Chemotherapy-triggered changes in stromal compartment drive tumor invasiveness and progression of breast cancer

Abstract

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.

Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer

“…This effect is consistent with data from the NCI-60 cell lines treated with doxorubicin. Although stromal cells can play a critical role in doxorubicin drug treatment response 12 , dose-response curves were superimposable for breast cancer cell lines and TM98 ex vivo slices suggesting that cancer cells rather than stromal cells are responsible for diacetylspermine secretion.…”

Glucose Enhances Pro-Tumorigenic Functions of Mammary Adipose-Derived Mesenchymal Stromal/Stem Cells on Breast Cancer Cell Lines

“…Recently, it has been shown that MSCs isolated from mammary AT (MAT-MSCs) of patients with BC displayed a dysregulated secretory profile and enhanced tumorigenicity compared to MAT-MSCs isolated from healthy donors, suggesting permanent changes induced by cancer cells in local MSCs [ 25 ]. Moreover, it has been reported that MAT-MSCs are largely modified by doxorubicin and paclitaxel, which influence cytokine release and potentiate the ability of MSCs to stimulate BC invasive potential in vivo [ 24 ]. Thus, local MSCs exhibit a pivotal role in BC progression and are extensively affected by external stimuli.…”

“…Thus, by switching on multiple, but still unclear mechanisms, MSCs may favor tumor growth and progression. However, different studies indicate MSCs as vectors for consolidated and innovative therapies [ 9 , 22 , 23 , 24 , 25 ].…”

The cellular composition of the tumor microenvironment is an important marker for predicting therapeutic efficacy in breast cancer

“…MSC-CD9 may become an important target for the treatment of BC ( 130 ). Adriamycin and paclitaxel promote the production of the serine enzymes E1, CCL2, IL-6 and IL-8 in MSCs and promote breast cancer cell proliferation and angiogenesis ( 131 ). Adriamycin can also cause MSCs to produce miR-21-5p to lead to chemotherapy resistance.…”