Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma

Abstract

Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.

Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats

“…Additionally, it was suggested that engrafted MSCs also differentiated into colonic interstitial lineage cells and secreted vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGF-β1) those playing an important role in healing of injured colonic mucosa [41]. Supporting this observation, BMCs allograft to sites of Kaposi’s sarcoma potently inhibits tumor growth by down-regulating protein kinase B (AKT) activity in tumor cells [44]. Furthermore, cancer cells may produce proteins that can activate signaling pathways that facilitate and attract BMCs migration to the tumor site.…”

Genotoxic damage of human adipose-tissue derived mesenchymal stem cells triggers their terminal differentiation

“…Therefore the introduction of a transgene into autologous stem cells possesses an attractive cell based delivery strategy [8,29]. On the contrary, other studies observed that MSCs may inhibit tumor growth in animal models [30,31] and posses antitumorigenic effects on a model of Kaposi's sarcoma [32].…”

“…Few contradictory reports appeared about spontaneous transformation of cultured bone marrow derived murine MSCs [32,33,34,35] and human MSCs [36,37]. It was reported that murine but not human mesenchymal stem cells generated osteosarcoma-like lesions in the lung [38].…”

Mesenchymal stem cells in tumor development

“…While certain studies suggest that MSCs play tumor-suppressive roles (e.g., ref. 121 MSCs have also been shown to drive hematopoietic malignancies, such as multiple myeloma, 122,123 and appear to sustain leukemia/ lymphoma development. 124 Finally, MSCs have recently been found to promote the progression of certain mesenchymal cancers as well, such as osteosarcomas, which are thought themselves to arise, in part, from the neoplastic transformation of MSC lineages 34 (discussed in more detail below).…”