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![SUMMARY Shortly before the DNA era began, PC Koller described lagging chromosomes and chromosome numerical abnormalities in human carcinomas. While present-day cancer geneticists would question some of Koller’s conclusions, this study ultimately contributed to the realisation that chromosomal instability is a widespread feature of solid tumours. Seventy-five years ago the molecular basis of tumorigenesis was unknown and even the field of cytogenetics was in its infancy. Morgan and others had established by the early decades of the twentieth century that normal cellular function was associated with the duplication and accurate segregation of chromosomes, within which genetic determinants somehow resided. It was only with the refinement of cytological techniques in the 1950s, however, that it became clear that the normal human karyotype consisted of 23 pairs of chromosomes [1] and not 24, as was generally thought in 1947. In the article reviewed here, Pius Károly Koller, known as Peo Charles, working at the Chester Beatty Laboratories in London, documented a variety of mitotic abnormalities in human carcinomas [2]. Five years earlier Koller had developed a technique for resorcin blue staining of chromosomes in acetic acid-alcohol fixed biopsy specimens [3]. These preparations, once squashed (according to the protocol with the blunt end of a bone needle-holder!), could be visualised by direct photomicroscopy or by hand drawing, using a camera lucida device to view the specimen and drawing surface simultaneously. Of the numerous observations made here using this technique, Koller’s description of the abundance of lagging (or ‘_sticky_’) chromosomes in mitotic carcinoma cells is perhaps the most significant and least contentious in the light of present-day understanding. Lagging chromosomes are now acknowledged to be a major underlying cause of mis-segregation and the consequent chromosomal instability characteristic of many solid tumours [4]. More recent studies have shed light on the causes of the ‘_stickiness_’ noted by Koller, including defects in sister chromatid cohesion, decatenation and cell cycle checkpoint responses, aspects of cell biology that were unknowable in the 1940s. Yet in interpreting his findings Koller adheres rigidly to the assumption—shown by subsequent studies to be an over-generalisation—that ‘_loss of chromosomes or of chromosome segments leads to the death of the cell_’. For this reason, he hastily dismisses as ‘_erroneous_’ the earlier conclusions of Boveri, who these days is celebrated as having been the first to suggest that chromosome mis-segregation in a single progenitor cell might be fundamental to tumorigenesis [5]. The key point is that while mis-segregation may frequently lead to the death of one or both daughter cells, as Koller had previously suggested, it also provides a substrate for natural selection of any minority aneuploid progeny that have growth or survival advantages. Some of the further claims made by Koller highlight technical limitations of his staining and imaging methodology, in particular the inability to distinguish between chromosomes or to count them accurately. For example, a mitotic figure from a rectal carcinoma is described as having only 16 chromosomes (‘_instead of 48_’), while a ‘_free giant tumour cell_’ aspirated from the abdomen has ‘_about 250 small chromosomes_’. Some of the images described may not represent intact chromosomes at all, but potentially apoptotic bodies, which had yet to be described, or simply artifacts of the fixation and staining procedure. Despite these issues, the data make a valuable contribution to the early characterisation of aneuploidy in carcinomas, now recognised as a general mechanism underlying intratumoral heterogeneity and the evolution of cancer phenotypes [6]. In clinging to the dogma that ‘_normal cellular activity stops when the nucleus does not contain the full chromosome complement_’, Koller feels obliged to explain the apparent ability of the aneuploid cells he describes to proliferate within the tumour. His chosen explanation revolves around the concept of cytoplasmic control, with malignant transformation involving some sort of critical cytoplasmic event that frees cells from the requirement to retain the normal karyotype. In support of this view, Koller notes that, in a rectal adenocarcinoma, there was ‘_synchronisation in the behaviour of adjacent cells_’, with 16 cells in one region undergoing simultaneous mitosis. This is taken as evidence of the aneuploid cells showing a ‘_great dependence_’ on each other and sharing a cytoplasmic driver of malignancy. The current consensus view of tumorigenesis through sequential acquisition of nuclear genomic changes has no place for rate-limiting heritable cytoplasmic changes, but Koller’s suggestion that an activator of mitosis (as opposed to transformation) might be shared between cells via the cytoplasm anticipates the identification in the 1980s of cyclin-dependent kinase 1 (CDK1) as the universal mitotic trigger [7]. It is unclear whether the synchronous mitoses seen by Koller reflected the presence of multinucleate cells or of intercellular connections somehow large enough to permit the free exchange of soluble proteins between adjacent cells. Perhaps the most intriguing claim made by Koller is that mitotic abnormalities are more frequent in poorly vascularised regions of carcinomas than in rapidly proliferating, peripheral regions. He cites inadequate ‘_food supply_’ and the possible involvement of ‘_toxic breakdown products_’ as potential underlying causes of chromosome mis-segregation. While the relationship between cell nutrition and mitotic fidelity remains rather poorly understood to this day, especially in the context of primary human tumours, recent literature has highlighted mechanisms by which hypoxia and/or oxidative base damage may generate lagging chromosomes [8, 9], providing support for Koller’s hypothesis. Koller’s chromosomal account of cancer biology is completely separable from the current DNA-centric view. Only three years earlier Avery, MacLeod and McCarty had demonstrated the of role of DNA in bacterial transformation [10], though the generality of this finding in relation to inheritance was not universally acknowledged in 1947. Koller instead regards ‘_nucleic acid_’ as being important for chromosome organisation and condensation, and even suggests that chromosome stickiness might be due to an ‘_excess of nucleic acid charge_’, a concept wholly at odds with current understanding of nucleic acid chemistry and chromatin structure. Progress in cancer research can often feel painfully slow, but this article is a useful reminder of just how far the field has advanced in the past 75 years. At the same time, it underscores the inherent advantages of studies based on direct observation of human tumours and hints at lines of investigation that may even now offer further insight into the fidelity of chromosome segregation in different tumour microenvironments. REFERENCES * Tjio JH, Levan A. The chromosome number of man. Hereditas. 1956;42:1–6. Article Google Scholar * Koller PC. Abnormal mitosis in tumours. Br J Cancer. 1947;1:38–47. Article CAS PubMed PubMed Central Google Scholar * Koller PC. A new technique for mitosis in tumours. Nature. 1942;149:193. Article Google Scholar * Thompson SL, Bakhoum SF, Compton DA. Mechanisms of chromosomal instability. Curr Biol. 2010;20:R285–95. Article CAS PubMed PubMed Central Google Scholar * Boveri T. Zur Frage der Entstehung maligner Tumoren. Jena: Gustav Fischer;1914. * Sansregret L, Swanton C. The role of aneuploidy in cancer evolution. Cold Spring Harb Perspect Med. 2017;7:a028373. Article PubMed PubMed Central Google Scholar * Nurse P. Universal control mechanism regulating onset of M-phase. Nature. 1990;344:503–8. Article CAS PubMed Google Scholar * Wang Z, Rhee DB, Lu J, Bohr CT, Zhou F, Vallabhaneni H, et al. Characterization of oxidative guanine damage and repair in mammalian telomeres. PLoS Genet. 2010;6:e1000951. Article PubMed PubMed Central Google Scholar * Nakada C, Tsukamoto Y, Matsuura K, Nguyen TL, Hijiya N, Uchida T, et al. Overexpression of miR-210, a downstream target of HIF1alpha, causes centrosome amplification in renal carcinoma cells. J Pathol. 2011;224:280–8. Article CAS PubMed Google Scholar * Avery OT, Macleod CM, McCarty M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med. 1944;79:137–58. Article CAS PubMed PubMed Central Google Scholar Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK Chris J. Norbury Authors * Chris J. Norbury View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS CJN wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Chris J. Norbury. ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing interests. ETHICS APPROVAL AND CONSENT TO PARTICIPATE Not applicable. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Norbury, C.J. Koller and the dawn of cancer cytogenetics. _Br J Cancer_ 128, 402–403 (2023). https://doi.org/10.1038/s41416-022-01996-z Download citation * Received: 25 August 2022 * Revised: 17 September 2022 * Accepted: 22 September 2022 * Published: 13 October 2022 * Issue Date: 02 February 2023 * DOI: https://doi.org/10.1038/s41416-022-01996-z SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. 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SUMMARY Shortly before the DNA era began, PC Koller described lagging chromosomes and chromosome numerical abnormalities in human carcinomas. While present-day cancer geneticists would
question some of Koller’s conclusions, this study ultimately contributed to the realisation that chromosomal instability is a widespread feature of solid tumours. Seventy-five years ago the
molecular basis of tumorigenesis was unknown and even the field of cytogenetics was in its infancy. Morgan and others had established by the early decades of the twentieth century that
normal cellular function was associated with the duplication and accurate segregation of chromosomes, within which genetic determinants somehow resided. It was only with the refinement of
cytological techniques in the 1950s, however, that it became clear that the normal human karyotype consisted of 23 pairs of chromosomes [1] and not 24, as was generally thought in 1947. In
the article reviewed here, Pius Károly Koller, known as Peo Charles, working at the Chester Beatty Laboratories in London, documented a variety of mitotic abnormalities in human carcinomas
[2]. Five years earlier Koller had developed a technique for resorcin blue staining of chromosomes in acetic acid-alcohol fixed biopsy specimens [3]. These preparations, once squashed
(according to the protocol with the blunt end of a bone needle-holder!), could be visualised by direct photomicroscopy or by hand drawing, using a camera lucida device to view the specimen
and drawing surface simultaneously. Of the numerous observations made here using this technique, Koller’s description of the abundance of lagging (or ‘_sticky_’) chromosomes in mitotic
carcinoma cells is perhaps the most significant and least contentious in the light of present-day understanding. Lagging chromosomes are now acknowledged to be a major underlying cause of
mis-segregation and the consequent chromosomal instability characteristic of many solid tumours [4]. More recent studies have shed light on the causes of the ‘_stickiness_’ noted by Koller,
including defects in sister chromatid cohesion, decatenation and cell cycle checkpoint responses, aspects of cell biology that were unknowable in the 1940s. Yet in interpreting his findings
Koller adheres rigidly to the assumption—shown by subsequent studies to be an over-generalisation—that ‘_loss of chromosomes or of chromosome segments leads to the death of the cell_’. For
this reason, he hastily dismisses as ‘_erroneous_’ the earlier conclusions of Boveri, who these days is celebrated as having been the first to suggest that chromosome mis-segregation in a
single progenitor cell might be fundamental to tumorigenesis [5]. The key point is that while mis-segregation may frequently lead to the death of one or both daughter cells, as Koller had
previously suggested, it also provides a substrate for natural selection of any minority aneuploid progeny that have growth or survival advantages. Some of the further claims made by Koller
highlight technical limitations of his staining and imaging methodology, in particular the inability to distinguish between chromosomes or to count them accurately. For example, a mitotic
figure from a rectal carcinoma is described as having only 16 chromosomes (‘_instead of 48_’), while a ‘_free giant tumour cell_’ aspirated from the abdomen has ‘_about 250 small
chromosomes_’. Some of the images described may not represent intact chromosomes at all, but potentially apoptotic bodies, which had yet to be described, or simply artifacts of the fixation
and staining procedure. Despite these issues, the data make a valuable contribution to the early characterisation of aneuploidy in carcinomas, now recognised as a general mechanism
underlying intratumoral heterogeneity and the evolution of cancer phenotypes [6]. In clinging to the dogma that ‘_normal cellular activity stops when the nucleus does not contain the full
chromosome complement_’, Koller feels obliged to explain the apparent ability of the aneuploid cells he describes to proliferate within the tumour. His chosen explanation revolves around the
concept of cytoplasmic control, with malignant transformation involving some sort of critical cytoplasmic event that frees cells from the requirement to retain the normal karyotype. In
support of this view, Koller notes that, in a rectal adenocarcinoma, there was ‘_synchronisation in the behaviour of adjacent cells_’, with 16 cells in one region undergoing simultaneous
mitosis. This is taken as evidence of the aneuploid cells showing a ‘_great dependence_’ on each other and sharing a cytoplasmic driver of malignancy. The current consensus view of
tumorigenesis through sequential acquisition of nuclear genomic changes has no place for rate-limiting heritable cytoplasmic changes, but Koller’s suggestion that an activator of mitosis (as
opposed to transformation) might be shared between cells via the cytoplasm anticipates the identification in the 1980s of cyclin-dependent kinase 1 (CDK1) as the universal mitotic trigger
[7]. It is unclear whether the synchronous mitoses seen by Koller reflected the presence of multinucleate cells or of intercellular connections somehow large enough to permit the free
exchange of soluble proteins between adjacent cells. Perhaps the most intriguing claim made by Koller is that mitotic abnormalities are more frequent in poorly vascularised regions of
carcinomas than in rapidly proliferating, peripheral regions. He cites inadequate ‘_food supply_’ and the possible involvement of ‘_toxic breakdown products_’ as potential underlying causes
of chromosome mis-segregation. While the relationship between cell nutrition and mitotic fidelity remains rather poorly understood to this day, especially in the context of primary human
tumours, recent literature has highlighted mechanisms by which hypoxia and/or oxidative base damage may generate lagging chromosomes [8, 9], providing support for Koller’s hypothesis.
Koller’s chromosomal account of cancer biology is completely separable from the current DNA-centric view. Only three years earlier Avery, MacLeod and McCarty had demonstrated the of role of
DNA in bacterial transformation [10], though the generality of this finding in relation to inheritance was not universally acknowledged in 1947. Koller instead regards ‘_nucleic acid_’ as
being important for chromosome organisation and condensation, and even suggests that chromosome stickiness might be due to an ‘_excess of nucleic acid charge_’, a concept wholly at odds with
current understanding of nucleic acid chemistry and chromatin structure. Progress in cancer research can often feel painfully slow, but this article is a useful reminder of just how far the
field has advanced in the past 75 years. At the same time, it underscores the inherent advantages of studies based on direct observation of human tumours and hints at lines of investigation
that may even now offer further insight into the fidelity of chromosome segregation in different tumour microenvironments. REFERENCES * Tjio JH, Levan A. The chromosome number of man.
Hereditas. 1956;42:1–6. Article Google Scholar * Koller PC. Abnormal mitosis in tumours. Br J Cancer. 1947;1:38–47. Article CAS PubMed PubMed Central Google Scholar * Koller PC. A new
technique for mitosis in tumours. Nature. 1942;149:193. Article Google Scholar * Thompson SL, Bakhoum SF, Compton DA. Mechanisms of chromosomal instability. Curr Biol. 2010;20:R285–95.
Article CAS PubMed PubMed Central Google Scholar * Boveri T. Zur Frage der Entstehung maligner Tumoren. Jena: Gustav Fischer;1914. * Sansregret L, Swanton C. The role of aneuploidy in
cancer evolution. Cold Spring Harb Perspect Med. 2017;7:a028373. Article PubMed PubMed Central Google Scholar * Nurse P. Universal control mechanism regulating onset of M-phase. Nature.
1990;344:503–8. Article CAS PubMed Google Scholar * Wang Z, Rhee DB, Lu J, Bohr CT, Zhou F, Vallabhaneni H, et al. Characterization of oxidative guanine damage and repair in mammalian
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Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK Chris J. Norbury Authors * Chris J. Norbury View author publications You can also search for this author inPubMed Google
Scholar CONTRIBUTIONS CJN wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Chris J. Norbury. ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing interests.
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THIS ARTICLE CITE THIS ARTICLE Norbury, C.J. Koller and the dawn of cancer cytogenetics. _Br J Cancer_ 128, 402–403 (2023). https://doi.org/10.1038/s41416-022-01996-z Download citation *
Received: 25 August 2022 * Revised: 17 September 2022 * Accepted: 22 September 2022 * Published: 13 October 2022 * Issue Date: 02 February 2023 * DOI:
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