gms | German Medical Science

Introduction: Mesenchymal stem cells (MSCs) are actively recruited to the stroma of some growing epithelial tumours and trans-differentiate into tumor-associated cells. MSC promote tumour growth and the formation of metastases in vivo by participating in angiogenesis and by expression of the chemotactic cytokine CCL5 within the tumor stroma.

Materials and methods: MSCs isolated from bone marrow of C57BL/6 p53^-/- mice were transfected with Red Fluorescent Protein (RFP, as “reporter gene”), or Herpes simplex virus thymidine kinase gene (HSV-Tk, as “suicide gene”) driven by CCL5 promoter or Tie-2 promoter/enhancer. Engineered MSCs were applied intravenously to nude mice carrying orthotopically growing human hepatocellular carcinoma (HCC). The prodrug ganciclovir (GCV) was administered intraperitoneally to drive HSV-Tk expressing cells and bystanding cells into apoptosis. Mice were sacrificed and tumour tissues as well as other organs were isolated and examined by immunohistochemistry (IHC).

Results: Systemic administration of large amounts of non-therapeutic MSCs (CCL5/RFP; Tie-2/RFP) results in increased tumour weight. IHC staining with anti-mouse anti-CCL5 revealed expression of CCL5 only in tumors exposed to non-therapeutic stem cells. IHC staining against RFP showed strong signaling within the tumor stroma in both reporter gene groups. Injection of therapeutic stem cells (CCL5/Tk or Tie-2/Tk) with GCV lead to significantly reduced tumor growth compared to animals of other groups. Ki67 staining revealed lower proliferation indices in the therapeutic groups.

Conclusion: Systemically injected MSCs home to the stroma of orthotopically growing HCCs, undergo differentiation by activation of both CCL5- and Tie2 promoter and enhance tumor growth. Increased expression of CCL5 is detectable within these tumors, which could favor tumor growth as shown in other tumor entities. However, this effect can be reversed when injecting MSCs carrying a suicide gene expressed under the control of the promoter of either CCL5 or Tie-2 resulting in smaller tumors. Especially in HCC the usage of therapeutic MSCs could easily be combined with existing trans-arterial methods (e.g. TACE) where large amounts of therapeutic MSCs could be injected directly into the tumor.