An analogy between the evolution of drug resistance in bacterial communities and malignant tissues

Abstract

Cancer cells rapidly evolve drug resistance through somatic evolution and, in order to continue growth in the metastatic phase, violate the organism-wide consensus of regulated growth and beneficial communal interactions. We suggest that there is a fundamental mechanistic connection between the rapid evolution of resistance to chemotherapy in cellular communities within malignant tissues and the rapid evolution of antibiotic resistance in bacterial communities. We propose that this evolution is the result of a programmed and collective stress response performed by interacting cells, and that, given this fundamental connection, studying bacterial communities can provide deeper insights into the dynamics of adaptation and the evolution of cells within tumours.

Figure 1. An alternative view of cancer development

a | The traditional view of cancer is as a cell-autonomous result of cumulative genetic mutations. Genes can be conceptualized according to their function as sectors on a dartboard that represent the hallmarks of cancer, and familial or acquired mutations can be thought of as randomly occurring dart strikes. A normal cell (yellow) can acquire a mutation (blue) that, for example, confers self-sufficiency in growth signals. As the progeny of the mutated cell expand, some daughter cells acquire additional mutations. Daughter cells displaying a full complement of hallmark lesions (dark blue) are malignant and capable of rapid proliferation and dissemination. b,c | An alternative view of cancer as a collective stress response. b | Stress emanates from a source, creating stressful conditions that are localized in space and time. This in turn induces ‘normal’ cells to exchange stress signals in regions of high stress. c | These stress signals orchestrate the display of multiple adaptive phenotypes that are traditionally considered ‘abnormal’ and can include rapid proliferation and tumour cell dissemination. Normal and abnormal cells can coexist. Part a is modified, with permission, from REF. © (2000) Elsevier Science.

Figure 2. Changes in microenvironments

a | A community of bacteria can form biofilms by attaching to a substrate and by producing large amounts of a polysaccharide-based exopolymer matrix that links cells together. As the extracellular matrix (ECM) encases the cells and greatly hinders their motion, cells switch from a motile to a sessile state. The matrix greatly limits nutrient and oxygen diffusion and cells inside the biofilm become specialized according to the metabolites present. (Subsistence on different nutrient sources is indicated by the different colours of the cells in different regions.) Some cells, not unlike metastatic cancer cells, are able to break through the exopolymer matrix and leave the biofilm to populate different environments. b | The type of cells associated with a tumour, notably carcinoma-associated fibroblasts, produce signals that influence the behaviour of tumour cells. Also, the stroma and ECM surrounding a tumour is much denser than that surrounding normal tissue and the diffusion of nutrients and oxygen from the blood vessels is therefore greatly diminished by the tumour-associated ECM and stroma. Metastatic cells (dark blue) may also leave the primary tumour and disseminate throughout the body.

Figure 3. Proposed experimental approaches to investigate drug resistance using bacterial models

The heterogeneous nature of a tumour may be modelled using microfluidics devices. a | A solid tumour is physiologically heterogeneous: insufficient vasculature decreases the amount of oxygen, nutrients and/or drugs that penetrate a tumour. For simplicity, only the gradient of oxygen is illustrated. b | Similarly, the growth of tumour lesions may occur in isolated subpopulations of cells, thereby limiting direct communication between various parts of a tumour (for example, region 1 and region 2 in the figure). As a result, weakly interacting subpopulations from the same initial cancer lesion may evolve and adapt independently. c | The physiological segmentation of a tumour and the presence of strong chemical gradients could be imitated inside a microfluidics device (the figure depicts the use of this device for bacteria). For instance, media flowing on each side of the chamber array could contain different levels of oxygen, mimicking the chemical composition of a tumour. Porous chamber walls (dashed lines) allow chemical exchange but prevent cellular escape. Furthermore, the movement and exchange of cells between different habitats can be limited by the presence of narrow channels. As a result, cells in habitat 1 have very limited interactions with cells in habitat 2 and these populations will therefore evolve independently.

Figure 4. Evolutionary aspects of biofilm development as a model of drug resistance in tumours

a,b | An interpretation of the work by Conibear et al. studying mutagenesis in biofilm communities of Pseudomonas aeruginosa bacteria containing a green fluorescent protein (GFP) reporter gene that has an inactivating +1 frameshift mutation. In this system, a simple base deletion restores the function of the gene and induces the expression of GFP. a | Biofilm colony growth on a glass substrate. The authors described the possibility that oxidative waste accumulates in microcolonies during biofilm expansion. This waste causes stress-induced mutagenesis and activates GFP expression. b | Top view of a P. aeruginosa biofilm microcolony containing both cells with reactivated GFP and cells without reactivated GFP. c | Biofilm experiments could mimic population dynamics occurring during tumorigenesis and during the development of drug resistance after therapy. In both situations, mutations (depicted by genotypes A and B) can appear in localized environments before spreading to the rest of the tumour. Panel b is reproduced from REF. .