In addition to their potential for cellular therapy and modeling of developmental processes and disease, mesenchymal cells (MSCs) are rapidly gaining traction in cancer therapy. Although they are not the only stem cells with anti-cancer activity, MSCs are often preferred because of their low immunogenicity and inherent ability to migrate to tumor sites, the latter feature believed to be the result of an inflammatory signaling cascade similar to that in wounded sites.
MSCs have documented tropism for many tumor types, such as breast, brain, and liver tumors, as well as pre-metastatic niches – sites in secondary organs that are favorable for metastasis by a primary tumor (1). Depending on many factors in the tumor microenvironment, including the source and type of MSCs and the cell-surface receptors they express (e.g., TLRs), the type of cancer cells, factors secreted in the tumor microenvironment, and interactions between MSCs, immune cells and cancer cells, MSCs can promote pro- or anti-tumorigenic effects (2).
Delivering Cancer Drugs Directly to Tumors?
Despite their dual capacities to promote and suppress tumor growth, their well-documented tropism for tumors has raised interest in exploring MSCs as novel cell-based vehicles for cancer therapies. In order to maximize this potential, it is critical to take into account tumor features such as the expression signature of immune signaling molecules and receptors, as well as the expression of tumor growth factors such as VEGF and TGF. This is because the ability of MSCs to hone in and exert effects on tumors is closely related to the secreted molecules present in the tumor microenvironment.
So far, numerous attempts have been made to load MSCs with therapeutic proteins, oncolytic viruses, chemotherapeutic drugs or nanoparticles bearing anti-cancer drugs, with some very promising results. Let’s take a look at some of the advances in this area to date!
Delivery of Therapeutic Proteins
Using MSCs as a delivery vehicle circumvents some of the major challenges associated with therapeutic proteins – their very short half-life in the body and their rapid clearance by the immune system when injected. Furthermore, delivery by MSCs cells directs these proteins to tumor cells to promote localized rather than systemic effects, thus maintaining a high concentration of the therapeutic protein in the vicinity of the tumor while simultaneously protecting healthy cells.
The most intensely studied anti-tumor property of MSCs to date is probably their ability to secrete TRAIL (tumor necrosis factor related apoptosis inducing ligand), a cytokine that binds death ligands and selectively induces apoptosis in a broad range of cancer types in vitro and in murine models of human cancer. TRAIL is also effective in inducing apoptosis in cancer stem cells, a subset of cancer cells with self-renewal and differentiation properties that are believed to evade conventional cancer therapies eventually leading to relapses (3). These observations have prompted many attempts to develop novel apoptosis-driven cancer therapies based on TRAIL and its receptors, including potentiating TRAIL’s effects through genetic engineering of MSCs. However, none of these efforts have yet translated into a clinical treatment for cancer, owing in part to TRAIL-resistance in many cancer types (4).
Besides TRAIL, cytokines such as IFN-β and interleukins (e.g., IL-12) have been investigated for their anti-tumor properties. Early studies investigating MSCs engineered to produce IFN-β yielded promising results in mouse and xenograft models for several cancer types including breast and lung cancer, and IFN-β-modified MSCs in combination with cisplatin therapy were found to be superior to cisplatin therapy alone, supporting the notion of augmenting conventional chemotherapies with engineered MSCs. Other related approaches involve modifying MSCs to express tumor suppressor genes, the death-inducing protein apoptin, tumor suppressing ncRNAs, as well as modifying cytokine-encoding genes to promote the activation of immune cells with anti-tumor activity, e.g., natural killer cells.
Transport of Anti-Cancer Drugs
MSCs were not the first ‘trojan horse’ under investigation for anti-cancer drug delivery. Nanoparticles have also been investigated for direct delivery of anti-cancer drugs or proteins to cancer cells without being degraded by the immune system. A popular approach here has been to attach molecules of tumor necrosis factor alpha (TNF) to gold nanoparticles along with a specific polymer that can hide the TNF-carrying nanoparticle from the immune system. The nanoparticle is then transported via the bloodstream without triggering an immune response. Although the approach has it merits, it is limited by the fact that nanoparticles lack specificity for cancer cells. Nowadays, exploiting the tumor-tropism of MSCs is seen by many as a more promising approach to deliver anti-cancer drugs to tumors. In support of this approach, MSCs also exhibit relative resistance to conventional chemotherapeutic drugs.
Among the most recent efforts in this area is the use of bone marrow derived MSCs to deliver the broad spectrum chemotherapeutic paclitaxel to multiple myeloma cells in an advanced 3D culture platform. This approach led to a significant reduction in myeloma cell growth, and supports the idea that MSC-mediated paclitaxel delivery has potential in the treatment against multiple myeloma (5). The same researchers also investigated the potential of MSC-mediated paclitaxel transport in human glioblastoma cell lines, again with promising results (6).
Others have combined nanotechnology with MSCs to deliver another broad-spectrum chemotherapeutic doxorubicin (DOX) to metastatic lung melanoma in vitro and in vivo (7). Here, MSCs were loaded with polymer nanoparticles containing DOX, and the ability of the MSCS to release DOX was monitored in vitro (in 2D and 3D culture conditions) and in vivo. The DOX-loaded MSCs displayed tropism for the tumor tissue in all cases, DOX-toxicity to MSCs was low, and both anti-tumor and anti-metastatic activity was observed upon treatment with the DOX-loaded MSCs. This, and other similar studies, highlight the huge potential of using MSCs to delivery marketed chemotherapeutics to the sites of tumors for more effective anti-tumor effects, while reducing their toxicity towards healthy cells, thus lessening one of the major drawbacks associated with broad-spectrum chemotherapeutic drugs like paclitaxel and DOX.
Oncolytic Virus Delivery
In 2015, the FDA approved the first and only oncolytic virus for the treatment of melanoma. The treatment, known as Imlygic® (or T-VEC) is a genetically modified version of the human herpes virus. Oncolytic viruses such as the one in T-VEC not only actively kill cancer cells, but they also provoke anti-tumor immune responses, and are viewed as a potential way to augment the effects of other immunotherapies. Researchers recently used MSCs to release T-VEC into murine models of human metastatic brain cancer, with migration to tumors, involvement of tumor-infiltrating cytotoxic T cells, and significant improvements in survival among the outcomes (8).
Elsewhere, MSCs were investigated for their ability to deliver replication-competent adenovirus to malignant brain tumors (9). After determining the most suitable adenovirus type and virus titer in vitro, brain tumors were challenged in vivo with MSCs bearing replication-competent adenovirus. The researchers found that a particular adenovirus known as type 35 fiber-modified adenovirus showed high infectivity in MSCs, and that MSCs carrying significantly inhibited tumor growth in vivo compared to control.
From Lab to Clinic – Successes on Their Way?
The role of MSCs in tumor biology is a double-edged sword, with their inherent capacity for both pro- and anti-tumor properties, and a much deeper understanding of the interplay between MSCs and the tumor microenvironment will be necessary before MSC-based cancer therapies can enter the clinic (1). Nevertheless, intense work is underway and clinical trials for cancer with MSCs-based therapies beginning to emerge. We have just given you a taster of what is going on, and we are looking forward to seeing how this field develops in the near future!
References
- Chulpanova DS, Kitaeva KV, Tazetdinova LG, James V, Rizvanov AA, Solovyeva VV. Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment. Front Pharmacol. 2018;9:259.
- Yagi H, Kitagawa Y. The role of mesenchymal stem cells in cancer development. Front Genet. 2013;4:261.
- Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-44.
- Kretz AL, von Karstedt S, Hillenbrand A, Henne-Bruns D, Knippschild U, Trauzold A, et al. Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy. Cancers (Basel). 2018;10(3).
- Bonomi A, Steimberg N, Benetti A, Berenzi A, Alessandri G, Pascucci L, et al. Paclitaxel-releasing mesenchymal stromal cells inhibit the growth of multiple myeloma cells in a dynamic 3D culture system. Hematol Oncol. 2017;35(4):693-702.
- Bonomi A, Ghezzi E, Pascucci L, Aralla M, Ceserani V, Pettinari L, et al. Effect of canine mesenchymal stromal cells loaded with paclitaxel on growth of canine glioma and human glioblastoma cell lines. Vet J. 2017;223:41-7.
- Zhao Y, Tang S, Guo J, Alahdal M, Cao S, Yang Z, et al. Targeted delivery of doxorubicin by nano-loaded mesenchymal stem cells for lung melanoma metastases therapy. Sci Rep. 2017;7:44758.
- Du W, Seah I, Bougazzoul O, Choi G, Meeth K, Bosenberg MW, et al. Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas. Proc Natl Acad Sci U S A. 2017;114(30):E6157-E65.
- Hai C, Jin YM, Jin WB, Han ZZ, Cui MN, Piao XZ, et al. Application of mesenchymal stem cells as a vehicle to deliver replication-competent adenovirus for treating malignant glioma. Chin J Cancer. 2012;31(5):233-40.
Article by Karen O’Hanlon Cohrt PhD. Contact Karen at karen@tempobioscience.com.
Karen O’Hanlon Cohrt is a Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen moved to Denmark and held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for writing helps her to keep abreast of exciting research developments as they unfold. Follow Karen on Twitter @KarenOHCohrt. Karen has been a science writer since 2014; you can find her other work on her portfolio.
