Pancreatic fibroblast exosomes regulate survival of cancer cells.

Abstract

With high enthusiasm, we enjoyed reading the recent article published by Richards et al. where they have shown that exosomes secreted by gemcitabine (GEM)-treated cancer-associated fibroblasts (CAFs) promote proliferation and drug resistance of pancreatic cancer cells (PCCs).1 The exosomes released from GEM-treated CAFs when added to recipient PCCs, it upregulated Snail expression, which is known to confer resistance to GEM.2 At the same time, GEM is already known to upregulate Snail expression in PCCs.2 Here an important point that deserves clarification is ‘exosomes isolated from GEM-treated CAFs might carry some amount of GEM and/or its active metabolites and transfer it to PCCs’ (Figure 1). In recent past, it has been shown that conditioned medium (CM) of pancreas-derived mesenchymal stromal cells primed with GEM-induced cytotoxicity in CFPAC-1 PCCs.3 Moreover, exosomal release of another chemotherapeutic drug, paclitaxel from treated mesenchymal cells has already been reported.4 Hence, it is highly possible that after GEM treatment to CAFs, some amount of GEM and/or its active metabolites will be retained inside CAFs and later on gets released to the CM (Figure 1). As a consequence, GEM and/or its metabolites present in CAFs’ exosomes will be directly released into PCCs and induce Snail expression in PCCs.2 Though the mechanism(s) behind GEM-mediated Snail expression in PCCs is not clear, but GEM-induced Hif1α upregulation in PCCs5 followed by Hif1α-mediated Snail overexpression6 might be a potential mechanism (Figure 1). In our ongoing study, we have observed that CM (GEM treatment for 24 h followed by conditioning for 24 h) collected from pancreatic stellate cells (GEM-PSCs) confers less survival advantage to GEM-treated PCCs compared with 24 h CM collected from GEM-PSCs with a second round of media replacement after 8 h of first removal. Together, it indicates that CM from GEM-treated CAFs might contain some level of drug that either sensitizes or alters PCCs property toward additional GEM treatment. To induce cytotoxicity, the GEM concentration present in the exosomes should be at the optimal level; however, GEM concentration that is required for HIF1α and/or Snail upregulation might be below the cytotoxic dose.5 Together, it is potentially possible that in the current study the exosomes obtained from 5 × 105 numbers of CAFs treated with 1 μM of GEM might have GEM concentration that is not cytotoxic but good enough to induce Snail expression in PCCs. Therefore, transfer of GEM through CAF-derived exosomes into PCCs and its role in induction of chemoresistance warrants further investigation.