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      Spatially resolved optical and ultrastructural properties of colorectal and pancreatic field carcinogenesis observed by inverse spectroscopic optical coherence tomography

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          Abstract.

          Field carcinogenesis is the initial stage of cancer progression. Understanding field carcinogenesis is valuable for both cancer biology and clinical medicine. Here, we used inverse spectroscopic optical coherence tomography to study colorectal cancer (CRC) and pancreatic cancer (PC) field carcinogenesis. Depth-resolved optical and ultrastructural properties of the mucosa were quantified from histologically normal rectal biopsies from patients with and without colon adenomas ( n = 85 ) as well as from histologically normal peri-ampullary duodenal biopsies from patients with and without PC ( n = 22 ). Changes in the epithelium and stroma in CRC field carcinogenesis were separately quantified. In both compartments, optical and ultra-structural alterations were consistent. Optical alterations included lower backscattering ( μ b ) and reduced scattering ( μ s ) coefficients and higher anisotropy factor g . Ultrastructurally pronounced alterations were observed at length scales up to 450    nm , with the shape of the mass density correlation function having a higher shape factor D , thus implying a shift to larger length scales. Similar alterations were found in the PC field carcinogenesis despite the difference in genetic pathways and etiologies. We further verified that the chromatin clumping in epithelial cells and collagen cross-linking caused D to increase in vitro and could be among the mechanisms responsible for the observed changes in epithelium and stroma, respectively.

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          Most cited references74

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          Optical coherence tomography.

          A technique called optical coherence tomography (OCT) has been developed for noninvasive cross-sectional imaging in biological systems. OCT uses low-coherence interferometry to produce a two-dimensional image of optical scattering from internal tissue microstructures in a way that is analogous to ultrasonic pulse-echo imaging. OCT has longitudinal and lateral spatial resolutions of a few micrometers and can detect reflected signals as small as approximately 10(-10) of the incident optical power. Tomographic imaging is demonstrated in vitro in the peripapillary area of the retina and in the coronary artery, two clinically relevant examples that are representative of transparent and turbid media, respectively.
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            Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer.

            Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.
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              A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications.

              The concept of "field cancerization" was first introduced by Slaughter et al. [D. P, Slaughter et al., Cancer (Phila.), 6: 963-968, 1953] in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular findings support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. In the initial phase, a stem cell acquires genetic alterations and forms a "patch," a clonal unit of altered daughter cells. These patches can be recognized on the basis of mutations in TP53, and have been reported for head and neck, lung, skin, and breast cancer. The conversion of a patch into an expanding field is the next logical and critical step in epithelial carcinogenesis. Additional genetic alterations are required for this step, and by virtue of its growth advantage, a proliferating field gradually displaces the normal mucosa. In the mucosa of the head and neck, as well as the esophagus, such fields have been detected with dimensions of >7 cm in diameter, whereas they are usually not detected by routine diagnostic techniques. Ultimately, clonal divergence leads to the development of one or more tumors within a contiguous field of preneoplastic cells. An important clinical implication is that fields often remain after surgery of the primary tumor and may lead to new cancers, designated presently by clinicians as "a second primary tumor" or "local recurrence," depending on the exact site and time interval. In conclusion, the development of an expanding preneoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed.
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                Author and article information

                Journal
                J Biomed Opt
                J Biomed Opt
                JBOPFO
                JBO
                Journal of Biomedical Optics
                Society of Photo-Optical Instrumentation Engineers
                1083-3668
                1560-2281
                18 March 2014
                March 2014
                : 19
                : 3
                : 036013
                Affiliations
                [a ]Northwestern University , Department of Biomedical Engineering, 2145 Sheridan Road, Evanston, Illinois 60208
                [b ]Boston Medical Center , Department of Medicine, Boston, Massachusetts 02118
                [c ]NorthShore University Health Systems , Department of Internal Medicine, Evanston, Illinois 60201
                Author notes
                [* ]Address all correspondence to: Vadim Backman, E-mail: v-backman@ 123456northwestern.edu
                Article
                JBO-130508RRRR 130508RRRR
                10.1117/1.JBO.19.3.036013
                4019430
                24643530
                ed735d0e-bd70-442f-8af2-e967bf516a98
                © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
                History
                : 18 July 2013
                : 13 February 2014
                : 17 February 2014
                Page count
                Figures: 14, Tables: 4, References: 87, Pages: 17
                Funding
                Funded by: National Institutes of Health
                Award ID: R01CA128641
                Award ID: R01CA165309
                Award ID: R01CA156186
                Funded by: National Science Foundation
                Award ID: CBET-1240416
                Funded by: National Science Foundation Graduate Research Fellowship
                Award ID: DGE-0824162
                Categories
                Research Papers: Imaging
                Paper
                Custom metadata
                Yi et al.: Spatially resolved optical and ultrastructural properties of colorectal and pancreatic field…

                Biomedical engineering
                colorectal,pancreatic,field carcinogenesis,ultrastructural,optical properties

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