Molecular alterations in prostate carcinomas that associate with in vivo exposure to chemotherapy: identification of a cytoprotective mechanism involving growth differentiation factor 15

Abstract

Purpose: To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance.

Experimental design: Patients with high-risk localized prostate cancer (tumor-node-metastasis >or= T(2b) or prostate-specific antigen >or= 15 ng/mL or Gleason glade >or= 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done.

Results: Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1beta. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone.

Conclusions: Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-kappaB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.