Biological Mechanisms Underlying Structural Changes Induced by Colorectal Field Carcinogenesis Measured with Low-Coherence Enhanced Backscattering (LEBS) Spectroscopy

We previously reported the utility of Low-Coherence Enhanced Backscattering (LEBS) Spectroscopy in detecting optical changes in uninvolved rectal mucosa, changes that are indicative of the presence of advanced colorectal adenomas elsewhere in the colon (field carcinogenesis). We hypothesized that the alterations in optical signatures are due to structural changes in colonocytes. To elucidate those colonocyte changes, we used LEBS and an early time point in an animal model of colorectal field carcinogenesis – rats treated with azoxymethane (AOM). Changes in LEBS markers in intact mucosa from AOM-treated rats could be at least partially attributed to changes in colonocytes. To investigate the molecular mechanisms underlying the colonocyte abnormalities in premalignant colon, we took a candidate approach. We compared expression profiles of genes implicated directly or indirectly in cytoskeletal dysregulation in colorectal tissues from saline-treated versus AOM-treated rats. Our data suggest that a number of genes known to affect colon tumorigenesis are up-regulated in colonocytes, and genes previously reported to be tumor suppressors in metastatic cancer are down-regulated in colonocytes, despite the colonocytes being histologically normal. To further understand the role of the cytoskeleton in generating changes in optical markers of cells, we used pharmacological disruption (using colchicine) of the cytoskeleton. We found that differences in optical markers (between AOM- and control-treated rats) were negated by the disruption, suggesting cytoskeletal involvement in the optical changes. These studies provide significant insights into the micro-architectural alterations in early colon carcinogenesis, and may enable optimization of both bio-photonic and molecular risk stratification techniques to personalize colorectal cancer screening.

[1]  Vadim Backman,et al.  Nonscalar elastic light scattering from continuous random media in the Born approximation. , 2009, Optics letters.

[2]  İlker R. Çapoğlu,et al.  Nonscalar elastic light scattering from continuous media in the Born approximation: erratum , 2010 .

[3]  W. Bodmer,et al.  Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. , 2003, Cancer research.

[4]  Vadim Backman,et al.  Nanocytology of rectal colonocytes to assess risk of colon cancer based on field cancerization. , 2012, Cancer research.

[5]  Vadim Backman,et al.  Measurement of optical scattering properties with low-coherence enhanced backscattering spectroscopy. , 2011, Journal of biomedical optics.

[6]  N. Wright,et al.  STEM CELL IN GASTROINTESTINAL STRUCTURE AND NEOPLASTIC DEVELOPMENT , 2004, Gut.

[7]  Vadim Backman,et al.  Risk Stratification of Colon Carcinogenesis through Enhanced Backscattering Spectroscopy Analysis of the Uninvolved Colonic Mucosa , 2006, Clinical Cancer Research.

[8]  C. J. Barnes,et al.  Presence of well‐differentiated distal, but not poorly differentiated proximal, rat colon carcinomas is correlated with increased cell proliferation in and lengthening of colon crypts , 1999, International journal of cancer.

[9]  C. Bagowski,et al.  LIMK1 and LIMK2 are important for metastatic behavior and tumor cell-induced angiogenesis of pancreatic cancer cells. , 2009, Zebrafish.

[10]  H. Lynch,et al.  Morphological and morphometric measurements in colorectal mucosa of subjects at increased risk for colonic neoplasia. , 1993, Cancer letters.

[11]  S. Tavaré,et al.  Pretumor progression: clonal evolution of human stem cell populations. , 2004, The American journal of pathology.

[12]  R. Barer,et al.  Refractometry of Living Cells , 1952, Nature.

[13]  T. Shaler,et al.  Mitogen-activated protein kinase (MAPK/ERK) regulates adenomatous polyposis coli during growth-factor-induced cell extension , 2012, Journal of Cell Science.

[14]  S. J. Mills,et al.  Proteomic analysis reveals field-wide changes in protein expression in the morphologically normal mucosa of patients with colorectal neoplasia. , 2006, Cancer research.

[15]  R. Sampliner,et al.  A bile acid-induced apoptosis assay for colon cancer risk and associated quality control studies. , 1999, Cancer research.

[16]  T. Mcgarrity,et al.  Protein kinase C activity as a potential marker for colorectal neoplasia , 1994, Digestive Diseases and Sciences.

[17]  L. Kopelovich,et al.  Defective organization of actin in cultured skin fibroblasts from patients with inherited adenocarcinoma. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[18]  K. Min,et al.  Cellular F-actin levels as a marker for cellular transformation: correlation with bladder cancer risk. , 1991, Cancer research.

[19]  Charles Giardina,et al.  Mouse models for the study of colon carcinogenesis. , 2008, Carcinogenesis.

[20]  Junji Kato,et al.  Aberrant crypt foci of the colon as precursors of adenoma and cancer , 1998, The New England journal of medicine.

[21]  G. Dakubo,et al.  Clinical implications and utility of field cancerization , 2007, Cancer Cell International.

[22]  Vadim Backman,et al.  Simultaneous measurement of angular and spectral properties of light scattering for characterization of tissue microarchitecture and its alteration in early precancer , 2003 .

[23]  D. Moore,et al.  Alteration of Gene Expression in Normal-Appearing Colon Mucosa of APCmin Mice and Human Cancer Patients , 2004, Cancer Research.

[24]  J. Rosenblatt,et al.  The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium , 2011, Molecular biology of the cell.

[25]  M. Bissonnette,et al.  1,25-Dihydroxyvitamin D3 and 12-O-tetradecanoyl phorbol 13-acetate cause differential activation of Ca(2+)-dependent and Ca(2+)-independent isoforms of protein kinase C in rat colonocytes. , 1995, The Journal of clinical investigation.

[26]  Vadim Backman,et al.  Association between rectal optical signatures and colonic neoplasia: potential applications for screening. , 2009, Cancer research.

[27]  S. Martin,et al.  Response of microtubules to the addition of colchicine and tubulin-colchicine: evaluation of models for the interaction of drugs with microtubules. , 1997, The Biochemical journal.

[28]  K. Wakabayashi,et al.  Gene mutations and altered gene expression in azoxymethane‐induced colon carcinogenesis in rodents , 2004, Cancer science.

[29]  Vadim Backman,et al.  Role of cytoskeleton in controlling the disorder strength of cellular nanoscale architecture. , 2010, Biophysical journal.

[30]  M. Anti,et al.  Rectal epithelial cell proliferation patterns as predictors of adenomatous colorectal polyp recurrence. , 1993, Gut.

[31]  Rebecca Richards-Kortum,et al.  Light scattering from collagen fiber networks: micro-optical properties of normal and neoplastic stroma. , 2007, Biophysical journal.

[32]  K. Jacobson,et al.  Overexpression of profilin reduces the migration of invasive breast cancer cells. , 2004, Cell motility and the cytoskeleton.