Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models

Abstract

Inflammatory breast cancer (IBC) is a unique and deadly disease with unknown drivers. We hypothesized the inflammatory environment contributes to the IBC phenotype. We used an in vitro co-culture system to investigate interactions between normal and polarized macrophages (RAW 264.7 cell line), bone-marrow derived mesenchymal stem cells (MSCs), and IBC cells (SUM 149 and MDA-IBC3). We used an in vivo model that reproduces the IBC phenotype by co-injecting IBC cells with MSCs into the mammary fat pad. Mice were then treated with a macrophage recruitment inhibitor, anti-CSF1. MSC and macrophages grown in co-culture produced higher levels of pro-tumor properties such as enhanced migration and elevated IL-6 secretion. IBC cells co-cultured with educated MSCs also displayed enhanced invasion and mammosphere formation and blocked by anti-IL-6 and statin treatment. The treatment of mice co-injected with IBC cells and MSCs with anti-CSF1 inhibited tumor associated macrophages and inhibited pSTAT3 expression in tumor cells. Anti-CSF1 treated mice also exhibited reduced tumor growth, skin invasion, and local recurrence. Herein we demonstrate reciprocal tumor interactions through IL-6 with cells found in the IBC microenvironment. Our results suggest IL-6 is a mediator of these tumor promoting influences and is important for the IBC induced migration of MSCs.

Upregulated <b><i>EBI3</i></b> Correlates with Poor Outcome and Tumor Progression in Breast Cancer

“…Although evidence was provided for EBI3 as a prognostic biomarker for breast cancer, the precise underlying molecular mechanisms remain unclear and warrant further investigation. Besides, pivotal roles of inflammatory factors during the development of inflammatory breast cancer have been reported [27], and IL-35 represents an extensively studied inflammatory factor correlated with various inflammatory diseases [28]. Thus, EBI3 might also be involved in the progression of inflammatory breast cancer, which still needs to be confirmed in further research.…”

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Accumulating evidence has supported that MSCs play critical roles in tumor development and progression, by increasing stemness of tumor cells, stimulating tumor cell migration, promoting angiogenesis, supporting immune responses, and inducing drug resistance. Additionally, MSCs increase the metastatic potential of tumor cells by advancing their motility and invasiveness and thereby play a role in the nature of a metastatic niche at the secondary site (Bott et al, 2017; Donnarumma et al, 2017; Gonzalez et al, 2017; Luo et al, 2009; McAndrews et al, 2015; Wolfe et al, 2016). Therefore, a comprehensive knowledge on the biology and mechanism of interaction between MSCs and TME of breast and prostate cancer is essential for the development of therapeutics that capitalize on vulnerabilities in these tumor cell-MSC interplay.…”

Inflammatory Breast Cancer: a model for investigating cluster-based dissemination

“…These cells indicate a higher proclivity for Notch-Jagged signaling instead of Notch-Delta signaling 19 , and are consistent with observations that drug-resistant small cell lung cancer H69-AR cells have higher levels of JAG1 but lower levels of DLL4 as compared to the parental H69 population 83 . Significantly high levels of IL-6 in serum of IBC patients as compared to non-IBC patients, overexpression of IL-6 in IBC carcinoma tissues, and secretion of IL-6 by IBC cell lines SUM149 and SUM190 84,85 and supporting stromal cells 86 can augment Notch-Jagged signaling, thereby contributing to radiation resistance of these cell lines 87 and IBC progression. Notch-Jagged signaling can also mediate high tumor-initiating potential in IBC.…”