Mini-review Sarcomas as a mise en abyme of mesenchymal stem cells: Exploiting interrelationships for cell mediated anticancer therapy Jorge S. Burns a,⇑ , Akmal Safwat b,c,1 , Giulia Grisendi a,2 , Moustapha Kassem d,e,3 , Massimo Dominici a,4 a Laboratory of Cell Biology and Advanced Cancer Therapies, Department of Oncology, Hematology and Respiratory Disease, University Hospital of Modena and Reggio Emilia, Modena, Italy b Department of Oncology, Aarhus University Hospital, Aarhus, Denmark c Oncology Department, College of Medicine, King Saud University, Riyadh, KSA, Saudi Arabia d Laboratory for Molecular Endocrinology, Odense University Hospital, Odense, Denmark e Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, KSA, Saudi Arabia article info Article history: Received 15 February 2012 Received in revised form 22 May 2012 Accepted 24 May 2012 Available online xxxx Keywords: Sarcoma Mesenchymal stem cell Cell therapy Radiation TRAIL abstract Mise en abyme meaning ‘‘placed into abyss or infinite recurrence’’ is an apt paradigm for the relentless growth of sarcoma cells. Its alternative meaning, ‘‘self-reflexive embedding’’ fits the central role attrib- uted to cancer stem cells (CSCs). Diversely sourced and defined, mesenchymal stem cells (MSCs) may be the cells of sarcoma origin, evolve a CSC phenotype and/or contribute to tumor growth through inher- ent qualities for homing, neovascularization, paracrine cross-feeding, microvesicle secretion, cell fusion, entosis and immune modulation. Exploiting these qualities, MSC expressing modified forms of the TNF- related apoptosis-inducing ligand (Apo2L/TRAIL) are being developed to complement more conventional radiation and chemotherapy. Ó 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The French term ‘‘mise en abyme’’ means ‘‘placed into abyss or infinite recurrence’’ an appropriate paradigm for the relentless growth of sarcoma cells. Moreover, in Heraldry, the abyme is the smaller center shield found in a coat of arms, apt for the central role being attributed to cancer stem cells. Modern meaning in- cludes notions of self-reflexive embedding, as found in Shake- speare’s Hamlet portraying a ‘‘play within a play’’. Just as popular understanding of mise en abyme has evolved, so too has our under- standing of the interrelationship between mesenchymal stem cells (MSCs) and sarcomas. Recent findings from cultured cell models and clinical observations support a very direct role for MSC in sar- coma biology, providing insights likely to be useful for novel ther- apeutic approaches against sarcomas. 2. MSC definitions and safe culture The conceptualized term mesenchymal stem cell (MSC) can be justifiably criticized for ambiguity, implying a confusing idea of broadly distributed equivalent populations of mesodermally de- rived stem cells; an oversimplification given that mesodermal pro- genitors diverge at an early point of development once regions of mesoderm are specified [1]. For bone marrow derived cells, the ap- plied nomenclature has aimed to be authentic to the cell source and lineage potential, stressing a bone-forming potential [2]. Since Alexander Friedenstein’s original referral to osteogenic stem cells, others have proposed the term skeletal stem cells to reflect the po- tential to readily differentiate into cellular components of skeletal tissue, mineralized osteoblasts, adipose cells and chondrocytes. Emphasis on the stromal nature of expanded cultures led to the term marrow stromal stem cells and considerations that the cells have progressed from embryonic tissues to show a restricted mul- tipotentiality generated a view that mesenchymal progenitor cells is more appropriate. The International Society for Cellular Therapy (ISCT) favored the term multipotent mesenchymal stromal cells, usefully defining a minimal set of criteria based on adhesion to cell 0304-3835/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canlet.2012.05.027 ⇑ Corresponding author. Address: Laboratory of Cell Biology and Advanced Cancer Therapies, Department of Oncology Hematology and Respiratory Disease, Univer- sity Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy. Tel.: +39 059 422 2261. E-mail addresses: jorge.burns@unimore.it (J.S. Burns), akmal@aarhus.rm.dk (A. Safwat), giulia.grisendi@unimore.it (G. Grisendi), mkassem@health.sdu.dk (M. Kassem), massimo.dominici@unimore.it (M. Dominici). 1 Tel.: +45 7846 4420. 2 Tel.: +39 059 422 3307. 3 Tel.: +45 6550 4084 (Office), +45 6541 1233 (Secretary). 4 Tel.: +39 059 422 2858x4019 (Office). Cancer Letters xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Please cite this article in press as: J.S. Burns et al., Sarcomas as a mise en abyme of mesenchymal stem cells: Exploiting interrelationships for cell mediated anticancer therapy, Cancer Lett. (2012), http://dx.doi.org/10.1016/j.canlet.2012.05.027