Optical redox imaging indices discriminate human breast cancer from normal tissues

Abstract

Our long-term goal was to investigate the potential of incorporating redox imaging technique as a breast cancer (BC) diagnosis component to increase the positive predictive value of suspicious imaging finding and to reduce unnecessary biopsies and overdiagnosis. We previously found that precancer and cancer tissues in animal models displayed abnormal mitochondrial redox state. We also revealed abnormal mitochondrial redox state in cancerous specimens from three BC patients. Here, we extend our study to include biopsies of 16 patients. Tissue aliquots were collected from both apparently normal and cancerous tissues from the affected cancer-bearing breasts shortly after surgical resection. All specimens were snap-frozen and scanned with the Chance redox scanner, i.e., the three-dimensional cryogenic NADH/Fp (reduced nicotinamide adenine dinucleotide/oxidized flavoproteins) fluorescence imager. We found both Fp and NADH in the cancerous tissues roughly tripled that in the normal tissues ( p < 0.05 ). The redox ratio Fp/(NADH + Fp) was ? 27 % higher in the cancerous tissues ( p < 0.05 ). Additionally, Fp, or NADH, or the redox ratio alone could predict cancer with reasonable sensitivity and specificity. Our findings suggest that the optical redox imaging technique can provide parameters independent of clinical factors for discriminating cancer from noncancer breast tissues in human patients.

Optical Redox Imaging of Fixed Unstained Muscle Slides Reveals Useful Biological Information

“…For example, using a spectroscopic approach, Majumder et al found that significant differences are detected in formalin-fixed slides derived from cancerous breast tissue and normal surrounding tissue, with the cancerous tissue having higher signal in the spectral range of NADH fluorescence [26]. This is consistent with our findings on snap-frozen tissues from clinical breast cancer patients [9]. Conklin et al investigated fixed unstained tissue slides from a transgenic mouse model of breast carcinoma in situ consisting of both cancerous and normal tissues employing multiphoton excitation and photon-counting techniques [28].…”

“…Pioneered by Chance et al [1–5], ORI has been widely applied to investigate cell/tissue energetics and metabolism for acquiring biological and pathological information and detecting therapeutic response [6–23]. For example, by ORI of the snap-frozen core biopsies from clinical breast cancer patients, we discovered that compared to normal surrounding tissues, cancerous breast tissues have higher Fp and NADH signals and a higher Fp redox ratio Fp/(NADH+Fp), indicating a more oxidized state [9]. We also found in breast tumor xenografts models that the highly metastatic tumor MDA-MB-231 has a higher level of redox heterogeneity with localized regions of higher redox ratio compared to the less metastatic tumor MCF-7 [12].…”

Differential Expression of PGC1α in Intratumor Redox Subpopulations of Breast Cancer

“…We previously observed distinct intratumor redox heterogeneity and identified the ORI-based redox state as potential diagnostic/prognostic biomarkers for breast tumor [5, 13]. This paper reports for the first time the differential gene expressions among the redox subpopulations based on ORI mapping.…”

“…Our studies have shown that the heterogeneity-based mitochondrial redox indices (NADH, Fp and FpR) can differentiate between tumors with different levels of aggressiveness and between premalignant and normal tissues [8–10]. Higher mitochondrial redox indices were found in breast cancer clinical specimens compared to the adjacent normal tissues [11–13]. …”

Optical Redox Imaging of Lonidamine Treatment Response of Melanoma Cells and Xenografts

“…Optical redox imaging (ORI) techniques, pioneered by Chance et al [2, 10, 14, 15], have increasing applications in cancer research, such as discrimination between cancer and normal tissues [16, 17], differentiation among cancer aggressiveness [18–21], distinguishing among receptor status of breast cancer [22], discerning genetic mutation [23, 24], and monitoring therapeutic effects [25–30]. For example, Walsh et al reported that NADH/FAD ratio normalized by percentage of mitotic cells correlates with a cellular glycolytic index across a panel of human breast cell lines, and the redox ratio and the fluorescence life-times of both NADH and FAD could be sensitive to herceptin-induced early metabolic changes, whereas 2-deoxy-2-[ 18 F]fluoro- D -glucose positron emission tomography did not resolve the early changes in xenograft models [28].…”