Abstract
Cell type specific radial positioning of chromosome territories (CTs) and their sub-domains in the interphase seem to have functional relevance in non-neoplastic human nuclei, while much less is known about nuclear architecture in carcinoma cells and its development during tumor progression. We analyzed the 3D-architecture of the chromosome 8 territory (CT8) in carcinoma and corresponding non-neoplastic ductal pancreatic epithelium. Fluorescence-in-situ-hybridization (FISH) with whole chromosome painting (WCP) probes on sections from formalin-fixed, paraffin wax-embedded tissues from six patients with ductal adenocarcinoma of the pancreas was used. Radial positions and shape parameters of CT8 were analyzed by 3D-microscopy. None of the parameters showed significant inter-individual changes. CT8 was localized in the nuclear periphery in carcinoma cells and normal ductal epithelial cells. Normalized volume and surface of CT8 did not differ significantly. In contrast, the normalized roundness was significantly lower in carcinoma cells, implying an elongation of neoplastic cell nuclei. Unexpectedly, radial positioning of CT8, a dominant parameter of nuclear architecture, did not change significantly when comparing neoplastic with non-neoplastic cells. A significant deformation of CT8, however, accompanies nuclear atypia of carcinoma cells. This decreased roundness of CTs may reflect the genomic and transcriptional alterations in carcinoma.
Highlights
Understanding the nuclear architecture [6, 9] is indispensable for understanding nuclear functions and dysfunctions during cellular changes in neoplastic transformation
Tissue microarrays (TMA) were assembled from selected areas of non-neoplastic pancreatic tissue including ducts without dysplasia or inflammation and areas of ductal adenocarcinoma. 2-mm tissue-cores were taken from the paraffin blocks and transferred into a new paraffin block, creating a TMA-block including 12 tissue cores from all patients
All 3D images of cell nuclei and hybridized CT8 were quantitatively analyzed in terms of their 3D radial positioning and geometric parameters, such as territory volume, surface, and roundness
Summary
Understanding the nuclear architecture [6, 9] is indispensable for understanding nuclear functions and dysfunctions during cellular changes in neoplastic transformation. Current knowledge about nuclear architecture and spatial chromatin organization acknowledges that individual chromosomes in the cell nucleus occupy distinct chromosome territories (CTs) divided into function-. Radial positioning of individual CTs seems to be unique in different tissues [31] and it has been described to be evolutionarily conserved, for instance, in lymphocytes and fibroblasts over 300 million years [43, 44]. These facts suggest a functional relevance of non-random CT positioning [14, 23, 40]. In breast cancer cells distinct positional changes of several gene domains were noticed during malignant transformation [28]
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