Abstract
Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a partial benefit against prostate adenocarcinoma, because of inhibition of supportive MCs. However, they show an unexpected outgrowth of prostate NE tumors, likely because of defective signaling pathway downstream of cKit receptor. Also unexpected but very effective was the inhibition of epithelial-stromal tumors of the seminal vesicles achieved by imatinib treatment. These tumors normally arise in the seminal vesicles of TRAMP mice, independently of the degree of prostatic glandular lesions, and resemble phyllodes tumors found in human prostate and seminal vesicles, and in breast. In both mice and in patients, these tumors are negative for cKit but express PDGFR-β, another tyrosine kinase receptor specifically inhibited by imatinib. Our results imply a possible detrimental effect of imatinib in prostate cancer patients but suggest a promising therapeutic application of imatinib in the treatment of recurrent or metastatic phyllodes tumors. Mol Cancer Ther; 16(2); 365-75. ©2016 AACR.
Highlights
Prostate cancer is one of the leading causes of cancer-related death worldwide [1], and effective therapies for advanced, hormone-refractory, and metastatic disease are still lacking
Imatinib treatment restrains growth of adenocarcinoma but not of NE prostate tumors Aiming at targeting the cKit receptor in prostate cancers of TRAMP mice, we tested its expression in adenocarcinoma and NE prostate cancers spontaneously occurring in 25-week-old untreated TRAMP mice
The different proliferative attitude of TRAMP adenocarcinomas and NE tumors is evidenced by immunostaining for Ki-67, which reveals that NE tumors display a higher fraction of actively proliferating malignant elements in comparison with adenocarcinomas (Supplementary Fig. S1B)
Summary
Prostate cancer is one of the leading causes of cancer-related death worldwide [1], and effective therapies for advanced, hormone-refractory, and metastatic disease are still lacking. TRAMP mice develop epithelial–stromal tumors in the seminal vesicles [9, 10], which arise independently from prostatic lesions [9] and resemble human phyllodes tumors found in breast [11, 12], prostate [13], and seminal vesicles [14]. In humans, these rare neoplasms are commonly managed with surgical removal; local recurrence is common and metastatic spread associated with a poor prognosis has been reported in some patients [12, 14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
