Abstract
Intratumoural heterogeneity (ITH) contributes to local recurrence following radiotherapy in prostate cancer. Recent studies also show that ecological interactions between heterogeneous tumour cell populations can lead to resistance in chemotherapy. Here, we evaluated whether interactions between heterogenous populations could impact growth and response to radiotherapy in prostate cancer. Using mixed 3D cultures of parental and radioresistant populations from two prostate cancer cell lines and a predator-prey mathematical model to investigate various types of ecological interactions, we show that reciprocal interactions between heterogeneous populations enhance overall growth and reduce radiation sensitivity. The type of interaction influences the time of regrowth after radiation, and, at the population level, alters the survival and cell cycle of each population without eliminating either one. These interactions can arise from oxygen constraints and from cellular cross-talk that alter the tumour microenvironment. These findings suggest that ecological-type interactions are important in radiation response and could be targeted to reduce local recurrence.
Highlights
Intratumoural heterogeneity (ITH) contributes to local recurrence following radiotherapy in prostate cancer
We evaluated whether ecological interactions between tumour cell populations with different radiation sensitivities alter tumour growth kinetics and radiation response
Using biological experiments and ecological mathematical models, we found that prostate cancer spheroids comprising mixed tumour cell populations have enhanced growth and reduced radiation sensitivity
Summary
Intratumoural heterogeneity (ITH) contributes to local recurrence following radiotherapy in prostate cancer. Using mixed 3D cultures of parental and radioresistant populations from two prostate cancer cell lines and a predator-prey mathematical model to investigate various types of ecological interactions, we show that reciprocal interactions between heterogeneous populations enhance overall growth and reduce radiation sensitivity. These interactions can arise from oxygen constraints and from cellular cross-talk that alter the tumour microenvironment These findings suggest that ecological-type interactions are important in radiation response and could be targeted to reduce local recurrence. Phenotypic variations, such as changes in metabolism, affect therapeutic response among prostate tumour clones[1,6,7,8,9] Given this genotypic and phenotypic diversity, a population-based approach in targeting ITH with radiotherapy may help to reduce local recurrence. Characterising ecological-type interactions between tumour populations with differing radiation sensitivities may lead to new approaches that account for ITH at the radiotherapy treatment planning stage. Our results show that different types of ecological interactions enhance the growth of untreated tumours before and after radiation and that these interactions may arise in part from microenvironmental pressures and cellular cross-talk
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