Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature

Abstract

A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.

Keywords: Anti-angiogenesis; Mesenchymal stem cells; Tumor microenvironment; Tumor therapy.

Fig. 1

Naïve MSCs can inhibit Wnt signalling pathways through Dickkopf-related protein 1 (DKK1) released by tumor cells and subsequently downregulated c-Myc and Cyclin D2 and upregulated expression of P21CIP1 and P27KIP1, leading to tumor cells suppression. Naïve MSCs can cause apoptosis vascular endothelial cells by inhibiting angiogenesis

Fig. 2

MSCs have some adverse effect on tumor cells, such as differentiation of vascular endothelial cells in melanoma, enhancing the expansion of gastric cancer cell lines, inducing of cancer stem cells (CSCs) that are involved in metastasis, tumorigenesis, and recurrence of tumors. When co-cultured with peripheral blood mononuclear cells (PBMC), MSCs from breast cancer promote the development of CD4⁺CD25^highFOXP3⁺ regulatory T cells. MSCs derived from breast cancer tissues contain high levels of immunosuppressive mediators, such as IL-4, TGFβ and IL-10. Upregulation of bone morphogenetic proteins (BMPs), including BMP2, BMP4 and BMP6 in ovarian cancer derived MSCs can promote the development of CSCs

Fig. 3

a Adenoviral transduction is employed to modulate the human placenta-derived-MSCs for delivering endostatin. Such MSCs expressing human endostatin are homed into the cancer tissue and remarkably mitigate the size of tumor without considerable systemic toxic adverse effects. The beneficial effects in favour of tumor treatment are due to the promoted apoptosis of cancer cell as well as disturbed neovascularization, thereby decreased tumor cell proliferation and decelerated expansion. b Delivering the anti-angiogenic compounds resulted in normalization of the aberrant constructions and impaired function of the blood vessels, resulting in a remarkable diminished tumor-associated vasogenic brain edema, decreased vessel diameter and permeability was the underlying cause of the vessel normalization