Chemotherapy-triggered changes in stromal compartment drive tumor invasiveness and progression of breast cancer.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Apoptosis
Breast Neoplasms
/ drug therapy
Cell Proliferation
Cell Transformation, Neoplastic
/ chemically induced
Doxorubicin
/ administration & dosage
Female
Humans
Mesenchymal Stem Cells
/ drug effects
Mice
Mice, SCID
Neoplasm Invasiveness
Paclitaxel
/ administration & dosage
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Breast cancer
Cancer progression
Chemotherapy
Mesenchymal stromal cells
Tumor microenvironment
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
27 Sep 2021
27 Sep 2021
Historique:
received:
11
05
2021
accepted:
26
08
2021
entrez:
28
9
2021
pubmed:
29
9
2021
medline:
1
2
2022
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 34579743
doi: 10.1186/s13046-021-02087-2
pii: 10.1186/s13046-021-02087-2
pmc: PMC8477536
doi:
Substances chimiques
Doxorubicin
80168379AG
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
302Subventions
Organisme : Agentúra na Podporu Výskumu a Vývoja
ID : APVV-16-0178
Organisme : Agentúra na Podporu Výskumu a Vývoja
ID : APVV 16-0010
Organisme : EraCoSysMed
ID : RESCUER
Organisme : ERA-NET EuroNanoMed II
ID : INNOCENT
Organisme : Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
ID : 2/0138/20
Organisme : Operational Programme Integrated Infrastructure
ID : IMTS: 313011V446
Informations de copyright
© 2021. The Author(s).
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