Eco-evolutionary causes and consequences of temporal changes in intratumoural blood flow

Abstract

Temporal changes in blood flow are commonly observed in malignant tumours, but the evolutionary causes and consequences are rarely considered. We propose that stochastic temporal variations in blood flow and microenvironmental conditions arise from the eco-evolutionary dynamics of tumour angiogenesis in which cancer cells, as individual units of selection, can influence and respond only to local environmental conditions. This leads to new vessels arising from the closest available vascular structure regardless of the size or capacity of this parental vessel. These dynamics produce unstable vascular networks with unpredictable spatial and temporal variations in blood flow and microenvironmental conditions. Adaptations of evolving populations to temporally varying environments in nature include increased diversity, greater motility and invasiveness, and highly plastic phenotypes, allowing for broad metabolic adaptability and rapid shifts to high rates of proliferation and profound quiescence. These adaptive strategies, when adopted in cancer cells, promote many commonly observed phenotypic properties including those found in the stem phenotype and in epithelial-to-mesenchymal transition. Temporal variations in intratumoural blood flow, which occur through the promotion of cancer cell phenotypes that facilitate both metastatic spread and resistance to therapy, may have substantial clinical consequences.

Fig. 1 |. Multiscalar spatial and temporal variations in vascular flow lead to heterogeneous cell densities and properties.

a | A T1 post-gadolinium sequence from a magnetic resonance imaging (MRI) scan of glioblastoma shows spatially variable blood flow with high levels of contrast enhancement at the rim (arrows) and little to no flow in the central tumour regions. b | A T2-weighted sequence from the same MRI shows a corresponding increased signal in the low flow regions (arrows), indicating high fluid and diminished cell density. c, d | A haematoxylin and eosin-stained histological section from a clinical sarcoma shows high cell density in the upper half and almost complete necrosis in the lower half — highlighted in part d. The orange circle in part d indicates blood vessels in the midst of the necrotic region. The absence of viable cells next to these blood vessels suggests that the flow is temporary (literally a dry ‘streambed’). e-g | The complex spatial and temporal feedback pathways involving evolving cancer cells and host vasculature can be framed mathematically as shown. A hybrid cellular automata model captures tumorigenesis (see REF for details) by integrating both discrete elements (cells and blood vessels) and the continuous microenvironmental concentration gradients in substrate, metabolites and growth factors. In part e, the simulation considers infrequent vascular turnover. Vessels remained fixed for the entire simulation (6,756 ‘days’). The scale bar represents 400 μm. With a spatially and temporally stable environment, metabolically normal tumour cells (green cells) expand slowly into normal tissue. In part f, the simulation considers high vascular turnover and angiogenesis. Tumour perfusion is high but temporally unstable. In just 2,721 simulation days, the evolved tumour cells are mostly glycolytic (red), acid resistant (blue) or both (pink). Small regions of necrosis (black) are evident. In part g, the simulation considers high vascular turnover but only moderate angiogenesis. In 1,912 simulation days, the rapidly growing tumour is formed primarily by the glycolytic and acid resistant phenotype (pink), with extensive necrosis.

Fig. 2 |. The evolutionary constraints on tumour angiogenesis.

Angiogenesis in cancers must rely entirely on local interactions. Part a shows a well-organized vascular network of normal tissue, and part b shows a magnified region. In parts c,d, tumour growth at the edge of this tissue is initially supported by diffusion from the vessels in the existing network. Individual cancer cells farthest from the existing vessels become hypoxic (dark blue) and produce angiogenic factors. In parts e,f, this uncoordinated angiogenic signalling by individual cells produces vascular budding in only the closest vessels regardless of their size or flow capacity In part g, progressive maturation of blood vessels results in an organized network and allows rapid and efficient haemodynamics, similar to traffic flow in a modern highway. In part h, tumour angiogenesis is more similar to the dynamics of villages or modern cities, in which each new household or small groups of households are constrained to build a connection with the nearest existing road or passageway regardless of their size or capacity Part g image courtesy of Ivoha/Alamy Stock Photo. Part h image courtesy of Mitch Diamond/Alamy Stock Photo.

Fig. 3 |. Key dynamics that result from variations in intratumoural blood flow.

Here, we summarize the role of environmental instability in key evolutionary properties of cancer cells as defined in the outer ring. A constant environment (inner ring), even if harsh, will select for stable phenotypes that are optimally adapted to local conditions and, therefore, tend to remain in place. By contrast, temporal variations in environmental conditions select for highly plastic phenotypes that can move from quiescence to rapid proliferation during periods of local feast or famine (middle ring). These adapted phenotypes are typically metabolic generalists — able to utilize a range of substrates including scavenging of macromoiecuies from dead and dying cells. Finally, because intratumoural blood flow is often coupled so that absence of flow in one region is accompanied by increased flow in an adjacent environment, these dynamics will select from motile, invasive phenotypes. Thus, tumour properties selected by spatiotemporal fluctuations in blood flow may promote formation of metastases and resistance to cytotoxic therapy.