Mesenchymal stem cells in vascular structure and remodeling in cancer

Abstract

Mesenchymal stem cells (MSCs) are present in vascular structure and play an important role in vessel remodeling in normal, as well as pathological conditions, such as transplant arteriosclerosis or tumor angiogenesis. Moreover, MSCs affect tumor growth and metastasis by production of chemokines, such as (C-C motif) ligand 7 (CCL7). Similar effect on tumor biology exert multiple other factors, such as CCAAT-enhancer binding protein β (C/EBPβ), which is a transcription factor playing an essential role in mammary gland development and breast cancer progression.

In study I, presence of MSCs in vascular structure, as well as their role in vascular remodeling in transplant arteriosclerosis was analyzed. Specifically, rat allograft model was used to identify the predominant cell types associated with this process and to find factors crucial for their recruitment into the graft. This study identified adventitia as a potentially important source of mesenchymal stem cells that contribute to formation of intimal hyperplasia. Furthermore, monocyte chemoattractant protein-1 (MCP-1) was found as a potent chemokine for the recruitment of adventitial vascular progenitor cells to intimal lesions.

Study II and III focus on the role of C/EBPβ transcription factor in breast cancer progression. Namely, in study II C/EBPβ was associated with epithelial-to-mesenchymal transition (EMT) features in triple-negative human breast cancer and invasive areas of mammary tumors in MMTV-PyMT mice. In vitro studies showed that C/EBPβ was repressed during EMT by miR-155, a breast cancer oncomiR. Moreover, C/EBPβ depletion enhanced TGFβ response towards EMT and contributed to evasion of growth inhibitory response to TGFβ. C/EBPβ loss caused potentiated invasion and metastasis of breast cancer cells to the lungs in mouse 4T1 model. In addition, C/EBPβ was shown to transcriptionally activate genes encoding epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor (CAR). Study III was focused on explaining the mechanism of C/EBPβ effect on metastasis, as well as determining the relationship between C/EBPβ expression and survival of breast cancer patients. Firstly, study showed that decrease in C/EBPβ expression was associated with shorter overall survival of breast cancer patients. Next, loss of C/EBPβ affected tumor growth, morphology and lung metastasis in murine 4T1 breast cancer model. Moreover, inhibition of C/EBPβ caused enhanced histocompatibility complex II (MHCII) expression and accumulation of CD45+, CD3+ and CD4+ lymphocytes in the tumors. Additional experiments confirmed the role of inflammation in C/EBPβ-mediated metastasis formation.

Study IV involved analysis of crosstalk between MSCs and colon cancer. Results demonstrated that MSCs affect CT26 tumor cell proliferation, migration and expression of different chemokines in coculture with CT26 cells in vitro, such as (C-C motif) ligand 7 (CCL7). The next goal of the study was to analyze the effect of CCL7 overexpression on tumor progression in mouse CT26 colon cancer model. Cells overexpressing CCL7 accelerated early phase of tumor growth and led to higher lung metastasis rate in tumor-bearing mice. Lastly, higher CCR2 expression, which is a CCL7 receptor, was associated with shorter overall survival of colorectal cancer patients.