Breast cancer characteristics are modified by first trimester human placenta: in vitro co-culture study

Tartakover-Matalon, Shelly; Mizrahi, Ariel; Epstein, Gil S.; Shneifi, A.; Drucker, Liat; Pomeranz, Meir; Fishman, Ami; Radnay, Judith; Lishner, Michael

doi:10.1093/humrep/deq227

Cited by 14 publications

(13 citation statements)

References 40 publications

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“…While cancer during pregnancy is more aggressive than in matched non‐pregnant women , metastases are rarely found near the placenta . Indeed, previously we demonstrated that BCCL migrated away from placental explants, leaving areas empty of BCCL around EVT implantation sites . In the current study, we analyzed the effect of placenta‐conditioned ECM on BCCL.…”

Section: Discussionmentioning

confidence: 91%

“…The placenta and embryo are non‐supportive microenvironments for cancer cells . Previously, we showed that breast cancer cells (BCCL) were eliminated from the area around first trimester placental explants . This cell elimination took place only in the regions of placental implantation sites and was a result of a small increase in BCCL death, cancer cell epithelial mesenchymal transition (EMT), and migration away from the placenta .…”

Section: Introductionmentioning

confidence: 99%

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First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix

et al. 2016

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The extracellular matrix (ECM) affects cancer cell characteristics. Its detachment from the ECM induces cell apoptosis, termed anoikis. Cancer cells can develop anoikis resistance, a necessary step for metastasis, by switching integrins, over-expressing growth factor receptors, and inducing epithelial mesenchymal transition (EMT). The placenta is a non-supportive microenvironment for cancer cells. We showed that breast cancer cells (BCCL) were eliminated from placental implantation sites. During implantation, the placenta manipulates its surrounding matrix, which may induce BCCL elimination. Here, we explored the effect of placenta-induced ECM manipulations on BCCL. During experiments, BCCL (MCF-7/T47D) were cultured on placenta/BCCL-conditioned ECM (Matrigel used for first trimester placenta/BCCL culture and cleared by NH OH). After culturing the cells, we analyzed cancer cell phenotype (death, count, aggregation, MMP) and signaling (microarray analysis and pathway validation). We found that the BCCL did not attach to previous placental implantation sites and instead, similarly to anoikis-resistant cells, migrated away, displayed increased MMP levels/activity, and formed aggregates in distant areas. T47D were less affected than the MCF-7 cells, since MCF-7 also showed modest increases in cell death, EMT, and increased proliferation. Microarray analysis of the MCF-7 highlighted changes in the integrin, estrogen, EGFR, and TGFβ pathways. Indeed, placental ECM reduced ERα, induced Smad3/JNK phosphorylation and increased integrin-α5 expression (RGD-dependent integrin) in the BCCL. Addition of RGD or TGFβR/JNK inhibitors reversed the phenotypic changes. This study helps explain the absence of metastases to the placenta and why advanced cancer is found in pregnancy, and provides possible therapeutic targets for anoikis-resistant cells. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix

et al. 2016

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“…Previously, we found that ERα + BCCL were eliminated from placental implantation sites . The placenta‐conditioned ECM itself (matrigel used for first trimester placenta growth and cleared by NH 4 OH) had similar effects on the BCCL, suggesting that ECM‐embedded factors were responsible for these effects.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, we chose MCF‐7 and T47D cell lines with established response to ER and progesterone. We found that coculturing breast cancer cells (BCCL) with the placenta facilitated their autophagy, epithelial mesenchymal transition (EMT) and migration . Further study demonstrated that the EVT cells manipulate their surrounding ECM in a way that prevents breast cancer cell from settling and induces EMT in the BCCL .…”

Section: Introductionmentioning

confidence: 99%

“…In order to investigate this interesting discrepancy we developed a unique ex-vivo model that contains placental explants cocultured with ERα positive (ERα+) breast cancer cells, capable of responding to placental hormones. 6 Specifically, we chose MCF-7 and T47D cell lines with established response to ER and progesterone. We found that coculturing breast cancer cells (BCCL) with the placenta facilitated their autophagy, 7 epithelial mesenchymal transition (EMT) and migration.…”

Section: Introductionmentioning

confidence: 99%

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

Komemi

Shochet

Pomeranz

et al. 2018

Intl Journal of Cancer

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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 this 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. This article is protected by copyright. All rights reserved.

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Placental supernatants’ enhancement of the metastatic potential of breast cancer cells: is estrogen receptor (ERα) essential for this phenomenon?

Bar

Komemi

Pomeranz

et al. 2019

Arch Gynecol Obstet

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Breast cancer characteristics are modified by first trimester human placenta: in vitro co-culture study

Abstract: MCF-7/T47D cells are eliminated from the placental surroundings. Analyzing the causes of these phenomena may suggest biological pathways for this event and raise new therapeutic targets.

Cited by 14 publications

References 40 publications

First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix

First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix

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

Placental supernatants’ enhancement of the metastatic potential of breast cancer cells: is estrogen receptor (ERα) essential for this phenomenon?

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