TY - JOUR
T1 - In Vivo Autofluorescence Imaging of Tumor Heterogeneity in Response to Treatment
AU - Shah, Amy T.
AU - Diggins, Kirsten E.
AU - Walsh, Alex J.
AU - Irish, Jonathan M.
AU - Skala, Melissa C.
N1 - Funding Information:
The Vanderbilt University Translational Pathology Shared Resource was used for immunohistochemistry staining. Funding sources include the NIH R01 CA185747 (M.C.S.), DoD W81XWH-13-1-0194 (M.C.S.), Mary Kay Foundation 067–14 (M.C.S.), NSF Graduate Research Fellowship DGE-0909667 (A.T.S.), NIH / NCI R25 CA136440-04 (K.E.D.), R00 CA143231-03 (J.M.I.), the Vanderbilt-Ingram Cancer Center (VICC, P30 CA68485 ), and VICC Ambassadors (J.M.I., M.C.S.).
Funding Information:
The Vanderbilt University Translational Pathology Shared Resource was used for immunohistochemistry staining. Funding sources include the NIH R01 CA185747 (M.C.S.), DoD W81XWH-13-1- 0194 (M.C.S.), Mary Kay Foundation 067–14 (M.C.S.), NSF Graduate Research Fellowship DGE-0909667 (A.T.S.), NIH/NCI R25 CA136440-04 (K.E.D.), R00 CA143231-03 (J.M.I.), the Vanderbilt-Ingram Cancer Center (VICC, P30 CA68485), and VICC Ambassadors (J.M.I., M.C.S.).
Publisher Copyright:
© 2015 The Authors.
PY - 2015
Y1 - 2015
N2 - Subpopulations of cells that escape anti-cancer treatment can cause relapse in cancer patients. Therefore, measurements of cellular-level tumor heterogeneity could enable improved anti-cancer treatment regimens. Cancer exhibits altered cellular metabolism, which affects the autofluorescence of metabolic cofactors NAD(P)H and FAD. The optical redox ratio (fluorescence intensity of NAD(P)H divided by FAD) reflects global cellular metabolism. The fluorescence lifetime (amount of time a fluorophore is in the excited state) is sensitive to microenvironment, particularly protein-binding. High-resolution imaging of the optical redox ratio and fluorescence lifetimes of NAD(P)H and FAD (optical metabolic imaging) enables single-cell analyses. In this study, mice with FaDu tumors were treated with the antibody therapy cetuximab or the chemotherapy cisplatin and imaged in vivo two days after treatment. Results indicate that fluorescence lifetimes of NAD(P)H and FAD are sensitive to early response (two days post-treatment, P < .05), compared with decreases in tumor size (nine days post-treatment, P < .05). Frequency histogram analysis of individual optical metabolic imaging parameters identifies subpopulations of cells, and a new heterogeneity index enables quantitative comparisons of cellular heterogeneity across treatment groups for individual variables. Additionally, a dimensionality reduction technique (viSNE) enables holistic visualization of multivariate optical measures of cellular heterogeneity. These analyses indicate increased heterogeneity in the cetuximab and cisplatin treatment groups compared with the control group. Overall, the combination of optical metabolic imaging and cellular-level analyses provide novel, quantitative insights into tumor heterogeneity.
AB - Subpopulations of cells that escape anti-cancer treatment can cause relapse in cancer patients. Therefore, measurements of cellular-level tumor heterogeneity could enable improved anti-cancer treatment regimens. Cancer exhibits altered cellular metabolism, which affects the autofluorescence of metabolic cofactors NAD(P)H and FAD. The optical redox ratio (fluorescence intensity of NAD(P)H divided by FAD) reflects global cellular metabolism. The fluorescence lifetime (amount of time a fluorophore is in the excited state) is sensitive to microenvironment, particularly protein-binding. High-resolution imaging of the optical redox ratio and fluorescence lifetimes of NAD(P)H and FAD (optical metabolic imaging) enables single-cell analyses. In this study, mice with FaDu tumors were treated with the antibody therapy cetuximab or the chemotherapy cisplatin and imaged in vivo two days after treatment. Results indicate that fluorescence lifetimes of NAD(P)H and FAD are sensitive to early response (two days post-treatment, P < .05), compared with decreases in tumor size (nine days post-treatment, P < .05). Frequency histogram analysis of individual optical metabolic imaging parameters identifies subpopulations of cells, and a new heterogeneity index enables quantitative comparisons of cellular heterogeneity across treatment groups for individual variables. Additionally, a dimensionality reduction technique (viSNE) enables holistic visualization of multivariate optical measures of cellular heterogeneity. These analyses indicate increased heterogeneity in the cetuximab and cisplatin treatment groups compared with the control group. Overall, the combination of optical metabolic imaging and cellular-level analyses provide novel, quantitative insights into tumor heterogeneity.
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U2 - 10.1016/j.neo.2015.11.006
DO - 10.1016/j.neo.2015.11.006
M3 - Article
C2 - 26696368
AN - SCOPUS:84963972033
SN - 1522-8002
VL - 17
SP - 862
EP - 870
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 12
ER -