Chemotherapy-induced hyaluronan production: a novel chemoresistance mechanism in ovarian cancer

BMC Cancer

Carmela Ricciardelli³  Miranda P Ween¹  Noor A Lokman³  Izza A Tan³  Carmen E Pyragius³  Martin K Oehler² 

[1] Research Centre for Infectious Diseases, School of Molecular Biosciences, University of Adelaide, Adelaide 5005, South Australia, Australia

[2] Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide 5005, South Australia, Australia

[3] 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

关键词: Ovarian cancer;    ABC transporters;    Chemotherapy;    Hyaluronan;    Extracellular matrix;   

Others  :  1079516
DOI  :  10.1186/1471-2407-13-476

 received in 2013-05-21, accepted in 2013-10-01,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Ricciardelli et al.; licensee BioMed Central Ltd.

【 图 表 】

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