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The Fractal Dimension Suggests Two Chromatin Configurations in Small Cell Neuroendocrine Lung Cancer and Is an Independent Unfavorable Prognostic Factor for Overall Survival

Published online by Cambridge University Press:  23 February 2022

Amilcar Castro de Mattos ,
João Batista Florindo ,
Randall L. Adam ,
Irene Lorand-Metze  and
Konradin Metze Open the ORCID record for Konradin Metze [Opens in a new window]
Amilcar Castro de Mattos
Affiliation:
Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil Laboratory of Pathology, Pontifical Catholic University of Campinas PUCC, Campinas, Brazil
João Batista Florindo
Affiliation:
Institute of Mathematics, Statistics and Scientific Computing, University of Campinas (UNICAMP), Campinas, Brazil
Randall L. Adam
Affiliation:
Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Irene Lorand-Metze
Affiliation:
Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Konradin Metze*
Affiliation:
Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
*
*Corresponding author: Konradin Metze, E-mail: [email protected]
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Abstract

Experimental studies have shown that in small cell neuroendocrine lung carcinomas (SCLC) global opening of the chromatin structure is associated with a higher transcription activity and increase of tumor aggressiveness and metastasis. The study of the fractal characteristics (FD) of nuclear chromatin has been widely used to describe the cell nuclear texture and its changes correspond to changes in nuclear metabolic and transcription activity. Hence, we investigated whether the nuclear fractal dimension could be a prognostic factor in SCLC. Hematoxylin-eosin stained brush cytology slides from 49 patients with SCLC were retrieved from our files. The chromatin (FD) was calculated in digitalized and interactively segmented nuclei using a differential box-counting method. The 3,575 nuclei studied showed a bimodal distribution (peaks at FD1 = 2.115 and FD2 = 2.180). The 75 percentile of the FD was an independent unfavorable prognostic factor for overall survival when tested together with ECOG (Eastern Cooperative Oncology Group) performance status, tumor extension, and therapy in a multivariate Cox regression. Our study corroborates the concept of two main chromatin configurations in small cell neuroendocrine carcinomas and that globally more open chromatin indicates a higher risk of metastasis and therefore a shorter survival of the patient.

Keywords

chromatinfractalprognosissmall cell neuroendocrine lung cancer
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 28 , Issue 2 , April 2022 , pp. 522 - 526
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Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press on behalf of the Microscopy Society of America

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References

Adam, RL, Silva, RC, Pereira, FG, Leite, NJ, Lorand-Metze, I & Metze, K (2006). The fractal dimension of nuclear chromatin as a prognostic factor in acute precursor B lymphoblastic leukemia. Cell Oncol 28(1–2), 55–59. doi:10.1155/2006/409593Google ScholarPubMed
Almassalha, LM, Tiwari, A, Ruhoff, PT, Stypula-Cyrus, Y, Cherkezyan, L, Matsuda, H, Dela Cruz, MA, Chandler, JE, White, C, Maneval, C, Subramanian, H, Szleifer, I, Roy, HK & Backman, V (2017). The global relationship between chromatin physical topology, fractal structure, and gene expression. Sci Rep 7, 41061. doi:10.1038/srep41061CrossRefGoogle ScholarPubMed
Bedin, V, Adam, RL, de Sá, BC, Landman, G & Metze, K (2010). Fractal dimension of chromatin is an independent prognostic factor for survival in melanoma. BMC Cancer 10, 260. doi:10.1186/1471-2407-10-260CrossRefGoogle ScholarPubMed
Chalut, KJ, Kulangara, K, Wax, A & Leong, KW (2011). Stem cell differentiation indicated by noninvasive photonic characterization and fractal analysis of subcellular architecture. Integr Biol 3, 863–867. doi:10.1039/c1ib00003aCrossRefGoogle ScholarPubMed
Denny, SK, Yang, D, Chuang, CH, Brady, JJ, Lim, JS, Grüner, BM, Chiou, SH, Schep, AN, Baral, J, Hamard, C, Antoine, M, Wislez, M, Kong, CS, Connolly, AJ, Park, KS, Sage, J, Greenleaf, WJ & Winslow, MM (2016). Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell 166(2), 328–342. doi:10.1016/j.cell.2016.05.052CrossRefGoogle ScholarPubMed
Dinčić, M, Todorović, J, Nešović Ostojić, J, Kovačević, S, Dunđerović, D, Lopičić, S, Spasić, S, Radojević-Škodrić, S, Stanisavljević, D & Ilić, AŽ (2020). The fractal and GLCM textural parameters of chromatin may be potential biomarkers of papillary thyroid carcinoma in Hashimoto's thyroiditis specimens. Microsc Microanal 26(4), 717–730. doi:10.1017/S1431927620001683CrossRefGoogle ScholarPubMed
Ferro, DP, Falconi, MA, Adam, RL, Ortega, MM, Lima, CP, de Souza, CA, Lorand-Metze, I & Metze, K (2011). Fractal characteristics of May-Grünwald-Giemsa stained chromatin are independent prognostic factors for survival in multiple myeloma. PLoS One 6(6), e20706. doi:10.1371/journal.pone.0020706CrossRefGoogle ScholarPubMed
Khan, P, Siddiqui, JA, Maurya, SK, Lakshmanan, I, Jain, M, Ganti, AK, Salgia, R, Batra, SK & Nasser, MW (2020). Epigenetic landscape of small cell lung cancer: Small image of a giant recalcitrant disease. Semin Cancer Biol. S1044-579X(20)30240-6. Advance online publication. doi:10.1016/j.semcancer.2020.11.006Google ScholarPubMed
Kiernan, JA (2018). Does progressive nuclear staining with hemalum (alum hematoxylin) involve DNA, and what is the nature of the dye-chromatin complex? Biotech Histochem 93, 133–148. doi:10.1080/10520295.2017.1399466CrossRefGoogle ScholarPubMed
Ko, J, Winslow, MM & Sage, J (2021). Mechanisms of small cell lung cancer metastasis. EMBO Mol Med 13(1), e13122. doi:10.15252/emmm.202013122CrossRefGoogle ScholarPubMed
Martinovic, T, Ciric, D, Pantic, I, Lalic, K, Rasulic, I, Despotovic, S, Lalic, I, Djuricic, D, Bumbasirevic, V & Kravic-Stevovic, T (2018). Unusual shape and structure of lymphocyte nuclei is linked to hyperglycemia in type 2 diabetes patients. Tissue Cell 52, 92–100. doi:10.1016/j.tice.2018.04.005CrossRefGoogle ScholarPubMed
Metze, K (2010). Fractal dimension of chromatin and cancer prognosis. Epigenomics 2(5), 601–604. doi:10.2217/epi.10.50CrossRefGoogle ScholarPubMed
Metze, K (2013). Fractal dimension of chromatin: Potential molecular diagnostic applications for cancer prognosis. Expert Rev Mol Diagn 13(7), 719–735. doi:10.1586/14737159.2013.828889CrossRefGoogle ScholarPubMed
Metze, K, Adam, R & Florindo, JB (2019). The fractal dimension of chromatin - A potential molecular marker for carcinogenesis, tumor progression and prognosis. Expert Rev Mol Diagn 19(4), 299–312. doi:10.1080/14737159.2019.1597707CrossRefGoogle ScholarPubMed
Metze, K, Adam, RL & Ferreira, RC (2010). Robust variables in texture analysis. Pathology 42(6), 609–611. doi:10.3109/00313025.2010.508794CrossRefGoogle ScholarPubMed
Metze, K, Adam, RL, Vido, JR & Lorand-Metze, IG (2009). The influence of staining characteristics on nuclear texture features in cytology. Anal Quant Cytol Histol 31(4), 241–246.Google ScholarPubMed
Metze, K, Mello, MRB, Albanez, KB, Adam, R & Lorand-Metze, I (2012). Chromatin texture and molecular features in acute myeloid leukemia. Histopathology 61(S1), 49–50.Google Scholar
Pantic, I, Basta-Jovanovic, G, Starcevic, V, Paunovic, J, Suzic, S, Kojic, Z & Pantic, S (2013 b). Complexity reduction of chromatin architecture in macula densa cells during mouse postnatal development. Nephrology (Carlton, Vic.) 18(2), 117–124. doi:10.1111/nep.12003CrossRefGoogle ScholarPubMed
Pantic, I, Harhaji-Trajkovic, L, Pantovic, A, Milosevic, NT & Trajkovic, V (2012). Changes in fractal dimension and lacunarity as early markers of UV-induced apoptosis. J Theor Biol 303, 87–92. doi:10.1016/j.jtbi.2012.03.013CrossRefGoogle ScholarPubMed
Pantic, I, Paunovic, J, Basta-Jovanovic, G, Perovic, M, Pantic, S & Milosevic, NT (2013 c). Age-related reduction of structural complexity in spleen hematopoietic tissue architecture in mice. Exp Gerontol 48(9), 926–932. doi:10.1016/j.exger.2013.06.011CrossRefGoogle ScholarPubMed
Pantic, I, Paunovic, J, Perovic, M, Cattani, C, Pantic, S, Suzic, S, Nesic, D & Basta-Jovanovic, G (2013 a). Time-dependent reduction of structural complexity of the buccal epithelial cell nuclei after treatment with silver nanoparticles. J Microsc 252(3), 286–294. doi:10.1111/jmi.12091CrossRefGoogle ScholarPubMed
Pantic, I, Paunovic, J, Vucevic, D, Radosavljevic, T, Dugalic, S, Petkovic, A, Radojevic-Skodric, S & Pantic, S (2017). Postnatal developmental changes in fractal complexity of giemsa-stained chromatin in mice spleen follicular cells. Microsc Microanal 23(5), 1024–1029. doi:10.1017/S1431927617012545CrossRefGoogle ScholarPubMed
Pantic, I, Petrovic, D, Paunovic, J, Vucevic, D, Radosavljevic, T & Pantic, S (2016). Age-related reduction of chromatin fractal dimension in toluidine blue-stained hepatocytes. Mech Ageing Dev 157, 30–34. doi:10.1016/j.mad.2016.07.002CrossRefGoogle ScholarPubMed
Rudin, CM, Brambilla, E, Faivre-Finn, C & Sage, J (2021). Small-cell lung cancer. Nat Rev Dis Primers 7(1), 3. doi:10.1038/s41572-020-00235-0CrossRefGoogle ScholarPubMed
Sarkar, N & Chaudhuri, B (1994). An efficient differential box counting approach to compute fractal dimension of image. IEEE Trans Syst Man Cybern 24, 115–120. doi:10.1109/21.259692CrossRefGoogle Scholar
Takahashi, M (1989). A fractal model of chromosomes and chromosomal DNA replication. J Theor Biol 141(1), 117–136. doi:10.1016/s0022-5193(89)80012-8CrossRefGoogle ScholarPubMed
Vesković, M, Labudović-Borović, M, Zaletel, I, Rakočević, J, Mladenović, D, Jorgačević, B, Vučević, D & Radosavljević, T (2018). The effects of betaine on the nuclear fractal dimension, chromatin texture, and proliferative activity in hepatocytes in mouse model of nonalcoholic fatty liver disease. Microsc Microanal 24(2), 132–138. doi:10.1017/S1431927617012806CrossRefGoogle ScholarPubMed
Vido-Marques, JR, Reis-Alves, SC, Saad, S, Metze, K & Lorand-Metze, I (2020). A simple score derived from bone marrow immunophenotyping is important for prognostic evaluation in myelodysplastic syndromes. Sci Rep 10(1), 20281. doi:10.1038/s41598-020-77158-zCrossRefGoogle ScholarPubMed
Xie, S, Wu, Z, Qi, Y, Wu, B & Zhu, X (2021). The metastasizing mechanisms of lung cancer: Recent advances and therapeutic challenges. Biomed Pharmacother 138, 111450. doi:10.1016/j.biopha.2021.111450CrossRefGoogle ScholarPubMed