Annals of Anatomy 192 (2010) 292–301 Contents lists available at ScienceDirect Annals of Anatomy journal homepage: www.elsevier.de/aanat Nuclear imaging in three dimensions: A unique tool in cancer research Thomas Klonisch a,b,c,∗ , Landon Wark d , Sabine Hombach-Klonisch a,e , Sabine Mai a,d,f,g a Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada b Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada c Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada d Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada e Department of Obstetics, Gynaecology, and Reproductive Medicine, University of Manitoba, Winnipeg, Manitoba, Canada f Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada g Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada article info Article history: Received 18 July 2010 Accepted 18 July 2010 Keywords: 3D nuclear imaging Telomeres Chromosomes Shelterin Genomic instability Nucleus Cancer summary Tumorigenesis includes alterations in the three-dimensional (3D) nuclear organization of the genome. The combination of sensitive quantitative fluorescent in situ hybridization (Q-FISH) and three- dimensional (3D) microscopy have evolved as powerful tools in studying the dynamic 3D organization of telomeres and chromosomes in the interphase nucleus of individual normal and tumor cells. Tumor- specific alterations in 3D telomere architecture, particularly the appearance of telomeric aggregates, are early events in tumorigenesis and have diagnostic and prognostic value. Novel tools in the 3D nuclear imaging arsenal now include high-throughput scanning capabilities and new 3D nano-resolution microscopy of tissues and cells. In this review, we summarize our current understanding of the biology of telomeres in the context of tumorigenesis and elucidate the important integrating function of advanced 3D imaging technologies in translating new discoveries in basic cancer research into new diagnostic tools for clinical oncologists to improve patient care. © 2010 Elsevier GmbH. All rights reserved. 1. Introduction 1.1. Introduction to nuclear imaging and role of chromosomes/telomeres in tumorigenesis Theodore Boveri (1862–1915), in his seminal work, postulated the three-dimensional (3D) organization of the nuclear genome in a cell to be an essential contributing factor to tumorigenesis (Boveri, 1902, 1914, 1929). A century later and with sophisticated molecular tools and high resolution 3D imaging technology at our fingertips, Boveri’s visionary discovery still forms the conceptual basis for cur- rent work in nuclear genomic events contributing to tumorigenesis. This includes our better understanding of the interaction between the nuclear matrix and chromosomes (Berezney and Coffey, 1975; Parnaik, 2008) and the existence of specific chromosomal territo- ries (CT) within the nucleus as identified by chromosome-specific paints (Cremer and Cremer, 2006, 2010; Cremer et al., 2006; Meaburn and Misteli, 2007). These seminal discoveries have pro- vided an structural insight into the importance of the nuclear genomic micro-environment and its relevance in tumorigenesis. ∗ Corresponding author at: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada. E-mail address: klonisch@cc.umanitoba.ca (T. Klonisch). Genomic instability (GI) is a key feature in cancer initiation and a hallmark of pre-neoplastic and neoplastic cells. GI is an acquired genetic trait and it can be detected with certainty. For instance, in a study on the onset of genomic instability in p53-/- mice, GI was detected as early as Day 10 of embryo development (Fukasawa et al., 1997). Young mice (3–4 weeks old) already pos- sessed much higher levels of instability in all organs examined and at 5 months of age most of the mice succumbed to malignant thy- momas. The p53-/- mice also developed a spectrum of additional cancers but the thymomas were most aggressive and caused the death of the animals (Donehower et al., 1992). However, a higher level of GI is not always associated with a greater incidence of malignancy (Weaver et al., 2007). Thus, those genetic changes are important that ultimately contribute to tumor development in a specific micro-environment (Fest et al., 2005). GI includes structural and numerical chromosomal aberrations, point mutations, altered methylation profiles, new profiles of miRNA expression, extrachromosomal elements (EEs), and a reor- ganized, remodelled nuclear organization (Mai and Imreh, 2007). Cancer-initiating events are causally linked to (i) non-random genomic changes to tumor susceptibility and initiation, e.g., in Li- Fraumeni patients with loss of heterozygosity (LOH) of the tumor suppressor gene p53 (Iwakuma et al., 2005; Santibanez-Koref et al., 1991), LOH of the retinoblastoma protein encoding gene (pRB) that is causal to the development of retinoblastoma in infants 0940-9602/$ – see front matter © 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.aanat.2010.07.007