Abstract
The progression of neoplastic malignancies is a complex process resulting not only from the accumulation of mutations within tumor cells, but also modulation of the tumor microenvironment. Recent advances have shown that the recruitment and subsequent heterotypic interactions of stromal cells—including fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs)—are crucial for carcinogenesis. Though extensive work has been done analyzing the signals that recruit these cells, the governing mechanical properties have not been fully investigated. Here, we report that despite their initial similarities, MSCs respond not only faster but also more dramatically to pro-migratory tumor-secreted soluble factors. Utilizing multiple particle tracking microrheology to probe the cytoskeletal mechanical properties, we show that MSCs stiffen completely within one hour, three times faster than fibroblasts. In addition, unlike fibroblasts, MSCs exposed to tumor-secreted soluble factors display a functionally different phenotype characterized by morphological elongation, decreased actin stress fiber density, and decreased adhesion. Quantitative real-time PCR indicates these phenomena occur based on differential expression of small GTPases RhoA and Cdc42, but not Rac1. These findings demonstrate a fundamental difference in the recruitment of fibroblasts and MSCs.
Highlights
The microenvironment in a solid tumor develops under the constant influence of inflammatory mediators [1]
Literature on 4T1 tumor cell conditioned media shows that it contains soluble growth factors including platelet derived growth factor (PDGF), transforming growth factor (TGF-b1), and vascular endothelial growth factor (VEGF) [37], as well as cytokines, chemokines, acute phase proteins and proteases
Menon et al found that mesenchymal stem cells (MSCs) exposure to tumor cell conditioned media up-regulates mRNA levels of 104 genes, including genes for stromal cell-derived factor 1 (SDF-1/CXCL12), monocyte chemotactic protein 1 (MCP-1/CCL2), and growth-regulated protein b (Gro-b/ CXCL2), which are all potent chemokines that act in an autocrine fashion to further stimulate MSC migration [35]
Summary
The microenvironment in a solid tumor develops under the constant influence of inflammatory mediators [1] These molecules, which include a milieu of cytokines, chemokines, and growth factors, are important targets for recruitment of a variety of cells such as leukocytes, macrophages, monocytes, fibroblasts and mesenchymal stem cells (MSCs) [2]. Increased numbers of myofibroblasts in the wound bed and in other sites of chronic inflammation have been associated with MSC progenitors [2]. Both cell types aid in tumor growth and metastasis via autocrine and paracrine signaling [7,8]. Recent studies have begun to investigate these cells as alternative targets for anti-cancer therapy [9], and for use as targeted gene-delivery vehicles [10]
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