models for the dynamics of space-, phenotype-

DOI of original article: https://doi.org/10.1016/j.plrev.2021.10.001.

E-mail address: tommaso.lorenzi@polito.it.

https://doi.org/10.1016/j.plrev.2022.01.003
1571-0645/© 2022 Elsevier B.V. All rights reserved.
T. Lorenzi Physics of Life Reviews 40 (2022) 3–5

and age-structured cell populations carefully drawn up by Kuznetsov, Clairambault and Volpert. In fact, the study of
the qualitative and quantitative properties of the solutions to initial-boundary value problems, transmission problems,
free boundary problems and optimal control problems for these PDEs, motivated by the need to address open ques-
tions in cancer research, has stimulated the extension and integration of existing mathematical tools as well as the
development of novel analytical techniques and numerical methods [9–11].
Ideally, instead of defining such PDE models for the evolutionary dynamics of cell populations and the growth
of solid tumours on the basis of population- and tissue-scale phenomenological assumptions, one wants to derive
them from first principles, that is, as the deterministic continuum limits of stochastic discrete models that track the
dynamics of single cells [12,13]. This is to ensure that the terms comprised in the model equations provide a faithful
mean-field representation of the underlying cellular dynamics. In fact, although being computationally intensive to
simulate for large cell numbers and, to a wide extent, inaccessible to analytical techniques, single-cell-based models
permit the representation of the finer details of cell-scale mechanisms and capture stochastic intercellular variability
in spatial and evolutionary trajectories. These aspects, which cannot be directly incorporated into phenomenological
deterministic continuum models, become especially important in scenarios where cell numbers and densities are
low (e.g. in the early stages of tumour development, during the formation of distant metastases upon cancer cell
extravasation, and when tumour size is severely reduced after therapy), due to the stronger impact that single-cell
processes and demographic stochasticity have on cellular dynamics. For this reason, a range of asymptotic techniques,
probabilistic methods and limiting procedures have been developed and used to systematically derive PDE models like
those presented in this review from their stochastic discrete counterparts [14–20]. This is another remarkable example
of how mathematical models that have found application in cancer research have also promoted cross-fertilisation of
multiple branches of mathematics.
In summary, the review article by Kuznetsov, Clairambault and Volpert gives both biologists and mathematicians
food for thought by showcasing how cancer modelling can act as a catalyst of interdisciplinary research at the interface
between oncology and mathematics as well as intradisciplinary research across the spectrum of the mathematical
sciences.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have
appeared to influence the work reported in this paper.

Acknowledgements

T.L. gratefully acknowledges support from the MIUR grant “Dipartimenti di Eccellenza 2018-2022” (Project no.
E11G18000350001).

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