NE Differentiation Research Articles

Bedeutung der neuroendokrinen Differenzierung im Prostatakarzinom

NE tumor cells are present in virtually all prostatic adenocarcinomas. As they express no androgen receptor they are hormone independent. During anti-androgenic therapy their number increases. Their prognostic value is controversial. In 233 patients with prostatic carcinoma the NE differentiation was determined in a hot spot (7.9 mm(2)) with maximum CgA positive cell density. A high NE differentiation (HNE) was defined by a least 30 NE tumor cells, while less means a low NE differentiation (LNE). In addition the occurrence of NE tumor cells was defined as solitary or clustered (> or =5 NE tumor cells in close proximity). In advanced and high grade tumors more and clustered NE tumor cells could be found than in low grade and organ confined tumors. Moreover HNE tumors and occurrence of NE clusters resulted in a significant shorter progression-free interval. Besides the quantity of NE differentiation the quality of the growth pattern of NE tumor cells is of relevance in prostatic carcinoma.

Androgen ablation promotes neuroendocrine cell differentiation in dog and human prostate.

Mechanisms triggering prostatic NE differentiation are poorly understood. Since dog and man naturally develop prostatic proliferative diseases with age, our objectives were to confirm the presence of NE cells in the dog prostate and test their hormonal regulation in both species. Serotonin staining was examined by immunohistochemistry in 37 dog prostates: 17 from intact and 20 from castrated animals. In intact dogs, 9 prostates were normal and 8 hyperplastic. In the castrated group, 6 dogs were left untreated while androgens and estrogens were administered to 7 dogs, each. Human prostates were from 48 prostate cancer patients; half of them were submitted to androgen ablation prior to prostatectomy. The density of serotonin-positive NE cells was expressed relatively to the number of acini. Serotonin-positive NE cells were morphologically similar in dog and human prostates and identified in all groups, independent of the hormonal status. NE cell densities were within the same range in normal and hyperplastic dog prostates but significantly higher after castration. Androgens and estrogens after castration restored NE cell density to normal values and induced luminal differentiation and basal metaplasia, respectively. In human, the density of serotonin-positive NE cells was also significantly higher in benign glands after androgen ablation. The dog is a suitable animal model and mimics the human, since androgen ablation favored prostatic NE differentiation in both species. The down-regulation elicited by steroids suggests that the process may be reversible and hormonally-repressed.

Study on the specific expressions of p53, bcl-2 and c-myc in non-small cell lung cancer with neuroendocrine differentiation

To study the specific expression of tumor-related genes (p53, bcl-2 and c-myc) in non small cell lung cancer with neuroendocrine differentiation (NSCLC-NE). The expression of neuron-specific enolase (NSE), chromogranin A (CgA), synaptophysin(Syn), c-myc, bcl-2 and p53 was detected in 60 surgically resected and paraffin-embedded non-small cell lung cancer (NSCLC) specimens by immunohistochemistry (S-P method). The positive rates of NSE, CgA, Syn expressed in 60 cases of NSCLC were 45.00%(27/60), 13.33%(8/60), 31.67% (19/60) respectively. According to the results of these three markers, 41.67%(25/60) of 60 specimens was proved to be as NE differentiation cancer. The NE differentiation in NSCLC was remarkably related to differentiation of tumor cells (P < 0.05). NSCLC-NE had a higher metastatic rate (P < 0.05) and a higher clinical staging (P < 0.05) than NSCLC without NE differentiation. The positive rates of bcl-2, p53 and c-myc expression in NSCLC-NE were 68.00% (17/25), 80.00% (20/25), 68.00% (17/25) respectively, and the expression of bcl-2 and p53 was closely related to NE differentiation (P < 0.05). A certain part of NSCLC have NE differentiation, which has different biological features from NSCLC without NE differentiation. High expression of bcl-2 and mutant p53 can be observed in NSCLC-NE, and bcl-2/Bax unbalance associated with p53 mutation may play an important role in oncogenesis and development of NSCLC-NE.

Peptidylglycine alpha-amidating monooxygenase- and proadrenomedullin-derived peptide-associated neuroendocrine differentiation are induced by androgen deprivation in the neoplastic prostate.

Most PCs show NE differentiation. Several studies have tried to correlate NE expression with disease status, but the reported findings have been contradictory. Prostatic NE cells synthesize peptides with a wide spectrum of potential functions. Some of these active peptides, such as PAMP, are amidated. PAM is the only carboxy-terminal peptide-amidating enzyme identified. We studied expression of PAMP and PAM in normal prostate and prostatic tumors (clinical specimens and human xenograft models) with or without prior androgen-deprivation therapy and found a wide distribution of both molecules in NE subpopulations of all kinds. Although the correlation of either marker to tumor grade, clinical progression or disease prognosis did not reach statistical significance, PAMP- or PAM-immunoreactive cells were induced after androgen-blockade therapy. In the PC-310 and PC-295 androgen-dependent models, PAMP or PAM NE differentiation was induced after castration in different ways, being higher in PC-310, which might explain its long-term survival after androgen deprivation. We show induction of expression of 2 new NE markers in clinical specimens and xenografted PC after endocrine therapy.

Expression of the gastrin‐releasing peptide gene in carcinomas of the breast

Expression of gastrin-releasing peptide (GRP), the mammalian homologue of the amphibian bombesin, has been investigated at gene and protein level in a series of 28 primary breast carcinomas, in 6 mammary cancer cell lines and in one transplantable rat mammary carcinoma. Moderate to strong expression of GRP mRNA was detected in 5 breast carcinomas by Northern blot analysis with a pre-pro-GRP probe; 4 other cases were weakly reactive. Two of these cases also gave a specific immunocytochemical reaction for GRP, controlled with absorption experiments. Correlation with NE differentiation [as shown by chromogranins (Cg) and/or NSE and/or Grimelius positivity] was low, since only one case of breast carcinoma co-expressed GRP and Cg mRNAs. Breast cancer cell lines and a rat carcinoma gave negative results. GRP production in breast cancer did not appear to bear prognostic implications, but longer follow-up periods are needed to confirm these data. As shown in small-cell lung cancer, GRP might be involved in autocrine growth control mechanisms of a group of breast carcinomas.