March 14, 2014

Using MSCs to Beat Cancer: The Next Big MSC Application

Genetically-modified MSCs home to tumor cells and
accumulate at the tumor site. Image adapted from
In the body, MSCs are known to home to sites of acute injury and inflammation and migrate to tumors in response to tumor secretion of growth factors, cytokines, and extracellular matrix (ECM) molecules. However, given their secretion of biomolecules that augment new blood vessel formation, increase inflammation, and degrade the ECM (lending to tumor metastasis), MSCs may promote rather than impede tumor growth and migration, and confounding results from a number of in vitro and in vivo studies have been published to date.  Furthermore, it has been suggested that the ability of MSCs to interact with malignant cells and cancer stem cells might preclude their safe therapeutic application, particularly in patients with dormant or undiagnosed cancers. Despite these concerns, MSCs can serve as an effective ‘Trojan Horse’ for the targeted delivery of anticancer genes, proteins and drugs to tumor cells.  Such targeted delivery can reduce the unsavory systemic side effects that often result from the use of anti-cancer agents, reducing patient morbidity and improving quality of life.  

MSCs can serve as an effective ‘Trojan Horse’ for the targeted delivery of anticancer genes, proteins and drugs to tumor cells.

Recently, a review was published focusing not only on the application of MSCs for the targeted delivery of anti-cancer agents to tumors, but also on the molecular mechanisms of MSC accumulation in tumors, a poorly understood mechanism.  For MSC-based anti-cancer therapies to be effective clinically, these mechanisms must be understood and successfully exploited.  The authors identified several methods to genetically-modify MSCs that resulted in tumor growth inhibition, metastasis suppression, and prolonged survival upon MSC injection in various tumor-laden animal models.  However, in addition to modification with anti-cancer agents, MSCs must be able to accumulate at the site of the tumor for effective cancer eradication.   The authors postulate that increasing the accumulation efficiency of MSCs at tumor sites can effectively target not only primary tumors but also metastatic lesions. 

Conventional thought has dictated that cytokine secretion by inflammatory cells within the tumor microenvironment promotes MSC recruitment and accumulation.  The authors of this review, however, found that MSC accumulation at tumor sites could not be solely accounted for by cytokine-mediated migration.  Interestingly, they found that MSC accumulation occurred at the junction between tumors and tumor stroma laden with blood vessels.  Probing of this phenomenon revealed that MSC accumulation in tumors occurs through MSC-tumor endothelial cell (EC) adhesion mediated by vascular cell adhesion molecule (VCAM)-1 expression in MSCs.

They propose that the mechanism for MSC accumulation at tumor sites is as follows:

(1) Growth factors and chemokines recruit MSCs to the tumor microenvironment. (2) Inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, stimulate MSCs and induce VCAM-1 expression.
(3) Activated MSCs attach to the tumor vasculature, penetrate and accumulate at tumor sites.

Thus, simple methods to prime MSCs prior to therapeutic administration, using commercially-available molecules (such as TNF-alpha), may effectively promote MSC accumulation at tumor sites and allow for efficient delivery of anti-cancer agents by genetically-modified MSCs to tumors and metastatic lesions.  Such targeted therapies could be more successful in tumor eradication, and potentially without the systemic effects often seen upon administration of anti-cancer drugs.  

Just last year, Mesoblast Ltd, Intrexon Corp, and ZIOPHARM Oncology, Inc announced a partnership to develop a new class of cancer therapeutics.  The press release mentions that the companies will combine Mesoblast's proprietary Mesenchymal Lineage Cells (MLCs) with Intrexon's RheoSwitch Therapeutic System® (RTS®) platform to deliver therapeutic transgenes to targeted tumors at specific sites in the body to treat lung cancer.  If successful, this targeted therapy with modified MLCs could address a significant unmet clinical need.  As mentioned by Mesoblast CEO, Silviu Itescu, a key to successful development of cell-based cancer therapeutics is the availability of clinically relevant cells that can be used for product development efforts and be commercially manufactured to industrial scale for off-the-shelf patient use.

These recent developments in MSC technology are opening up new lines of research in cancer, and will require high quality and well characterized MSCs to shorten the time from discovery to clinical application.

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