Placenta‐conditioned extracellular matrix (ECM) activates breast cancer cell survival mechanisms: A key for future distant metastases

The extracellular matrix (ECM) affects cancer cell characteristics. Inability of normal epithelial cells to attach to the ECM induces apoptosis (anoikis). Cancer cells are often anoikis resistant, a prerequisite for their metastatic spread. Previously we demonstrated that the placenta manipulates it...

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Bibliographic Details
Published in:International journal of cancer 2019-04, Vol.144 (7), p.1633-1644
Main Authors: Komemi, Oded, Shochet, Gali Epstein, Pomeranz, Meir, Fishman, Ami, Pasmanik‐Chor, Metsada, Drucker, Liat, Matalon, Shelly Tartakover, Lishner, Michael
Format: Article
Language:English
Subjects:
Anoikis
Apoptosis
Autophagy
Breast cancer
Cancer
Cell interactions
Cell survival
Cellular stress response
Conditioning
Drug resistance
ECM
Epithelial cells
Extracellular matrix
Medical research
Metastases
metastasis
Paclitaxel
Phagocytosis
Placenta
Pregnancy
siRNA
survival pathways
Taxol
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Summary:The extracellular matrix (ECM) affects cancer cell characteristics. Inability of normal epithelial cells to attach to the ECM induces apoptosis (anoikis). Cancer cells are often anoikis resistant, a prerequisite for their metastatic spread. Previously we demonstrated that the placenta manipulates its surrounding ECM in a way that prevents breast cancer cells (BCCL) attachment and induces their motility and aggregation. This fits with the fact that although breast cancer during pregnancy is often advanced, metastasis to the placenta is rarely observed. Placental intervillous space provides suitable conditions for cancer cell arrival. Yet, the outcome of the short communication between the placental ECM to the BCCL and its effect on BCCL malignant potential are unknown, and are the focus of our study. In the current study we analyzed the effect of placental ECM on BCCL survival pathways and drug resistance. Microarray analysis suggested activation of the NF‐κB and stress response pathways. Indeed, the placenta‐conditioned ECM induced autophagy in ERα + BCCL, inactivated the NF‐κB inhibitor (IκB) and increased integrin α5 in the BCCL. The autophagy mediated MCF‐7 and T47D migration and the placental ECM‐BCCL interactions reduced the BCCL sensitivity to Taxol. We also demonstrated by using siRNA that integrin α5 was responsible for the MCF‐7 autophagy and suggest this molecule as a suitable target for therapy. What's new? Pregnancy‐associated breast cancer is usually identified in a more advanced stage of the disease. Yet, metastasis to the placenta is rare. Placenta‐conditioned extracellular matrix (ECM) prevents breast cancer cell (BCCL) adhesion and facilitates their motility and aggregation, but the effect of placental ECM on BCCL survival pathways and drug resistance remain unknown. Here, the authors report that placental ECM‐BCCL interactions induce elevated levels of integrin‐a5, IkB phosphorylation, and autophagy in BCCL and reduce their sensitivity to the drug Taxol. Integrin‐a5 modulates the autophagy that mediates the cell aggregation and survival, and thus emerges as a potentially suitable target for therapy.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.31861