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

Abstract

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.

SMAD specific E3 ubiquitin protein ligase�1 promotes ovarian cancer cell migration and invasion via the activation of the RhoA/ROCK signaling pathway

“…In addition, the inhibition of SYK significantly decreased the invasive ability of OC cells. Dorayappan et al (36) reported that patient-derived exosomes from ascites-associated OC cells cultured under hypoxic conditions, exhibited an increased abundance of potent oncogenic proteins, including signal transducer and activator of transcription 3 and Fas, which are capable of significantly increasing cell migration/invasion. Vascular endothelial growth factor (VEGF)-C and VEGF-D were proposed to contribute to tumor-associated lymphatic vessel growth, enhancing the metastatic spread of tumor cells to lymph nodes.…”

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

“…Besides, hypoxia is known to drive excessive exosome release from cancer cells in several tumor types [104]. Under hypoxic conditions, EOC cells showed activated STAT3 levels, increased the release of exosomes to promote proliferation, which occurs through altering proteins of the Rab family [105]. A microfluidic ChIP-based exosomes isolation method confirmed elevated pY-STAT3 levels in exosomes isolated from high-grade serous ovarian cancer cell lines and patients, implying that vesicles secreted from cancer patients have activated STAT3 signaling that could foster cancer metastasis [101].…”

Emerging roles and therapeutic value of exosomes in cancer metastasis

“…Tumor cells can affect recipient cells by releasing exosomes, thus promoting cancer metastasis, since exosomes can transfer molecules required for metastasis [53]. In particular, ovarian cancer cells can produce exosomes containing oncogenic proteins such as STAT3 and FAS, which increase the migratory ability of tumor cells [54]. Wang et al have observed that pancreatic cancer cells can secrete exosomes containing miR-301a-3p to promote metastasis by inducing the M2 polarization of macrophages [55].…”