Mesenchymal Stem Cells Promote Pancreatic Tumor Growth by Inducing Alternative Polarization of Macrophages

Abstract

Pancreatic cancer is characterized by an extensive desmoplastic stroma, the functional relevance of which is poorly understood. Activated fibroblasts are a prevalent component of the stroma, and traditionally, these cells have been considered as a homogenous population derived from pancreatic stellate cells. In this study, we highlight a previously unappreciated heterogeneity of the fibroblast population within the stroma. In particular, a subset of stromal fibroblasts has characteristics of mesenchymal stem cells (MSCs). MSCs are present in the normal pancreas as well as in the carcinomatous pancreas (CA-MSCs). Here, we determine that CA-MSCs have increased tumor-promoting function compared with MSCs in normal pancreas. This ability to promote tumor growth is associated with CA-MSCs’ unique ability to promote alternative macrophage polarization. Thus, our study identifies a previously uncharacterized cell population within the stroma and sheds light on tumor-promoting interactions between different components of the stroma.SignificanceTargeting the stroma is emerging as a new paradigm in pancreatic cancer; however, efforts to that effect are hampered by our limited understanding of the nature and function of stromal components. Here, we uncover previously unappreciated heterogeneity within the stroma and identify interactions among stromal components that promote tumor growth and could be targeted therapeutically.

GM-CSF Mediates Mesenchymal–Epithelial Cross-talk in Pancreatic Cancer

“…S7A and S7B), suggesting that GM-CSF plays a role in the recruitment and polarization of TAMs in the tumor microenvironment. These results are consistent with a recent report demonstrating a role for CA-MSCs in regulating macrophage polarization (26). …”

TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells

“…MSCs have been shown to have tumor‐promoting effects stimulating directly tumor growth . In order to explore whether the lack of TSG‐6 exacerbates this effect, we evaluated tumor growth in xenograft models by subcutaneously implanting two different adenocarcinoma cell lines (A549 lung cancer cell line or colon cancer cell line Caco‐2) in coadministration with MSCs (Fig.…”

“…Indeed, mice treated with TSG-6 −/− -MSCs displayed higher levels of IL-6 than those receiving WT-MSCs cells; i.e., consistent with the loss of TSG-6 in MSCs enhancing the release of IL-6 (see above), which could have the effect of amplifying the pro-tumorigenic effects of MSCs in specific tissues. MSCs have been shown to have tumor-promoting effects stimulating directly tumor growth [13,[50][51][52][53][54]. In order to explore whether the lack of TSG-6 exacerbates this effect, we evaluated tumor growth in xenograft models by subcutaneously implanting two different adenocarcinoma cell lines (A549 lung cancer cell line or colon cancer cell line Caco-2) in coadministration with MSCs ( Fig.…”

Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy

“…Initial studies reported that IL-6 produced by CAFs switched monocyte differentiation programs towards a tumor-promoting M2 lineage[25]. Subsequent in vitro studies of tumor cell-CAF interactions and proteomic profiles of CAFs isolated from tumor models identified numerous pro-inflammatory cytokines such as GM-CSF, CSF-1, CCL2, CCL7, CXCL1, CXCL2, and CXCL8 that are involved in MDSC recruitment and differentiation of macrophages into a pro-tumor M2 phenotype[26–28], which is likely due to suppression of M1-promoting pathways. Activated fibroblasts have also been reported to directly regulate myeloid cell maturation.…”