Abstract
Like in an ecosystem, cancer and other cells residing in the tumor microenvironment engage in various modes of interactions to buffer the negative effects of environmental changes. One such change is the consumption of common nutrients (such as glutamine/Gln) and the consequent accumulation of toxic metabolic byproducts (such as ammonium/NH4). Ammonium is a waste product of cellular metabolism whose accumulation causes cell stress. In tumors, it is known that it can be recycled into nutrients by cancer associated fibroblasts (CAFs). Here we present monoculture and coculture growth of cancer cells and CAFs on different substrates: glutamine and ammonium. We propose a mathematical model to aid our understanding. We find that cancer cells are able to survive on ammonium and recycle it to glutamine for limited periods of time. CAFs are able to even grow on ammonium. In coculture, the presence of CAFs results in an improved survival of cancer cells compared to their monoculture when exposed to ammonium. Interestingly, the ratio between the two cell populations is maintained under various concentrations of NH4, suggesting the ability of the mixed cell system to survive temporary metabolic stress and sustain the size and cell composition as a stable entity.
Highlights
Recent years have seen an increased appreciation of cancer as an ecological problem (Nagy, 2005; Kim et al, 2010)
For all experiments and before cell seeding, Cancer-Associated Fibroblasts (CAFs) were pretreated for 24 h with extracellular vesicles (EVs) collected from MDA-MB-231 cells at 2 mg of EVs per 2 × 105 recipient cells as described in Yan et al (2018) to simulate education by cancer-secreted EVs
We introduce to the model a second source of chemical energy, which could be other metabolites, including amino acids such as glutamate, as well as glucose-derived a-ketoglutarate
Summary
Recent years have seen an increased appreciation of cancer as an ecological problem (Nagy, 2005; Kim et al, 2010). This has led to a large number of sophisticated mathematical models, see Enderling & Chaplain (2014), Altrock, Liu & Michor (2015), Kuang, Nagy & Eikenberry (2016) for some contemporary introductions to mathematical modeling of cancer. Cancer-Associated Fibroblasts (CAFs), referred to as myofibroblasts, are the major cellular component of tumor stroma. Modeling the bidirectional glutamine/ammonium conversion between cancer cells and cancer-associated fibroblasts.
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