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Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules
Author(s) -
Ramteke Anand,
Ting Harold,
Agarwal Chapla,
Mateen Samiha,
Somasagara Ranganathan,
Hussain Anowar,
Graner Michael,
Frederick Barbara,
Agarwal Rajesh,
Deep Gagan
Publication year - 2015
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22124
Subject(s) - adherens junction , biology , lncap , microvesicle , microvesicles , cancer research , microbiology and biotechnology , tumor microenvironment , exosome , cancer cell , cancer , cadherin , microrna , cell , biochemistry , genetics , tumor cells , gene
Hypoxic conditions in prostate cancer (PCA) are associated with poor prognosis; however, precise mechanism/s through which hypoxia promotes malignant phenotype remains unclear. Here, we analyzed the role of exosomes from hypoxic PCA cells in enhancing the invasiveness and stemness of naïve PCA cells, as well as in promoting cancer‐associated fibroblast (CAF) phenotype in prostate stromal cells (PrSC). Human PCA LNCaP and PC3 cells were exposed to hypoxic (1% O 2 ) or normoxic (21% O 2 ) conditions, and exosomes secreted under hypoxic (Exo Hypoxic ) and normoxic (Exo Normoxic ) conditions were isolated from conditioned media. Nanoparticle tracking analysis revealed that Exo Hypoxic have smaller average size as compared to Exo Normoxic . Immunoblotting results showed a higher level of tetraspanins (CD63 and CD81), heat shock proteins (HSP90 and HSP70), and Annexin II in Exo Hypoxic compared to Exo Normoxic . Co‐culturing with Exo Hypoxic increased the invasiveness and motility of naïve LNCaP and PC3 cells, respectively. Exo Hypoxic also promoted prostasphere formation by both LNCaP and PC3 cells, and enhanced α‐SMA (a CAF biomarker) expression in PrSC. Compared to Exo Normoxic , Exo Hypoxic showed higher metalloproteinases activity and increased level of diverse signaling molecules (TGF‐β2, TNF1α, IL6, TSG101, Akt, ILK1, and β‐catenin). Furthermore, proteome analysis revealed a higher number of proteins in Exo Hypoxic (160 proteins) compared to Exo Normoxic (62 proteins), primarily associated with the remodeling of epithelial adherens junction pathway. Importantly, Exo Hypoxic targeted the expression of adherens junction proteins in naïve PC3 cells. These findings suggest that Exo Hypoxic are loaded with unique proteins that could enhance invasiveness, stemness, and induce microenvironment changes; thereby, promoting PCA aggressiveness. © 2013 Wiley Periodicals, Inc.