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 (μb) and reduced scattering (μs') 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.
Highlights
Cancer progression is a multistep process that develops through a number of stages, including dysplasia, tumorigenesis, and metastases
We apply inverse spectroscopic optical coherence tomography (ISOCT) to address three specific questions about field carcinogenesis: (1) In which mucosal compartment do changes occur? (2) What are the associated ultrastructural alterations that occur within each of these compartments? and (3) What are some of the specific mechanisms that contribute to these ultrastructural alterations? To answer these questions, we studied the optical and ultrastructural changes in colorectal cancer (CRC) field carcinogenesis and separately analyzed the epithelium and stroma compartments
We present the ISOCT analysis on the optical and ultrastructural changes in these two tissue compartments in CRC field carcinogenesis (Secs. 5.3 and 5.4) as compared with pancreatic cancer (PC) field carcinogenesis (Sec. 5.5)
Summary
Cancer progression is a multistep process that develops through a number of stages, including dysplasia, tumorigenesis, and metastases. One of the earliest stages is field carcinogenesis ( referred to as field cancerization, field effect, field of injury, field defect, etc.), the concept that a diffuse injury from genetic/environmental stimuli provides a fertile mutational field with focal tumorigenesis occurring via stochastic events such as inactivation of tumor suppressor genes.[1,2] The concept of field carcinogenesis is well established in cancer biology and clinical medicine and has been observed in essentially all solid cancers (lung,[3] colon and rectum,[4,5] prostate,[6,7] esophageal,[8] pancreatic,[9] ovarian, head and neck,[10] stomach,[11] and breast[12]). Because field carcinogenesis provides the key to tumor initiation, it has relevance for clinical medicine, and for fundamental cancer biology.
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