The ability to predict the future behavior of an individual cancer is crucial for precision cancer medicine. The discovery of extensive intratumor heterogeneity and ongoing clonal adaptation in human tumors substantiated the notion of cancer as an evolutionary process. Random events are inherent in evolution and tumor spatial structures hinder the efficacy of selection, which is the only deterministic evolutionary force. This review outlines how the interaction of these stochastic and deterministic processes, which have been extensively studied in evolutionary biology, limits cancer predictability and develops evolutionary strategies to improve predictions. Understanding and advancing the cancer predictability horizon is crucial to improve precision medicine outcomes.

Blood vessel networks form in a 2-step process of sprouting angiogenesis followed by selective branch regression and stabilization of remaining vessels. Pericytes are known to function in stabilizing blood vessels, but their role in vascular sprouting and selective vessel regression is poorly understood. The endosialin (CD248) receptor is expressed by pericytes associated with newly forming but not stable quiescent vessels. In the present study, we used the Endosialin ؊/؊ mouse as a means to uncover novel roles for pericytes during the process of vascular network formation. We demonstrate in a postnatal retina model that Endosialin ؊/؊ mice have normal vascular sprouting but are defective in selective vessel regression, leading to increased vessel density. Examination of the Endosialin ؊/؊ mouse tumor vasculature revealed an equivalent phenotype, indicating that pericytes perform a hitherto unidentified function to promote vessel destabilization and regression in vivo in both physiologic and pathologic angiogenesis. Mechanistically, Endosialin ؊/؊ mice have no defect in pericyte recruitment. Rather, endosialin binding to an endothelial associated, but not a pericyte associated, basement membrane component induces endothelial cell apoptosis and detachment. The results of the present study advance our understanding of pericyte biology and pericyte/endothelial cell cooperation during vascular patterning and have implications for the design of both proand antiangiogenic therapies. (Blood. 2012;120(7):1516-1527) IntroductionThe expansion of existing blood vessels, known as angiogenesis, is a critical process that occurs in response to an insufficient supply of nutrients and oxygen during development and tissue regeneration. The deregulated generation and abnormal remodeling of blood vessels can promote the expansion of tumors or fail to restore tissue oxygenation adequately, contributing to ischemic disease progression (eg, in diabetic retinopathy). Therefore, the identification of the cellular and molecular targets for therapeutic strategies to influence vascular network formation and remodeling is of considerable clinical importance. 1,2 Angiogenesis is initiated in response to local production of proangiogenic factors, in particular VEGF-A, which promote new vascular sprout formation by the induction and migration of leading tip cells and by stimulating the proliferation of neighboring stalk cells. In addition, VEGFmediated regulation of the Delta-like 4/Notch1 signaling pathway ensures the correct spatiotemporal coordination of tip versus stalk cell specialization required for organized patterning of new vascular networks. 3 Subsequent to sprouting angiogenesis, the initial vascular plexus is remodeled extensively. Key to this remodeling is the pruning of unwanted capillaries through selective branch regression. The remaining vessels mature and are stabilized, which marks the end of vessel plasticity and reflects the quiescent state of the new hierarchical vascular network. With the exception of the complete regr...

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10 High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10 High -enhanced metastatic colonisation with no impact on AKR1B10 Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.