Abstract
Obesity is an established risk factor for breast cancer incidence and mortality. However, the mechanism that links obesity to tumorigenesis is not well understood. Here we combined nonlinear optical imaging technologies with an early-onset diet-induced obesity breast cancer animal model to evaluate the impact of obesity on the composition of mammary gland and tumor stroma. Using coherent anti-Stokes Raman scattering and second harmonic generation on the same platform, we simultaneously imaged mammary adipocytes, blood capillaries, collagen fibrils, and tumor cells without any labeling. We observed that obesity increases the size of lipid droplets of adipocytes in mammary gland and collagen content in mammary tumor stroma, respectively. Such impacts of obesity on mammary gland and tumor stroma could not be analyzed using standard two-dimensional histologic evaluation. Given the importance of mammary stroma to the growth and migration of tumor cells, our observation provides the first imaging evidence that supports the relationship between obesity and breast cancer risk.
Highlights
Obesity is an established risk factor for breast cancer incidence and mortality
We found that multimodal nonlinear optical (NLO) imaging enables simultaneous visualization of adipocytes, collagen fibrils, and tubular structures representing blood capillaries (Figure 1A, supplementary movie 1 *)
Tumor cell visualization was possible owing to weak coherent anti-Stokes Raman scattering (CARS) signals arising from the cell membrane’s lipid bilayer and strong CARS signals from numerous small lipid droplets surrounding the nucleus, which gives a dark contrast in the CARS image
Summary
Obesity is an established risk factor for breast cancer incidence and mortality. the mechanism that links obesity to tumorigenesis is not well understood. NLO microscopy has demonstrated successfully the ability for deep tissue imaging with three-dimensional resolution.[11] Using second harmonic generation (SHG) and two-photon excitation fluorescence (TPEF) microscopy, a number of research groups have imaged collagen type I, tumor cells expressing green fluorescent protein, and dye-labeled vasculatures in living animals.[12,13,14,15,16] For molecules that cannot tolerate fluorophore labeling, coherent anti-Stokes Raman scattering (CARS) microscopy provides a highly sensitive vibrational imaging technique.[17] Recently, CARS has been successfully applied to image lipid domains, cell membranes, axonal myelin sheath in live tissues, and adipocytes in live animals.[18,19,20,21] Here we combine CARS, SHG, and TPEF microscopy into a multimodal platform to image components of the mammary stroma, such as adipocytes, collagen fibrils, blood vessels, and others. The impact of obesity on adipogenesis and collagen content should further our understanding of an established but mechanistically undefined role of obesity on breast cancer incidence and mortality
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