Understanding the role of the tumor microenvironment in carcinogenesis has reshaped cancer research. Events at both microscopic (molecular) and macroscopic (tissue) scales have been identified in engineered tumor microenvironments involving in vitro cultures, live tissue xenografts, and transgenic animals. However, these events have not been comprehensively observed under unperturbed (authentic) conditions free of exogenous labeling or genetic modification. The lack of a suitable imaging methodology has largely limited our understanding of the complex interrelations and possible causal links involved in carcinogenesis and metastasis within the tumor microenvironment. Using multicontrast nonlinear imaging, we visualize endogenous substances in rat and human mammary tumors through their intrinsic nonlinear optical properties, and simultaneously observe angiogenesis, extracellular matrix reorganization, and non-native cell recruitment. We find that all these macroscopic events in the tumor microenvironment require concurrent enrichment of specific extracellular vesicles and a metabolic switch toward biosynthesis. This concurrence at the microscopic scale provides not only new insights into carcinogenesis and metastasis but also a potentially new strategy for cancer diagnosis, surgery, and therapeutics.
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