The relationship of neuroendocrine carcinomas to anti-tumor therapies in TRAMP mice.
BACKGROUND
Neuroendocrine differentiation and neuroendocrine carcinoma (NEC) have been linked to androgen deprivation in prostate cancers. No previous study has directly connected neuroendocrine phenotypes to chemotherapy. The pathogenesis of prostatic NEC has not yet been determined.


METHODS
Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we studied tumor progression after hormone ablation (castration) and/or chemotherapy (docetaxel), and analyzed the incidence of NEC as a function of the anti-tumor therapies. Non-treated mice were used as controls. Protein expressions in tumor tissues were analyzed by Western blots and immunohistochemistry.


RESULTS
Although all animals developed prostate cancer, no NEC was found in control mice. However, over 30% of the mice that received an anti-tumor therapy developed NEC. A similar incidence of NEC was found in the castration-only and docetaxel-only treatment groups, while a higher incidence was observed in the combined treatment (castration and docetaxel) group. The NEC-bearing mice had smaller tumors in their prostates and lived longer than mice with adenocarcinoma (ADC-only). However, NEC tumors had a higher proliferative index and greater potential for metastasis and drug-resistance, as evidenced by significantly higher expression levels of PCNA, S100A4, and Pgp, but lower levels of E-cadherin. SV40 T-antigen was highly expressed in both NEC and ADC tumors.


CONCLUSIONS
Stress induced by anti-cancer treatments may play a role in NEC development. Although NEC and ADC differ in their expressions of many proteins, a high level of SV40 T-antigen in both tumor types suggest a common progenitor..
Tang
Yao
Y
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Wang
Linbo
L
Goloubeva
Olga
O
Khan
Mohammad Afnan
MA
Lee
Dongik
D
Hussain
Arif
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D018278:Carcinoma, Neuroendocrine / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D049109:Cell Proliferation; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D015994:Incidence; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects*
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D043823:Taxoids; D000077143:Docetaxel