Cancer Letters

Cancer Letters

Volume 325, Issue 1, 1 December 2012, Pages 1-10
Cancer Letters

Mini-review
Sarcomas as a mise en abyme of mesenchymal stem cells: Exploiting interrelationships for cell mediated anticancer therapy

https://doi.org/10.1016/j.canlet.2012.05.027Get rights and content

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 attributed 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 inherent 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.

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 includes notions of self-reflexive embedding, as found in Shakespeare’s Hamlet portraying a “play within a play”. Just as popular understanding of mise en abyme has evolved, so too has our understanding 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 sarcoma biology, providing insights likely to be useful for novel therapeutic approaches against sarcomas.

Section snippets

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 derived stem cells; an oversimplification given that mesodermal progenitors diverge at an early point of development once regions of mesoderm are specified [1]. For bone marrow derived cells, the applied nomenclature has aimed to be authentic to the cell source and lineage potential, stressing a bone-forming

Multiple roles for hMSC in sarcoma biology

Like two faces of the same drama, stem cell and tumor biologists both focus on similar cell phenotypes and functions, yet regard them as either beneficial for tissue regeneration or harmful in the context of tumorigenesis (Fig. 1). Thus intuitively, numerous phenotypic qualities of hMSC make them suspects in sarcoma biology.

The conceptual mechanisms by which hMSC may contribute to sarcoma growth are multiple (Fig. 2) and include: (1) A “cell of origin” ontogenic role, associated with loss of

Clinical perspective: Complementing existing therapeutic strategies

The hBM-MSC property of specifically homing to the sites of tumors and metastases whilst escaping immune surveillance encourages the strategy of making hMSC into delivery cells for tumor-targeted therapeutic agents [88], [89], [90] an approach termed “Mesenkillers” [91]. Though this review has thus far focused on hBM-MSC, therapeutic logistics may favor hMSC sourcing from other tissues, and adipose tissue derived hAD-MSC and umbilical cord derived hUCB-MSC have been shown to localize to tumor

Conclusions

Sarcoma cell lines [115] and oncogene-transduced primary hMSC and mMSC [39] provide experimental models that can test the effectiveness of novel cell-mediated therapeutic approaches against sarcomas. In addition, the hMSC-TERT20 strain and its derived clones provide one of the best-characterized hMSC tumorigenic models, advantageously derived from bona fide hMSC. The post-telomerase spontaneous molecular changes that led to tumorigenesis mimicked events common to sarcomas, such as small

Acknowledgements

This work was supported by the Lunbeck foundation, Karen Elise Jensen’s Fond, Novo Nordisk Foundation, Gross M. Brogaard og Hustru Foundation, Danish Cancer Society, the Danish Medical Research Council, CIRRO – The Lundbeck Foundation Centre for Interventional Research in Radiation Oncology & the Danish Council for Strategic Research, and the A.P. Møller Foundation for the Advancement of Medical Science, Ministero Italiano Istruzione Università e Ricerca-PRIN 2006 & 2008, Ministero della Salute

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