Homing-Mechanismen von zirkulierenden adulten mesenchymalen Stamzellen in hepatische Kolonkarzinommetastasen der regenerierenden Leber

Abstract

Background: 50 % of all patients with the diagnosis of colorectal cancer develop liver metastases [1]. Surgical treatment is still the gold standard [2]. Unfortunately, liver resection results not only in regeneration of healthy liver parenchyma, but may also induce the growth of microscopic metastases [3]. Liver regeneration and induction of the growth of microscopic metastases are dependent on growth factor expression and angiogenesis.

The focus of our project is to investigate the role of adult mesenchymal stem cells (MSC) in the growth of liver metastases and whether MSCs can be used as vehicle for combined suicide gene-stem cell therapy.

Methods: Balb/c SV-40 immortalized mesenchymal stem cells were stably transfected with red fluorescent protein (RFP) or HSV-thymidin kinase (tk) under the control of the tie2-promotor. Under these conditions, RFP (tk) is expressed only if tek/tie2-receptors are up-regulated and the tie2-promotor is activated. Tek/tie2-receptors are almost exclusively up-regulated on endothelial cells. Thymidin kinase is able to phosphorylate Ganciclovir, which then destroys the integrated stem cell and the surrounding tumour cells (»bystander effect«).

Results: Following intrasplenic injection of murine CT26 colon cancer cells, repetitive intravenous injections of MSCs led to an increase of liver weight and -volume as compared to control animals without MSC injection (3,4 g/10,25 cm³ vs.2,1 g/4,25 cm³, respectively).

Following 2/3-hepatectomy the liver weight increased up to 5,1 g in the presence of MSCs. Moreover, we detected an increase in the median amount of macroscopic visible metastases after 2/3-hepatectomy + MSC treatment (n = 21) as compared to animals, which did neither receive 2/3-hepatectomy nor MSC-treatment. The median amount of Ki67 positive cells in liver metastases following 2/3-hepatectomy was markedly higher as compared to groups without MSC treatment (43 + 7 vs. 35 + 5, respectively).

By immunohistochemical analysis we were able to detect RFP in tumour endothelial cells of the established liver metastases.

Conclusion: Liver regeneration after 2/3-hepatectomy and treatment with MSCs led to an increase in total liver weight and amount of macroscopically visible liver metastases. MSCs might transdifferentiate into cells with endothelial-like characteristics and therefore might be involved in neoangiogensis of growing liver metastases. More research has to be done to determine the exact role of MSCs and their differentiation potential in the setting of liver metastases.