Human adipose‑derived mesenchymal stem cells promote breast cancer MCF7 cell epithelial‑mesenchymal transition by cross interacting with the TGF‑β/Smad and PI3K/AKT signaling pathways

Abstract Background Tissue engineered and regenerative approaches for treating tendon injuries are challenged by the limited information on the cellular signaling pathways driving tenogenic differentiation of stem cells. Members of the transforming growth factor (TGF) β family, particularly TGFβ2, play a role in tenogenesis, which may proceed via Smad-mediated signaling. However, recent evidence suggests some aspects of tenogenesis may be independent of Smad signaling, and other pathways potentially involved in tenogenesis are understudied. Here, we examined the role of Akt/mTORC1/P70S6K signaling in early TGFβ2-induced tenogenesis of mesenchymal stem cells (MSCs) and evaluated TGFβ2-induced tenogenic differentiation when Smad3 is inhibited. Methods Mouse MSCs were treated with TGFβ2 to induce tenogenesis, and Akt or Smad3 signaling was chemically inhibited using the Akt inhibitor, MK-2206, or the Smad3 inhibitor, SIS3. Effects of TGFβ2 alone and in combination with these inhibitors on the activation of Akt signaling and its downstream targets mTOR and P70S6K were quantified using western blot analysis, and cell morphology was assessed using confocal microscopy. Levels of the tendon marker protein, tenomodulin, were also assessed. Results TGFβ2 alone activated Akt signaling during early tenogenic induction. Chemically inhibiting Akt prevented increases in tenomodulin and attenuated tenogenic morphology of the MSCs in response to TGFβ2. Chemically inhibiting Smad3 did not prevent tenogenesis, but appeared to accelerate it. MSCs treated with both TGFβ2 and SIS3 produced significantly higher levels of tenomodulin at 7 days and morphology appeared tenogenic, with localized cell alignment and elongation. Finally, inhibiting Smad3 did not appear to impact Akt signaling, suggesting that Akt may allow TGFβ2-induced tenogenesis to proceed during disruption of Smad3 signaling. Conclusions These findings show that Akt signaling plays a role in TGFβ2-induced tenogenesis and that tenogenesis of MSCs can be initiated by TGFβ2 during disruption of Smad3 signaling. These findings provide new insights into the signaling pathways that regulate tenogenic induction in stem cells.

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Molecular Network Pathway Of ERBB In Diffuse-Type Gastric Cancer, Mesenchymal Stem Cells And Epithelial-Mesenchymal Transition

Journal of Clinical Epigenetics ◽

10.21767/2472-1158.100098 ◽

2018 ◽

Vol 04 (02) ◽

Cited By ~ 1

Author(s):

Shihori Tanabe

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Epithelial Mesenchymal Transition ◽

Molecular Network ◽

Diffuse Type ◽

Mesenchymal Transition ◽

Diffuse Type Gastric Cancer

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A Role of Tumor-Released Exosomes in Paracrine Dissemination and Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms19123968 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3968 ◽

Cited By ~ 17

Author(s):

Enrico Spugnini ◽

Mariantonia Logozzi ◽

Rossella Di Raimo ◽

Davide Mizzoni ◽

Stefano Fais

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

The Body ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Target Organs

Metastatic diffusion is thought to be a multi-step phenomenon involving the release of cells from the primary tumor and their diffusion through the body. Currently, several hypotheses have been put forward in order to explain the origin of cancer metastasis, including epithelial–mesenchymal transition, mutagenesis of stem cells, and a facilitating role of macrophages, involving, for example, transformation or fusion hybridization with neoplastic cells. In this paradigm, tumor-secreted extracellular vesicles (EVs), such as exosomes, play a pivotal role in cell communications, delivering a plethora of biomolecules including proteins, lipids, and nucleic acids. For their natural role in shuttling molecules, EVs have been newly considered a part of the metastatic cascade. They have a prominent role in preparing the so-called “tumor niches” in target organs. However, recent evidence has pointed out an even more interesting role of tumor EVs, consisting in their ability to induce malignant transformation in resident mesenchymal stem cells. All in all, in this review, we discuss the multiple involvements of EVs in the metastatic cascade, and how we can exploit and manipulate EVs in order to reduce the metastatic spread of malignant tumors.

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