Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial–Stromal Tumors by Targeting PDGFR-β

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.

Cross-Talk between Myeloid-Derived Suppressor Cells and Mast Cells Mediates Tumor-Specific Immunosuppression in Prostate Cancer

“…We have previously identified mast cells as key stromal accomplices in prostate cancer, capable of influencing the balance between adenocarcinoma and neuroendocrine histotypes (9,10). Our data showing increase in the frequency of neuroendocrine tumors after pharmacologic inhibition of mast cell degranulation (refs.…”

“…The amount of mast cell infiltration into human prostate cancer correlates with prognosis; mast cells may be a useful therapeutic target (8). We have shown that pharmacologic inhibition of mast cells degranulation in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice reduces incidence and slows progression of prostate adenocarcinoma, but favors prostate tumors with neuroendocrine features (9,10). Thus, therapeutic targeting of mast cells (i.e., with imatinib; ref.…”

“…To study the contribution of mast cells to immunosuppression during prostate adenocarcinoma development, we used the TRAMP mouse model, in which prostate epithelium transforms because of the SV40 early genes [small and large T antigens (Tag)] driven by the androgen-responsive rat probasin regulatory element. Selective Tag expression in the prostate epithelium starts at puberty (17), driving progressive development of dysplasia, prostate intraepithelial neoplasia (PIN; weeks [6][7][8][9][10][11][12][13][14][15][16], adenocarcinoma (weeks [16][17][18][19][20][21][22][23][24][25], and lymph node and lung metastases (weeks [18][19][20][21][22][23][24][25][26][27][28][29][30], resembling the human pathology (18). A small percentage of TRAMP mice also develop neuroendocrine prostate cancer (19), an aggressive form of disease that in patients is associated with resistance to therapies and poor prognosis (20).…”

Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

“…Contrasting roles of MCs in supporting or inhibiting tumor progression have been reported ( 131 ). In solid neoplasms including thyroid, gastric, pancreatic, bladder cancers, prostate adenocarcinomas, and hematological malignancies, MCs have been associated with protumorigenic activity ( 69 , 131 , 137 ). In breast cancer ( 131 ) and in murine model of prostatic neuroendocrine tumors ( 137 ), MCs have antitumor activities.…”

hsa-miR-301a- and SOX10-dependent miRNA-TF-mRNA regulatory circuits in breast cancer

“…This tight regulation among miRNA-TF affected the cancer-related target genes HOXA3, KIT, and NFIB. The well-known regulation of these target genes in different cancers (Moon et al, 2011;Jachetti et al, 2017;Zhang et al, 2017) and validation of them to be downregulated in breast tumor samples by an independent microarray dataset support the idea of the systems biology approach in cancers originating from different tissues.…”