Please cite this article in press as: Hultman I, et al. Experimental teratoma: At the crossroad of fetal- and onco-development. Semin Cancer Biol (2014), http://dx.doi.org/10.1016/j.semcancer.2014.08.005 ARTICLE IN PRESS G Model YSCBI 1166 1–5 Seminars in Cancer Biology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Seminars in Cancer Biology j o ur na l ho me page: www.elsevier.com/locate/semcancer Review Experimental teratoma: At the crossroad of fetal- and onco-development Isabell Hultman, Lars Björk, Evelina Blomberg, Bengt Sandstedt, Lars Ährlund-Richter * Q1 Department of Women’s and Children’s Health, Karolinska Institutet, 17176 Stockholm, Sweden a r t i c l e i n f o Keywords: Stem cells Pluripotency Teratoma Cancer a b s t r a c t Xenografting is the so far only available in vivo model for assessing pluripotency of human stem cells. This review describes known biological features of experimental teratoma from human pluripotent stem cells. We focus on the dual nature mimicking both normal and abnormal development, and propose this model system to be particularly interesting for investigations of the relationship between developmentally controlled differentiation and neoplasia of embryonic origin. In resemblance to the wide range of clinical teratomas, pluripotent stem cell (PSC) induced teratoma (PSCT) typically shows a mixture of developing tissues in randomly distributed compartments. The com- bined literature suggests that for teratomas derived from human diploid bona fide PSC the embryonic development in the separate tissue-niches can show a controlled differentiation into organoid patterns closely mimicking early development. In the experimental situation such PSCT human homologous in vivo tissue-niches have been shown to provide also matching microenvironment for a micrometastatic colonization and outgrowth of embryonic tumors transplanted directly from patients. Single or small clusters of normal and neoplastic cells can easily be visualized together in microscope-based imaging systems, enabling multi-parameter detection of in the scans of tissue slides/specimens. © 2014 Published by Elsevier Ltd. 1. Human teratoma: short version of a long chronicle Germ cell tumors (GCT), to which teratoma belongs, is a het- erogeneous group of tumors that can appear at various anatomic sites, either gonadal or extragonadal [1]. The pluripotency of the reproductive cells from which this group of tumors originate likely contributes to their complexity and anatomical diversity [2]. Clin- ical routine for the classification of GCT’s is based on histology regardless of location but a classification based on also genetics and site of origin has been put forward [1,2]. The earliest known description of the condition in human is dated to Ancient time and the notion of teratoma reflecting embry- onic events can be traced back several hundred years ago [3]. The first description based on more modern principles of devel- opmental biology was reported 1926 by Budde; claiming that teratomas ‘probably represented misdirection of the action of a pri- mary embryonic organizer’, and that ‘the tumors originated in cells * Corresponding author at: Department of Women’s and Children’s Health, Karolinska University Hospital, Cancer Center Karolinska, R8:00, 17176 Stockholm, Sweden. Tel.: +46 08 51773450; fax: +46 08 51773184. E-mail address: lars.ahrlund@ki.se (L. Ährlund-Richter). released from normal developmental control at the stage of the primitive streak (as cited by Pierce and Dixon in their publication ‘Testicular teratomas’ 1959 [4]). Much has since been written on the history and characteristics of teratoma. Following the pioneering work of Leroy Stevens on the mouse strain 129, an array of elegant experiments on experimen- tal teratoma has paved the way, uncovering embryonal carcinoma (EC) and embryonic stem cells (ESC), till today’s concepts of cellular reprogramming into pluripotency and stemness (see [5] for a time lined review). 2. Pluripotency in normal and abnormal development Cellular pluripotency is defined as a capacity to develop progeny with the potential to reconstitute an entire organism given the adequate support from extra embryonic tissues. This strict crite- rion is for ethical reasons not applicable when testing human stem cells. However, a more limited capacity to derive progeny repre- senting all three germ layers is possible to test for. With either of these two demarcations, pluripotency is fundamental for building complex multicellular organisms and transiently effective in early phases of ontogeny. Stemness appearing later in life, renowned as http://dx.doi.org/10.1016/j.semcancer.2014.08.005 1044-579X/© 2014 Published by Elsevier Ltd. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50