During cancer progression, breast tumor cells interact with adjacent adipose tissue, which has been shown to be engaged in cancer aggressiveness. However, the tumor-directed changes in adipose tissue-resident stromal cells affected by the tumor–stroma communication are still poorly understood. The acquired changes might remain in the tissue even after tumor removal and may contribute to tumor relapse. We investigated functional properties (migratory capacity, expression and secretion profile) of mesenchymal stromal cells isolated from healthy (n = 9) and tumor-distant breast adipose tissue (n = 32). Cancer patient-derived mesenchymal stromal cells (MSCs) (MSC-CA) exhibited a significantly disarranged secretion profile and proliferation potential. Co-culture with MDA-MB-231, T47D and JIMT-1, representing different subtypes of breast cancer, was used to analyze the effect of MSCs on proliferation, invasion and tumorigenicity. The MSC-CA enhanced tumorigenicity and altered xenograft composition in immunodeficient mice. Histological analysis revealed collective cell invasion with a specific invasive front of EMT-positive tumor cells as well as invasion of cancer cells to the nerve-surrounding space. This study identifies that adipose tissue-derived mesenchymal stromal cells are primed and permanently altered by tumor presence in breast tissue and have the potential to increase tumor cell invasive ability through the activation of epithelial-to-mesenchymal transition in tumor cells.

Background Chemotherapy remains a standard treatment option for breast cancer despite its toxic effects to normal tissues. However, the long-lasting effects of chemotherapy on non-malignant cells may influence tumor cell behavior and response to treatment. Here, we have analyzed the effects of doxorubicin (DOX) and paclitaxel (PAC), commonly used chemotherapeutic agents, on the survival and cellular functions of mesenchymal stromal cells (MSC), which comprise an important part of breast tumor microenvironment. Methods Chemotherapy-exposed MSC (DOX-MSC, PAC-MSC) were co-cultured with three breast cancer cell (BCC) lines differing in molecular characteristics to study chemotherapy-triggered changes in stromal compartment of the breast tissue and its relevance to tumor progression in vitro and in vivo. Conditioned media from co-cultured cells were used to determine the cytokine content. Mixture of BCC and exposed or unexposed MSC were subcutaneously injected into the immunodeficient SCID/Beige mice to analyze invasion into the surrounding tissue and possible metastases. The same mixtures of cells were applied on the chorioallantoic membrane to study angiogenic potential. Results Therapy-educated MSC differed in cytokine production compared to un-exposed MSC and influenced proliferation and secretory phenotype of tumor cells in co-culture. Histochemical tumor xenograft analysis revealed increased invasive potential of tumor cells co-injected with DOX-MSC or PAC-MSC and also the presence of nerve fiber infiltration in tumors. Chemotherapy-exposed MSC have also influenced angiogenic potential in the model of chorioallantoic membrane. Conclusions Data presented in this study suggest that neoadjuvant chemotherapy could possibly alter otherwise healthy stroma in breast tissue into a hostile tumor-promoting and metastasis favoring niche. Understanding of the tumor microenvironment and its complex net of signals brings us closer to the ability to recognize the mechanisms that prevent failure of standard therapy and accomplish the curative purpose.

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Weexaminedthesurvivinexpressionpatternbyimmunohistochemistryin43fi-broadenomasand153ductalcarcinomasofthebreast.Thesubcellularlocalization ofsurvivin andtheintensityofimmunoreactionwereassessed.We analyzedthe differencesofsurvivinexpressionbetweenfibroadenomasandcarcinomas.Wealso correlatedthesurvivinexpressionpatternincarcinomaswithotherclinicomorphologicalparameterssuchastheageofpatients,thegradeandsizeofprimarytumor aswellasthelymphnodemetastasis.Overall,survivinwasdetectedin107/153 carcinomas(69.9%)andin26/43fibroadenomas(60.5%).Statisticalanalysisconfirmedsignificantcorrelationsbetweentheassessedparametersinfibroadenomas andcarcinomas.Gradeofcarcinomaswassignificantlyrelatedtosurvivinexpressioninbothsubcellularlocalizationandtheintensityofimmunoreaction.Tumor grade3wasassociatedwithnuclearpositivityandcombinednuclearandcytoplas-mic localization. Carcinomas larger than 20 mm showed nuclear and combined localizationin81%ofcasesandhigherintensityofsurvivinimmunoreactionwas alsonotablyrelatedtolargercarcinomas.Statisticallysignificantdifferenceswere alsoobservedbetweensubcellularsurvivinlocalizationandintensityofimmunoreaction.Ourresultsuggestthatnuclearaccumulationofsurvivinisassociatedwith proliferativefenotypeandsurvivinwasshowntobeaworseprognosticmarkerin breastductalcarcinoma.