Abstract
A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains.
Highlights
Cancer progression is an evolutionary process where cell lineages acquire somatic mutations due to exogenous (e.g. UV light) and endogenous (e.g. DNA repair deficiency) causes [1]
We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains
Cells and organisms evolve to better survive in their environments and to adapt to new challenges. Such dynamics manifest in a problematic way with the evolution of drug resistance, which is increasingly recognized as a key challenge for global health
Summary
Cancer progression is an evolutionary process where cell lineages (clones) acquire somatic mutations due to exogenous (e.g. UV light) and endogenous (e.g. DNA repair deficiency) causes [1]. Cancer driver mutations endow a competitive advantage to a cell, which leads to the corresponding lineage gaining in frequency within the population. The numbers of ratelimiting driver mutations required for tumour development were originally predicted using epidemiological age-incidence curves [2] and subsequently confirmed based on protein and DNA sequence data [3, 4]. Tumours have an estimated four driver substitutions, with some tumour type specific variability [4]. Allowing for additional events from copy number and epigenetic drivers, these numbers are consistent with the hallmarks of cancer comprising six biological capabilities acquired during the multistep progression of tumours [5]. The main hallmarks are sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
