Mesenchymal stem cell secretome and regenerative therapy after cancer

Abstract

Cancer treatment generally relies on tumor ablative techniques that can lead to major functional or disfiguring defects. These post-therapy impairments require the development of safe regenerative therapy strategies during cancer remission. Many current tissue repair approaches exploit paracrine (immunomodulatory, pro-angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC). Yet, a major concern in the application of regenerative therapies during cancer remission remains the possible triggering of cancer recurrence. Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli. Many of the components required for successful regenerative therapy (revascularization, immunosuppression, cellular homing, tissue growth promotion) are also critical for tumor progression and metastasis. While bidirectional crosstalk between tumorigenic cells (especially aggressive cancer cell lines) and MSC (including tumor stroma-resident populations) has been demonstrated in a variety of cancers, the effects of local or systemic MSC delivery for regenerative purposes on persisting cancer cells during remission remain controversial. Both pro- and anti-tumorigenic effects of MSC have been reported in the literature. Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC. The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFβ, VEGF), which have been implicated in tumor growth and/or metastasis. This article reviews published models for studying interactions between MSC and cancer cells with a focus on the impact of MSC secretome on cancer cell activity, and discusses the implications for regenerative therapy after cancer.

The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation

“…We focused our attention on upstream cytokines and growth factors since they play a key role in regulation of stem cell functions and also in immunomodulatory properties of MSCs. 7,17 Moreover, we looked also at transcription factors and miRNAs as general regulators of gene expression. The production of Muse cell secretome may rely on the exclusive activity of 7 cytokines, 3 growth factors, 67 transcription factors and 4 miRNAs (Suppl.…”

“…[14][15][16][17] Many findings aimed at identifying only a subset of factors released by MSCs at high levels, such as proteins involved in immune system signaling (i.e., IL-6, IL-8, MCP-1, and TGF-ß), extracellular matrix remodelers (i.e., TIMP-2, fibronectin, lumican, periostin, collagen, decorin, and metalloproteinase inhibitors), growth factors and their regulators (i.e., VEGF, GM-CSF, BMP2, bFGF, IGFBP3, IGFBP4, and IGFBP7). Only recently a more systematic and integrated approach for analysis of the MSC secretome that includes LC-MS/MS detection, antibody arrays, microarrays, and bioinformatic analysis has been employed.…”

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

“…The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications. T he use of mesenchymal stromal or stem cells (MSCs) in cancer patients or cancer survivors is a promising strategy to improve treatment of advanced cancer (1) and to repair tissues damaged by cancers or by radical cancer therapies (2). Based on the unique homing capability of tissue-derived MSCs to stroma of various primary and metastatic cancers (3)(4)(5)(6), MSCs have the potential to treat or even eliminate various cancers by delivering various anticancer agents (7)(8)(9).…”

Role of Adipose-Derived Mesenchymal Stem Cells in Full Thickness Wound Healing

“…Paracrine activities are important for wound healing. Some reports described the paracrine role of MSCs in wound healing [22,23]. Stem cells can be obtained easily from fat tissue, better than stem cells harvested from bone marrow.…”