FAK signaling in cancer-associated fibroblasts promotes breast cancer cell migration and metastasis by exosomal miRNAs-mediated intercellular communication

Wu, Hsin-Jung; Hao, Mingang; Yeo, Syn Kok; Guan, Jun‐Lin

doi:10.1038/s41388-020-1162-2

Cited by 127 publications

(90 citation statements)

References 50 publications

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“…The link between FAK and breast cancers is strongly suggested by a number of reports showing that FAK gene is amplified and overexpressed in a large fraction of breast cancer specimens [ 39 ]. Recently, it was shown that, while not affecting primary tumor development and growth, FAK deletion significantly suppressed breast cancer metastasis in vivo [ 40 ]. Another study demonstrated that knockdown of FAK expression in TNBC cells or the treatment of TNBC cells with a FAK inhibitor followed by co-culture with cytokine-induced killer (CIK) cells increased the death of TNBC cells, suggesting that FAK plays an important role in sensitizing tumor cells to CIK cells [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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“…In tumors, tumor cell-derived exosomal miRNAs are highly diverse and are capable of differentiating NFs into CAFs through a variety of signaling pathways. Exosomal miRNAs from cancer cells elicit a parenchymal signaling response at the receptor site and effectively inducing fibroblast activation, such as α-smooth muscle actin (α-SMA), fibroblast growth factor 2 (FGF2) and fibroblast activating protein (FAP) expression [98][99][100]. Matrix composed of CAFs is conducive to the proliferation and migration of tumor cells.…”

Section: Reshaping Ecm To Promote Tumor Progressionmentioning

confidence: 99%

Exosomal miRNAs in tumor microenvironment

Tan

Xia

et al. 2020

J Exp Clin Cancer Res

138

117

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Tumor microenvironment (TME) is the internal environment in which tumor cells survive, consisting of tumor cells, fibroblasts, endothelial cells, and immune cells, as well as non-cellular components, such as exosomes and cytokines. Exosomes are tiny extracellular vesicles (40-160nm) containing active substances, such as proteins, lipids and nucleic acids. Exosomes carry biologically active miRNAs to shuttle between tumor cells and TME, thereby affecting tumor development. Tumor-derived exosomal miRNAs induce matrix reprogramming in TME, creating a microenvironment that is conducive to tumor growth, metastasis, immune escape and chemotherapy resistance. In this review, we updated the role of exosomal miRNAs in the process of TME reshaping.

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“…This chemoresistance was found to be due to decreased secretion of TGF-β by CAFs, which led to increased activation of STAT3 signaling 49 . The importance of FAK in CAFs was further studied through the use of a fibroblast-specific FAK knockout mouse model in which the loss of FAK in CAFs led to decreased breast cancer metastasis 50 . This study found that exosomes isolated from FAK-null CAFs contained elevated levels of the tumor-suppressing microRNAs miR-16 and miR-148a 50 , suggesting that FAK expression in CAFs may play a role in exosome-mediated regulation of cancer cell proliferation.…”

Section: Cancer-associated Fibroblasts (Cafs) and Ecmmentioning

confidence: 99%

Targeting focal adhesion kinase in cancer cells and the tumor microenvironment

et al. 2020

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Focal adhesion kinase (FAK) is an integrin-associated protein tyrosine kinase that is frequently overexpressed in advanced human cancers. Recent studies have demonstrated that aside from FAK’s catalytic activity in cancer cells, its cellular localization is also critical for regulating the transcription of chemokines that promote a favorable tumor microenvironment (TME) by suppressing destructive host immunity. In addition to the protumor roles of FAK in cancer cells, FAK activity within cells of the TME may also support tumor growth and metastasis through various mechanisms, including increased angiogenesis and vascular permeability and effects related to fibrosis in the stroma. Small molecule FAK inhibitors have demonstrated efficacy in alleviating tumor growth and metastasis, and some are currently in clinical development phases. However, several preclinical trials have shown increased benefits from dual therapies using FAK inhibitors in combination with other chemotherapies or with immune cell activators. This review will discuss the role of nuclear FAK as a driver for tumor cell survival as well as potential therapeutic strategies to target FAK in both tumors and the TME.

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FAK signaling in cancer-associated fibroblasts promotes breast cancer cell migration and metastasis by exosomal miRNAs-mediated intercellular communication

Cited by 127 publications

References 50 publications

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Exosomal miRNAs in tumor microenvironment

Targeting focal adhesion kinase in cancer cells and the tumor microenvironment

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