Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

Leca, Julie; Martinez, Sébastien; Lac, Sophie; Nigri, Jérémy; Secq, Véronique; Rubis, Marion; Bressy, Christian; Sergé, Arnauld; Lavaut, Marie‐Noëlle; Dusetti, Nelson; Loncle, Céline; Roques, Julie; Pietrasz, Daniel; Bousquet, Corinne; García, Stéphane; Granjeaud, Samuel; Ouaïssi, Mehdi; Bachet, Jean‐Baptiste; Brun, Catherine; Iovanna, Juan; Zimmermann, Pascale; Vasseur, Sophie; Tomasini, Richard

doi:10.1172/jci87734

Cited by 181 publications

(169 citation statements)

References 51 publications

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“…The mechanisms of exosomal release by the tumor cells and its contribution to tumor metastasis and drug resistance likely play an important role in cancer biology 22, 23, 24, 25, 26 . Changes in the lysosomal phenotype observed in hypoxic conditions might be the reason for peripheral shift of secretory or exocytic lysosomes outward, to the plasma membrane 18, 19 .…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In this context, gemcitabine has been identified to promote release of EVs from CAFs thus inducing expression of Snail in pancreatic cancer cells and promote proliferation and drug resistance 85. Furthermore, EVs carrying annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex were discovered to be crucial for the CAF—tumour cell crosstalk promoting PDA aggressiveness 86. Another important pathway for tumour-stromal interactions is the hepatocyte growth factor/tyrosine-protein kinase Met (HGF/c-MET) pathway.…”

Section: Introductionmentioning

confidence: 99%

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Neeße

Bauer

Öhlund

et al. 2018

Gut

268

222

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Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

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“…For example, activated PDAC fibroblasts secrete ANXA6 positive EV containing the ANXA6/LRP1/TSP1 complex. Uptake of these EV by PDAC cells was shown to enhance tumorigenesis by stimulating cancer cell migration and driving tumor growth in vivo [77] . Activation of the Wntplanar cell polarity (PCP) pathway, and subsequent stimulation of cell motility and metastasis, can also be induced by stromal cell EV.…”

Section: Secretion Of Stroma-derived Exosomesmentioning

confidence: 99%

Prostate cancer exosomes as modulators of the tumor microenvironment

Shephard¹,

Yeung²,

Clayton³

et al. 2017

JCMT

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Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

Abstract: we explore a new cellular crosstalk between CAFs and tumor cells, based on extracellular vesicles (EVs), and investigate the inhibition of a related candidate therapeutic target as well as detecting it in serum as a diagnostic biomarker to discriminate PDA grade.

Cited by 181 publications

References 51 publications

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

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

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Prostate cancer exosomes as modulators of the tumor microenvironment

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