Cancer Letters

Cancer Letters

Volume 414, 1 February 2018, Pages 239-249
Cancer Letters

Mini-review
The future of mesenchymal stem cell-based therapeutic approaches for cancer – From cells to ghosts

https://doi.org/10.1016/j.canlet.2017.11.025Get rights and content

Highlights

  • MSC-based therapies have entered clinical trials.

  • Several open questions remain, such as safety and biodistribution of MSCs.

  • New developments such as iMSCs and nanoghosts.

Abstract

Mesenchymal stem cells (MSCs) are multipotent stromal cells which can differentiate into a variety of cell types including osteoblasts, adipocytes and chondrocytes. They are normally resident in adipose tissue, bone marrow and the umbilical cord, but can also be found in other tissues and are known to be recruited to sites of wound healing as well as growing tumours. The therapeutic potential of MSCs has been explored in a number of phase I/II and III clinical trials, of which several were targeted against graft-versus-host disease and to support engraftment of haematopoietic stem cells (HSCs), but currently only very few in the oncology field. There are now three clinical trials either ongoing or recruiting patients that use MSCs to treat tumour disease. In these, MSCs target gastrointestinal, lung and ovarian cancer, respectively. The first study uses MSCs loaded with a HSV-TK expression construct under the control of the CCL5 promoter, and has recently reported successful completion of Phase I/II. While no adverse side effects were seen during this study, no outcomes with respect to therapeutic benefits have been published. The other clinical trials targeting lung and ovarian cancer will be using MSCs expressing cytokines as therapeutic payload. Despite these encouraging early steps towards their clinical use, many questions are still unanswered regarding the biology of MSCs in normal and pathophysiological settings. In this review, in addition to summarising the current state of MSC-based therapeutic approaches for cancer, we will describe the remaining questions, obstacles and risks, as well as novel developments such as MSC-derived nanoghosts.

Section snippets

MSCs and their potential use in cancer treatment

MSCs were first isolated and characterised by Friedenstein and his colleagues in the 1960–1970s [1]. They are non-haematopoietic cell precursors, initially found in the bone marrow, but actually present in many other tissues [2]. The International Society of Cellular Therapy (ISCT) uses three criteria to define MSCs [3]: Firstly, MSCs can adhere to plastic under standard culture conditions; secondly, MSCs express cell surface markers including CD105, CD73 and CD90 with no expression of

Do MSCs undergo malignant transformation and form tumours?

In the 2000s it was reported that MSCs could undergo spontaneous, malignant transformation and form tumours in vivo, dramatically increasing the risk of therapeutic use of MSCs [50], [51], [52]. However, these initial reports were subsequently retracted as it turned out that the observed tumour formation was the result of cross-contaminations with cancer cells [53], [54]. In detail, the subsequent analyses showed that the MSC cultures were cross-contaminated with a human sarcoma cell line in

MSCs in preclinical studies and clinical trials

Efficient tumour homing properties will be of importance in MSC-based cancer treatments to surmount the limitations of current therapies such as short drug half-lives and insufficient delivery. The use of an MSC-delivered and continuously produced therapeutic agent could help to overcome these hurdles given that sufficient numbers of MSCs are indeed recruited to tumour lesions. Efforts in increasing the tumour tropism by local irradiation or by overexpressing molecules involved in homing of

The fate of MSCs in vivo

In contrast to other diseases [149], for the treatment of cancer it appears necessary for MSCs to engraft in the relevant tissues, i.e. primary cancer, dissemination routes (e.g. lymphatic system) and metastatic lesions [45]. However, currently, it is not entirely clear how exogenously administered MSCs behave in the human body but what we know is summarised in Supplementary Table 2. Multiple studies have demonstrated the presence of MSCs in the lung, immediately after injection [150], [151],

Concluding remarks

MSCs provide a powerful treatment modality for tumours owing to a series of beneficial features. However, there are still remaining issues that should be addressed and optimised such as the choice of vector and/or therapeutic gene, the optimal route of administration, the question whether allogenic cells provide a good and safe source or whether they will be replaced by autologous iMSCs in the future. Furthermore, it might be possible to derive so called NGs or exosomes from MSCs to avoid many

Conflicts of interest

The authors report no conflicts of interest.

Acknowledgements

The authors acknowledge support from Prostate Cancer UK (RIA15-ST2-014) and Pancreatic Cancer UK (2016 RIF Award).

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