Stem Cell Migration

The primary advantage of using stem cells over other means of treating cancer is their unique ability to migrate to and infiltrate bulk tumors. This tumor-specific tropism can be utilized by equipping stem cells with products capable of limiting replication or inducing apoptosis in malignant tissue. Additionally, the ability of stem cells to distribute throughout tumor masses is assumed to produce a more complete antitumor response than other methods that lack this ability such as the use of modified liposome, conjugates antibodies, or nanoparticles. This is due to the fact that the usage of these methods relies on interaction with protein receptors on tumor cells. To achieve any degree of treatment specificity, some degree of receptor uniqueness must be present. For example, several groups have reported using the transferrin receptor which is reported to be expressed at twice the normal level in tumors.(10) A twofold concentration difference of a given therapeutic agent may be insufficient for adequate treatment of cancerous cells while minimizing deleterious effects to healthy tissue. Stem cells thus have the potential to serve as a modality for cancer treatment with levels of pathology-specificity not currently available to patients.

To date, the vast majority of research utilizing stem cells as therapeutic vehicles has been related to treatment of brain tumors. There are several reasons for this, with the primary reason being that gliomas are notoriously difficult to treat and as a result patients suffering from gliomas have a very poor prognosis due to the metastatic nature of the cancer and the severe consequences of damaging the surrounding tissue. Additionally, neural stem cells have been shown to demonstrate significant tropism for tumors. It has been shown that they distribute themselves quickly and extensively throughout the brain tumor bed and migrate in juxtaposition with expanding tumors. Neural stem cells have also been shown to cross the brain blood barrier and target gliomas, demonstrating their unique ability to selectively target tumors even when significantly spatially separated.(11)

Other types of stem cells, specifically mesenchymal stem cells, have not been used as extensively but have nonetheless exhibited similar tumor-tropic properties compared to neural stem cells. Studies have shown that injection of mesenchymal stem cells transduced with an adenovirus exhibited a 6-fold to 11-fold increase in migration toward breast cancer xenografts as compared to the differentiated (non stem cell) control.(12) Additionally, mesenchymal stem cells derived from bone marrow are attractive due to their relative ease of collection from patients, simplicity of culture, and their high metabolic activity which results in strong expression of transgenes.(13) Finally, it has also been shown that bone marrow-derived mesenchymal stem cells demonstrate the greatest degree of plasticity among all adult stem cells, offering additional treatment possibilities which would make their collection and culture more valuable.(14)

Although the precise physical or chemical mechanism by which stem cells migrate preferentially to tumors is not yet well understood, several recent studies have indicated that this action is highly affected by cytokine secretion. For example, it was found that ß-chemokine receptor CCR₂ and monocyte chemoattractant protein-1 knock-out mice who were injected with an inflammatory stimulus near the fimbria and injected with neural stem cells demonstrated little or no stem cell migration. However, when the same procedure was performed in normal mice, substantial stem cell migration was recorded.(15) Several other groups have created cDNA libraries of injured mouse forebrains via subtractive suppression hybridization and have shown that stem cell factor mRNA and protein are highly and selectively upregulated in situations where neural stem cell migration has occurred.(16)(17)
A final benefit of the stem cell tropism is the recent finding that irradiation of severe combined immunodeficient mice followed by injection of human mesenchymal stem cells resulted in increased stem cell engraftment at the sites of irradiation.(18) This presents a clear possibility of current treatment modalities being combined synergistically with the use of stem cells transduced with trangenes producing anti-tumor factors.