Apoptotic pathways and stemness in the colorectal epithelium and lamina propria mucosae during the human embryogenesis and carcinogenesis.
OBJECTIVE
Programmed cell death is essential both during normal organ development and carcinogenesis. In this study we immunohistochemically analyzed different pathways of cell death in 11 human conceptuses 5th-10th-weeks old, 10 low and high grade colorectal carcinomas (CRC), and 10 normal colon samples by using markers for apoptosis (caspase-3, AIF, TUNEL), proliferation (Ki-67) and stemness (Oct-4).


RESULTS
Between the 5th and 10th week of development, caspase-3 and AIF showed moderate-to-strong expression in the developing gut wall. During development, number of caspase-3-reactive cells decreased, while AIF increased. While healthy colorectal control and low grade CRC showed moderate expression of caspase-3 and AIF, in high grade CRC their expression was strong. Tumor tissues displayed significantly higher number of positive cells than controls. Occasionally, co-expressing of both markers characterized dying cells. In developing colon, Oct-4 and Ki-67 showed moderate-to-strong expression, while some cells co-expressed both markers. Their number decreased in the epithelium and increased in the connective tissue in later development. Healthy colorectal control displayed moderate Ki-67 and mild Oct-4 reactivity. While in low-grade CRC expression Oct-4 and Ki-67 was moderate, in high-grade CRC their expression was strong. Although Oct-4 and TUNEL occasionally co-expressed in all samples, both grades of CRC contained cells that were Oct-4 positive only.


CONCLUSIONS
Our study revealed two different parallel pathways of cell death, with characteristic increase of AIF-mediated apoptosis when compared to caspase-3, and presence of stemness cells both during colon development and carcinogenesis. These finding might be considered as important diagnostic, survival and CRC therapy predictors.
Department of Oncology, University Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina.
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Tica Sedlar
Department of Pathology, Citology and Forensic Medicine, University Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina; Department of Pathology, School of Medicine, University of Mostar, Bijeli brijeg bb, 88000 Mostar, Bosnia and Herzegovina.
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Petricevic
Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.
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Saraga-Babic
Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.
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Pintaric
Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia; Department of Histology and Embryology, School of Medicine, University of Mostar, Bijeli brijeg bb, 88000 Mostar, Bosnia and Herzegovina. Electronic address: katarina.vukojevic@mefst.hr.
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Vukojevic
D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology*; D004848:Epithelium / Q000254:growth & development*; D006801:Humans; D009092:Mucous Membrane / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
D051033:Apoptosis Inducing Factor; C505407:CASP3 protein, human; D053148:Caspase 3
AIF; Colon; Embryo; Oct-4; caspase-3