Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model

Abstract

IntroductionInflammatory breast cancer (IBC) is an aggressive type of breast cancer, characterized by very rapid progression, enlargement of the breast, skin edema causing an orange peel appearance (peau d’orange), erythema, thickening, and dermal lymphatic invasion. It is characterized by E-cadherin overexpression in the primary and metastatic disease, but to date no robust molecular features that specifically identify IBC have been reported. Further, models that recapitulate all of these clinical findings are limited and as a result no studies have demonstrated modulation of these clinical features as opposed to simply tumor cell growth.MethodsHypothesizing the clinical presentation of IBC may be mediated in part by the microenvironment, we examined the effect of co-injection of IBC xenografts with mesenchymal stem/stromal cells (MSCs).ResultsMSCs co-injection significantly increased the clinical features of skin invasion and metastasis in the SUM149 xenograft model. Primary tumors co-injected with MSCs expressed higher phospho-epidermal growth factor receptor (p-EGFR) and promoted metastasis development after tumor resection, effects that were abrogated by treatment with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. E-cadherin expression was maintained in primary tumor xenografts with MSCs co-injection compared to control and erlotinib treatment dramatically decreased this expression in control and MSCs co-injected tumors. Tumor samples from patients demonstrate correlation between stromal and tumor p-EGFR staining only in IBC tumors.ConclusionsOur findings demonstrate that the IBC clinical phenotype is promoted by signaling from the microenvironment perhaps in addition to tumor cell drivers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0549-4) contains supplementary material, which is available to authorized users.

Developmental therapeutics for inflammatory breast cancer: Biology and translational directions

“…the role of mesenchymal transitional cells in promoting E-cadherin (pivotal to IBC metastasis) expression in IBC cell models and metastases in xenografts [50, 75]. …”

The impact of melatonin and carbon ion irradiation on cancer stem cells

“…This process is mediated by the activity of growth and transcription factors, leading to loss of the intercellular junction structure of epithelial cells, obtaining a mesenchymal morphology, loss of apical-basal cell polarity and migration/invasion capability [72][73][74]. Various investigations have also indicated that EMT is involved in cell plasticity, the process by which non-stem cells acquire stem cell characteristics [75][76][77]. The principal EMT molecular features include loss of the epithelial marker E-cadherin, and overexpression of mesenchymal markers N-cadherin and vimentin [78,79].…”

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

“…In a xenograft model, co-injection of MSCs with SUM149 inflammatory breast cancer cells increased skin invasion and metastasis in mice, mimicking clinical features of inflammatory breast cancer (IBC) (presenting as erythema and inflammation) compared with injection of SUM149 cells alone [47]. Compared with mice in which MSCs were not co-injected, primary tumors in mice with injected MSCs expressed higher phosphorylated EGFR levels and were associated with increased metastasis development after tumor resection, effects that were abrogated by treatment with the EGFR inhibitor erlotinib.…”