Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b

Chen, Y; Chen, Zeng; Yao, Zhan; Wang, H; Jiang, Xiaodan; Li, W

doi:10.1038/onc.2017.100

Cited by 113 publications

(96 citation statements)

References 58 publications

(63 reference statements)

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“…Wnt ligands (Wnt10b/3) or receptors (FZD7/LRP6) mediate activation of the β-catenin pathway responsible for EMT induction. 29,[57][58][59][60] In contrast, Wnt5a/5b-induced EMT is not dependent on β-catenin, but is involved in FZD2/STAT3 signaling. 61 Ectopic expression of DKK1/SFRP1 or recombinant DKK1/SFRP1 suppresses breast epithelial cell EMT, further proving the role of Wnt ligands and receptors in this process.…”

Section: Cancer Cell Epith Elial-mesenchymal Transitionmentioning

confidence: 99%

“…Both canonical and noncanonical Wnt pathways are involved in EMT of breast stem cells or cancer cells. Wnt ligands (Wnt10b/3) or receptors (FZD7/LRP6) mediate activation of the β‐catenin pathway responsible for EMT induction . In contrast, Wnt5a/5b‐induced EMT is not dependent on β‐catenin, but is involved in FZD2/STAT3 signaling .…”

Section: Wnt Signaling Induces Breast Cancer Cell Epithelial‐mesenchymentioning

confidence: 99%

“…Furthermore, Wnt ligand from breast cancer cells can activate fibroblasts into CAF in a TGF‐β signaling‐dependent way . CAF inversely secrete many molecules including Wnt ligands such as Wnt10b in exosomes to induce cancer cell EMT, metastasis and stemness . Interestingly, exosomes from fibroblasts can stimulate Wnt11 secretion by breast cancer cells, and then load Wnt11 to activate the Wnt/PCP pathway and drive cancer cell motility and metastasis .…”

Section: Wnt Signaling Is Involved In Epithelial‐stromal Crosstalk Ofmentioning

confidence: 99%

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Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

et al. 2018

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Wnt proteins, a group of secreted glycoproteins, mainly combine with receptors Frizzled (FZD) and/or low‐density‐lipoprotein receptor‐related proteins 5/6 (LRP5/6), initiating β‐catenin‐dependent and ‐independent signaling pathways. These pathways, which can be regulated by some secreted antagonists such as secreted Frizzled‐related proteins (SFRP) and dickkopf‐related protein (DKK), play a critical role in embryo development and adult homeostasis. Overactivation of Wnt signaling has been implicated in some human diseases including cancer. Wnt transgenic mice provide convincing evidence that Wnt signaling is involved in breast cancer initiation and progression, which is further strengthened by observations on human clinical breast cancer patients and studies on in vitro cultured human breast cancer cells. This review focuses on the roles of Wnt ligands, receptors and antagonists in breast cancer development instead of molecules or signaling transactivating β‐catenin independent on Wnt upstream components.

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Section: Cancer Cell Epith Elial-mesenchymal Transitionmentioning

confidence: 99%

Section: Wnt Signaling Induces Breast Cancer Cell Epithelial‐mesenchymentioning

confidence: 99%

Section: Wnt Signaling Is Involved In Epithelial‐stromal Crosstalk Ofmentioning

confidence: 99%

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Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

et al. 2018

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“…These cell contents, when transferred to recipient cells, can alter its biologic behavior, including intracellular signaling pathways 10 . Exosomal contents, therefore, have the ability to act as either tumor suppressors or promoters through their direct actions on a cell or by modifying the microenvironment 13, 14, 15 .…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins

et al. 2018

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Hypoxia-mediated tumor progression, metastasis, and drug resistance are major clinical challenges in ovarian cancer. Exosomes released in the hypoxic tumor microenvironment may contribute to these challenges by transferring signaling proteins between cancer cells and normal cells. We observed that ovarian cancer cells exposed to hypoxia significantly increased their exosome release by up-regulating Rab27a, down-regulating Rab7, LAMP1/2, NEU-1, and also by promoting a more secretory lysosomal phenotype. STAT3 knockdown in ovarian cancer cells reduced exosome release by altering the Rab family proteins Rab7 and Rab27a under hypoxic conditions. We also found that exosomes from patient-derived ascites ovarian cancer cell lines cultured under hypoxic conditions carried more potent oncogenic proteins - STAT3 and FAS that are capable of significantly increasing cell migration/invasion and chemo-resistance in vitro and tumor progression/metastasis in vivo. Hypoxic ovarian cancer cells derived exosomes (HEx) are proficient in re-programming the immortalized fallopian tube secretory epithelial cells (FT) to become pro-tumorigenic in mouse fallopian tubes. In addition, cisplatin efflux via exosomes was significantly increased in ovarian cancer cells under hypoxic conditions. Co-culture of HEx with tumor cells led to significantly decreased dsDNA damage and increased cell survival in response to cisplatin treatment. Blocking exosome release by known inhibitor Amiloride or STAT3 inhibitor and treating with cisplatin resulted in a significant increase in apoptosis, decreased colony formation and proliferation. Our results demonstrate that HEx are more potent in augmenting metastasis/chemotherapy resistance in ovarian cancer, and may serve as a novel mechanism for tumor metastasis, chemo-resistance and a point of intervention for improving clinical outcomes.

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“…Recent studies found that CAFs secret CD9+ exosomes to directly stimulate the migration ability of scirrhous‐type gastric cancer cells; they also deliver exosomal miR‐451 as a signaling molecule to provide a favorable niche for esophageal tumor cells migration and cancer progression. In breast cancer, stromal fibroblasts can acquire the hallmarks of CAFs as a result of the loss of p85α expression; subsequently, these p85α low‐expressed CAFs would transport exosomes containing Wnt10b to promote cancer metastasis via canonical Wnt pathway mediated EMT process . Additionally, in breast cancer, miR‐21 and two other miRNAs, 378e and 143, are increased in exosomes released from CAFs, promoting the aggressive nature of cancer cells, increasing stem cell amounts, and inducing EMT …”

Section: Exosomes In Sequential Processes Of Tumor Metastasismentioning

confidence: 99%

Exosomes play roles in sequential processes of tumor metastasis

Chen

et al. 2018

Intl Journal of Cancer

139

105

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Overwhelming evidence demonstrates that exosomes, a series of biologically functional small vesicles of endocytic origin carrying a variety of active constituents, especially tumor-derived exosomes, contribute to tumor progression and metastasis. This review focuses on the specific multifaceted roles of exosomes in affecting sequenced four crucial processes of metastasis, through which cancer cells spread from primary to secondary organs and finally form macroscopic metastatic lesions. First, exosomes modulate the primary tumor sites to assist cancer growth and dissemination. In this part, five main biological events are reviewed, including the transfer of oncogenic constituents, the recruitment and activation of fibroblasts, the induction of angiogenesis, immunosuppression and epithelial-mesenchymal transition (EMT) promotion. In Step 2, we list two recently disclosed mechanisms during the organ-specific homing process: the exosomal integrin model and exosomal epidermal growth factor receptor (EGFR)/miR-26/hepatocyte growth factor (HGF) model. Subsequently, Step 3 focuses on the interactions between exosomes and pre-metastatic niche, in which we highlight the specific functions of exosomes in angiogenesis, lymphangiogenesis, immune modulation and metabolic, epigenetic and stromal reprogramming of pre-metastatic niche. Finally, we summarize the mechanisms of exosomes in helping the metastatic circulating tumor cells escape from immunologic surveillance, survive in the blood circulation and proliferate in host organs.

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Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b

Cited by 113 publications

References 58 publications

Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins

Exosomes play roles in sequential processes of tumor metastasis

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