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9,10 FLIM can be exploited for cancer imaging because tumor cells have metabolic profiles different from those of normal epithelial cells and FLIM can be used for their differentiation.9�C12 For example, Williams et al investigated the metabolism through the measurement of the redox ratio of the endogenous fluorophores NAD(P)H and FAD and found that normal tissues had higher aerobic mitochondrial metabolism than diseased tissues.11,13 Using limited patient samples, women with BRCA1 and/or BRCA2 mutations (who are at a 30-fold increased risk of developing ovarian cancer) were found to have the most variable redox rates, suggesting its use as a potential surveillance method to capture the early cellular changes in the TME.11 Differences in fluorescent lifetimes have also been found in both the MMTV-PyMT breast cancer PRDX4 model and human breast cancer slides, with tumors cells expressing longer lifetimes.9 In addition to these lifetime measurements, autofluorescence from these endogenous species is often combined with SHG imaging to provide the cellular context in the fibrillar ECM. Second-harmonic generation SHG is a coherent process in which two photons are upconverted to exactly twice the frequency (half the wavelength) of the excitation laser. The first biological SHG imaging was reported in 1986 by Freund using rat tail tendon with a resolution of ?50 ��m.14 Much later, Mohler and Campagnola implemented a practical SHG tissue imaging approach with high resolution and rapid data acquisition.2 These advances have greatly increased the use of SHG as a powerful imaging modality Bleomycin (see Refs 15�C17 and references therein). SHG creation is governed by the nonlinear susceptibility tensor ��2, which requires a noncentrosymmetric assembly of the ��harmonophores�� and thus has a permanent dipole moment, on the size scale of ��SHG. These constraints limit the utility of SHG to imaging collagen, myosin, and microtubule assemblies.2 Angiogenesis inhibitor The primary application of SHG in imaging cancer lies in probing the collagen architecture and determining how it is altered from normal tissues. In general, collagen remodeling occurs in all epithelial cancers, where the specific changes in organization are different in different tumors: eg, alterations can occur in the form of collagen content and/or fibrillar morphology. Fibrillar collagen has a hierarchical structure in which individual procollagen molecules are comprised of a ?300-kDa triple helix in which three ��-chains are hydrogen-bonded to each other. The procollagen molecules are covalently linked into fibrils with a diameter of ?20�C250 nm, which then are covalently linked to form fibers on the order of ?500 nm in diameter. The hierarchical structure of the collagen fiber, the structure observed in the SHG microscope, aligns well with the size scale of ��SHG, allowing both molecular and supramolecular information to be encoded within the SHG signal.