title: Chemotherapy-induced hyaluronan production: a novel chemoresistance mechanism in ovarian cancer.
abstract: BACKGROUND
  Hyaluronan (HA) an important component of the extracellular matrix, has been linked to tumor progression and drug resistance in several malignancies. However, limited data is available for ovarian cancer. This study investigated the role of hyaluronan (HA) and a potential link between the HA-CD44 pathway and membrane ATP binding cassette (ABC) transporter proteins in ovarian cancer chemoresistance.
  
  
  METHODS
  We investigated the ability of HA to block the cytotoxic effects of the chemotherapy drug carboplatin, and to regulate the expression of ABC transporters in ovarian cancer cells. We also examined HA serum levels in ovarian cancer patients prior to and following chemotherapy and assessed its prognostic relevance.
  
  
  RESULTS
  HA increased the survival of carboplatin treated ovarian cancer cells expressing the HA receptor, CD44 (OVCAR-5 and OV-90). Carboplatin significantly increased expression of HAS2, HAS3 and ABCC2 and HA secretion in ovarian cancer cell conditioned media. Serum HA levels were significantly increased in patients following platinum based chemotherapy and at both 1st and 2nd recurrence when compared with HA levels prior to treatment. High serum HA levels (>50 μg/ml) prior to chemotherapy treatment were associated with significantly reduced progression-free (P = 0.014) and overall survival (P = 0.036). HA production in ovarian cancer cells was increased in cancer tissues collected following chemotherapy treatment and at recurrence. Furthermore HA treatment significantly increased the expression of ABC drug transporters (ABCB3, ABCC1, ABCC2, and ABCC3), but only in ovarian cancer cells expressing CD44. The effects of HA and carboplatin on ABC transporter expression in ovarian cancer cells could be abrogated by HA oligomer treatment. Importantly, HA oligomers increased the sensitivity of chemoresistant SKOV3 cells to carboplatin.
  
  
  CONCLUSIONS
  Our findings indicate that carboplatin chemotherapy induces HA production which can contribute to chemoresistance by regulating ABC transporter expression. The HA-CD44 signaling pathway is therefore a promising target in platinum resistant ovarian cancer.
authors.affiliation: Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Research Centre for Reproductive Health, Robinson Institute, University of Adelaide, Adelaide 5005, South Australia, Australia. carmela.ricciardelli@adelaide.edu.au.
authors.forename: Carmela
authors.initials: C
authors.lastname: Ricciardelli
authors.forename: Miranda P
authors.initials: MP
authors.lastname: Ween
authors.forename: Noor A
authors.initials: NA
authors.lastname: Lokman
authors.forename: Izza A
authors.initials: IA
authors.lastname: Tan
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Pyragius
authors.forename: Martin K
authors.initials: MK
authors.lastname: Oehler
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D011485:Protein Binding; D016896:Treatment Outcome
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D016190:Carboplatin; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human