Competitive exclusion of clonal subpopulations in heterogeneous tumours after stromal injury

Abstract

Summary Xenografted artificial heterogeneous tumours (AHTs) were created by admixing, in a ratio of 9:1 or 1:9, two clonal subpopulations (designated as clones A and D) obtained from a heterogeneous human colon adenocarcinoma. In unperturbed AHTs these percentages remain constant with increasing tumour size. At average volumes of 250 mm3, AHTs were X-irradiated (15 Gy) and changes in growth rate and composition assayed. A and D cells exhibited equivalent levels of survival after in vivo irradiation as determined by excision assay procedures. At about 2-3 weeks post-irradiation AHTs exhibited a significant enrichment of the majority population in both the 1:9 or 9:1 A:D AHTs. Additional studies were concomitantly performed to determine whether these changes were mostly a function of normal tissue damage or of parenchymal tumour cell killing. In these studies, the normal tissue only was irradiated, tumour cells were implanted one day after irradiation, and the composition of AHTs assayed as a function of time postirradiation. In these studies, similar shifts in composition with similar kinetics to that seen in the in situ irradiations were found. We therefore propose that these compositional shifts are mainly a reflection of radiation damage to the stromal microenvironment, which is consequently unable to support tumour growth adequately leading to competitive exclusion of the minority subpopulation.Many human solid cancers are clonally heterogeneous in composition . Mauro et al. (1986) and Hiddemann et al. (1986) have shown that approximately one-third of all human colorectal cancers contain two or more subpopulations based on flow cytometric analysis of DNA content. In this regard, we have been studying the biological characteristics of xenografted artificial heterogeneous tumours (AHTs). These are neoplasms comprised of admixtures of varying proportions of clonally related subpopulations (designated as A and D) originally derived from a human colon adenocarcinoma (Dexter et al., 1981). Zonality and compositional stability characteristics of unperturbed AHTs have been experimentally described (Leith et al., 1985(Leith et al., , 1987, and efforts to model AHT behaviour biomathematically have begun (Michelson et al., 1987a(Michelson et al., ,b,c, 1988Michelson, 1987 (1987).The tumour bed effect (TBE) is a well-documented phenomenon in which pre-irradiation of normal tissues modifies the subsequent growth behaviour of transplanted neoplasms in the damaged region (Hewitt & Blake, 1968;Urano & Suit, 1970;Jirtle et al., 1978;Trott & Kummemehr, 1983;Begg & Terry, 1983Ito et al., 1985;Milas et al., 1986). Due to the intimate relationship between tumour parenchyma and normal tissue stroma (Siemann et al., 1981), we thought that the relationship between TBE expression and tumour heterogeneity warranted investigation. While zonality and compositional stability aspects of unperturbed colon AHTs have been described (Leith et al., 1987), it is important to see if such characteristics would change in the face of a stress...

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

“…4 and 8). The existence of these dominant behaviours exhibited by the u 1 or u 2 populations are consistent with the principle of competitive exclusion of clonal sub-populations in heterogeneous tumours (Egan Keats et al, 2012;Leith et al, 1989). In Fisher et al (2013) the authors interpreted the experimental data, which showed suppression and reappearance of cancer clones in myeloma patients (Keats et al, 2012) and chronic lymphocytic leukaemia patients (Schuh et al, 2012), by suggesting that two subclones can exist in a dynamic equilibrium.…”

“…Note that these growth functions incorporate also the principle of competition between clonal sub-populations in heterogeneous tumours (Leith et al, 1989).…”

“…In this study, we will investigate the role of cancer mutation on the possibility of clonal competition with alternating dominance or even competitive exclusion between two cancer cell sub-populations (as discussed before, these types of competition have been observed experimentally (Leith et al, 1989;Keats et al, 2012;Schuh et al, 2012)). To this end, we will introduce a nonlocal model for cell-cell and cell-matrix adhesion for two populations of cells (this model is a generalization of the models in Armstrong et al (2006); Gerisch & Chaplain (2008); Painter et al (2015)).…”