Cancer and age related colonic crypt deficiencies in cytochromecoxidase I

Abstract

AIM:To investigate whether deficiency of expression of cytochrome c oxidase I (CcOI) in colonic crypts is associated with colon cancer. METHODS:The pattern and level of expression of CcOI in non-neoplastic colonic crypts, and in dysplastic tissues, was assessed using standard immunohistochemical methods. Biopsies were obtained from individuals undergoing colonoscopies for screening purposes or for a medically indicated reason. Tissue samples were also obtained from surgical colonic resections. Samples from resections were taken from colonic mucosa 1 and 10 cm from tumors and from the tumors themselves. Samples were evaluated for frequency of crypts with reduced or absent expression of CcOI. In most crypts the loss was apparent throughout the entire crypt, while in a small minority the loss was segmental. The strong immunoreactivity using this monoclonal antibody makes the scoring unambiguous. The percent of crypts with reduced or absent expression of CcOI or (infrequent) segmented loss of expression was then calculated. Data analyses were performed using SPSS statistical package 17.0. RESULTS:The average frequency of CcOI deficient crypts (CcOI-DC) is low in individuals between 20 and 39 years of age, with 0.48% ± 0.40% CcOI-DC for women and 1.80% ± 0.35% for men. CcOI-DC increases after age 40 years, so that between the ages of 40 and 44 years the average frequency of CcOI-DC goes up to 5.89% ± 0.84% in women and 2.15% ± 1.27% in men. By 80-84 years of age, the average frequency of CcOI-DC goes up in women to 15.77% ± 0.97% and in men to 22.6% ± 0.65%. The increases in CcOI-DC from ages 40-44 years compared to 80-84 years in women and men are significantly different with P < 0.01. For women over age 60 years, deficiency of CcOI expression is greater in those women who have had a cancer in their colon. The frequency of CcOI-DC, measured in men, increased in tissues adjacent to colon cancer, being 4.03% ± 0.27% in individuals free of neoplasia in the age range 55-64 years

Umbilical Cord Mesenchymal Stromal Cells Affected by Gestational Diabetes Mellitus Display Premature Aging and Mitochondrial Dysfunction

“…Mitochondrial DNA mutations and respiratory chain deficiency accumulate in aging human mitotic tissues, such as the colon and small intestine, leading to a decrease in crypt cell number and cell proliferation [43,44]. In fact, mice with a homozygous D257A mutation in the proofreading domain of mitochondrial DNA polymerase g display severe respiratory chain deficiency and a premature aging phenotype [45,46].…”

Epigenetic field defects in progression to cancer

“…Figure 3 shows an opened resected segment of a human colon that has a colon cancer. There are about 100 colonic microscopic epithelial crypts per sq mm in the human colonic epithelium [41] . The colonic epithelium in the resection shown in Figure 3 has an area of about 6.5 cm by 17 cm, or 111 sq cm, or 11 100 sq mm.…”

Maspin is a deoxycholate-inducible, anti-apoptotic stress-response protein differentially expressed during colon carcinogenesis

“…High maspin expression, however, was not observed as “field defects” in the non-neoplastic colonic mucosa,78 either directly adjacent to a tumor or at different distances proximal or distal to the tumor. In contrast, “field defects” were observed in the decreased expression of the DNA repair proteins Pms2, ERCC1, Xpf, and Ku86,41,79 and in an apoptosis-related mitochondrial protein, cytochrome c oxidase 40,42. It is possible that a dramatic and sustained increase in maspin expression at the polyp stage may drive sporadic colon tumorigenesis through its anti-apoptotic function and interaction with other survival signaling pathways in the colon.…”

“…These tissue samples were fixed immediately in formalin by CMP and HH, as previously described 39–41. All colonoscopy tissue samples (n = 10) from five patients without colonic disease were obtained at UMC and at SAVAHCS under the direct supervision of CB and fixed immediately in formalin, as previously described 42. Tissue samples from archived biopsies of polyps/adenomas (n = 8, including two hyperplastic polyps, six adenomatous polyps), and colon cancers (n = 7) were obtained from TMC and selected for the present study by GW.…”

“…Background Sniper from a Mach 3 (Biocare Medical, Concord, CA) kit was applied followed by mouse antihuman maspin antibody (catalog #554292; BD Biosciences Pharmingen), the secondary antibody (polyclonal rabbit antimouse biotinylated antibody [catalog #E0413; DAKO, Glostrup, Denmark]), and then by Vector PK6100 (Vectastain ABC kit; Vector Laboratories, Burlingame, CA) and 3,3′-diaminobenzidine (Sigma-Aldrich). Slides were counterstained with freshly filtered hematoxylin, dehydrated through a graded series of ethanols, immersed in xylene, and mounted using Cytoseal Mounting Medium (VWR, Tempe, AZ), as previously described 42,43…”