Neuroendocrine differentiation in the progression of prostate cancer

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Neuroendocrine differentiation in the progression of prostate cancer

    Neuroendocrine differentiation in the progression of prostate cancer

    1,2Akira Komiya,

    2Hiroyoshi Suzuki,

    2Takashi Imamoto,

    2Naoto Kamiya,

    2Naoki Nihei,

    2Yukio Naya,

    2Tomohiko Ichikawa,

    1Hideki Fuse

    Article first published online: 28 OCT 2008

    DOI: 10.1111/j.1442-2042.2008.02175.x

    ? 2008 The Japanese Urological Association


International Journal of Urology

    Volume 16, Issue 1, pages 3744, January 2009

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    Komiya, A., Suzuki, H., Imamoto, T., Kamiya, N., Nihei, N., Naya, Y., Ichikawa, T. and Fuse, H. (2009), Neuroendocrine differentiation in the progression of prostate cancer. International Journal of Urology, 16: 3744. doi: 10.1111/j.1442-2042.2008.02175.x Author Information


    Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, and


    Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan

*Correspondence: Akira Komiya, MD, PhD, Associate Professor of Urology, Department of Urology, Graduate School of Medicine and

    Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, Japan. Email:

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    Issue published online: 29 DEC 2008 Article first published online: 28 OCT 2008 Received 1 August 2008; accepted 19 August 2008. SEARCH

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    hormone-refractory prostate cancer;

    hormone therapy;

    neuroendocrine differentiation;

    prostate cancer

    Jump to…


    Neuroendocrine (NE) cells originally exist in the normal prostate acini and duct, regulating prostatic growth, differentiation and secretion. Clusters of malignant NE cells are found in most prostate cancer (PCa) cases. NE differentiation (NED) is the basic character of the prostate, either benign or malignant. NE cells hold certain peptide hormones or pro-hormones, which affect the target cells by endocrine, paracrine, autocrine and neuroendocrine transmission in an androgen-independent fashion due to the lack of androgen receptor. NED is accessed by immunohistochemical staining or measurement of serum levels of NE markers. The extent of NED is associated with progression and prognosis of PCa. Chromogranin A (CGA) is the most important NE marker. In metastatic PCa, pretreatment serum CGA levels can be a predictor for progression and survival after endocrine therapy. It is recommended to measure longitudinal change in serum CGA. The NE pathway can also be a therapeutic target.

    Jump to…


    Prostate cancer (PCa) is a leading cause of cancer deaths in Western countries and its incidence is also among the most rapidly increasing cancers in Japanese men. Many clinical, endocrinological, pathological, and genetic prognostic factors have been used for the management of

    16PCa. Understanding these factors will help to individualize PCa. Recently, increasing attention has been given to neuroendocrine (NE)

    719differentiation of PCa and its diagnostic, prognostic and therapeutic usefulness is recognized more widely. NE cells are

    20androgen-independent because of their negative androgen receptor expression; therefore, the NE pathway is thought to be one of the most

    21important mechanisms for hormone-refractory PCa.

    In this review, we describe basic and clinical aspects of NE differentiation (NED) in PCa in order to help understand its definition, mechanisms, functional roles and application to clinical management of PCa patients.

    Jump to…

    Neuroendocrine cells in the normal prostate

    2224Epithelium of prostatic ducts and acini consist of several kinds of cell. These include luminal secretory, basal and NE cells. As originally

    25described by Pretl in 1944, NE cells with the dual properties of endocrine and neurons, namely; acting in secretory and autocrine/paracrine

    fashions, are widely distributed throughout the normal prostatic acini and ducts. Although very little is known about the presence of NE cells of

    the developing prostate, recent studies have indicated that NE, basal and secretory luminal cells originate from a common endodermal

    262829pluripotent stem cell. According to Aprilian et al., double-labeling and serial section immunohistochemistry demonstrated the coexpression

    30of prostate specific antigen (PSA) in NE cells, suggesting a common precursor cell of origin. On the other hand, Aumuller et al. reported that human prostate NE cells were found to represent a cell lineage of their own, being of neurogenic origin and therefore distinct from the urogenital sinus-derived prostate secretory and basal cells. The secretory epithelial and NE cells may interact in a paracrine fashion with the stroma. There are two types of NE cells: (i) the open cells with extensions at their apex that connect with the lumen; and (ii) closed cells with dendritic-like processes that extend between adjacent cells, resting on the basal lamina and in close topographical relationship with nerves (Fig. 1). It is thought that via a variety of secretory products they form a communication network involved in cell regulation. The physiological role of prostatic NE cells is unknown, but these cells are supposed to be involved in the regulation, differentiation and secretion of the prostate. Prostatic NE cells contain dense-core cytoplasmic granules that store peptide hormones and pro-hormones. Therefore, NE cells are detected by immunohistochemical staining (IHS) using antibodies against these substances instead of conventional hematoxylin/eosin staining. These granules contain either a single product or a mix of different products such as chromogranin A (CGA), neuron-specific enolase (NSE), chromogranin B, somatostatin, human chorionic gonadotropin, thyroid-stimulating hormone, parathyroid hormone-related protein, bombesin, and calcitonin gene family (calcitonin, katacalcin, and calcitonin gene-related peptide). Furthermore, relatively high levels of several peptides are found in the seminal fluid. The majority of these products also can be released into the blood stream and measured by immunoassay

    7,8,10,12,15,1710,12,31techniques. Among these, CGA and NSE are the most intensively studied and thought to be the best markers of prostatic NED. The peptide hormones or pro-hormones are released from the NE cells by fusion of the granules with the cell membrane and exocytosis of the content. The target cells may be affected in four different ways: (i) endocrine transmission; (ii) paracrine transmission; (iii) autocrine

    1517 transmission; and (iv) neuroendocrine transmission, which make NE cells possible to regulate prostatic growth, differentiation and secretion.More importantly, normal prostatic NE cells lack the proliferation-associated Ki-67 and MIB-1 antigens, and therefore, are fully differentiated

    32,33postmitotic cells and have no androgen receptor expression, indicating that NE cells are androgen insensitive.

    Figure 1. Neuroendocrine cells in the normal prostate.

Jump to…

    Neuroendocrine differentiation in prostate cancer Neuroendocrine differentiation is one of the unique features of PCa. The concept of NED in PCa has become more widely recognized and has attracted considerable attention as a potential new finding with major diagnostic, prognostic and therapeutic implications. However, there is no accepted definition of NED of PCa. NED is often characterized by scattered clusters of differentiated NE cells among a predominant population

    34,35of adenocarinoma cells, except for rare cases of total NED of PCa (i.e. small cell carcinoma or carcinoid). Most of these NE cells contain serotonin and, less frequently, calcitonin, somatostatin, or human chorionic gonadotropin. Ectopic hormonal secretion is not evident in most

    34cases. Malignant NE cells are usually determined by IHS for certain NE markers such as NSE and/or CGA, which are produced by NE cells.

    11,19,23Using IHS, NE cells were identified in approximately 10100% of PCa tissues. This large discrepancy in prevalence between studies can

    be partially explained by the lack of quantitative and consistent tissue-imaging techniques. By using double staining of MIB-1 and CGA, proliferative activity of malignant NE cells are positive but very weak. In contrast, small cell carcinoma of the prostate has a very high index of

    36proliferation. Due to the lack of androgen receptor expression, malignant prostatic NE cells are independent from androgen regulation.

    Therefore, malignant NE cells are thought to play an important role in androgen-independent progression of PCa.

    Jump to…

    Molecular mechanism and roles of NED in PCa

How prostate cancer obtains NED is unclear. However, it is said that hormone therapy itself induces NED in PCa cells. This supports the

    hypothesis that NE cells are derived from the non-NE secretory-type cancer cells. Interleukin-6 (IL-6) can regulate cell growth and NED in

    LNCaP cells by binding either to membrane or to soluble IL-6 receptors activating multiple signaling pathways, such as signal transducer and

    activator of transcription (STAT-3), mitogen activated protein kinases (MAPKs), cyclic AMP-dependent protein kinase (PKA) and

    3740phosphatidylinositol 3-kinase (PI3K) dependent signaling pathways. It has been demonstrated that IL-6-induced NE transdifferentiation in

    384041PCa cells had a significant inhibitory effect on tumor growth. Recently, Wu et al. showed that the phosphatidylinositol

    3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is essential for NED in PCa. Androgen deprivation of LNCaP, an

    42androgen-dependent PCa cell line, induced NED as well as the activation of ERK and the PI3K-AKT-mTOR signaling pathways. But only PI3K-AKT-mTOR was required for NED. A constitutively active AKT promoted NED. Activation of AKT by IGF-1 leads to NED, and NED

    43induced by epinephrine requires AKT activation. Rapamycin, an inhibitor of mTOR, significantly inhibited the expression of NSE in LNCaP cells induced by androgen withdrawal.

    44An increased proliferation has been demonstrated in close relation to NE tumor cells in PCa. Ki-67 labeling index represents proliferation and

    45,46is also an independent prognostic factor in specimens of prostate biopsy or radical prostatectomy. Grobholz et al. examined the influence of

    NED in proliferation in PCa using Ki-67 expression as proliferation index. It was demonstrated that PCa with high NED had higher Ki-67

    47expression as compared with PCa with low NED or without NED. A significant and clustered NED in PCa may lead to an increased proliferation and earlier tumor progression, whereas few and solitary NE tumor cells have no prognostic effect.

    48 showed that CGA fragment 286301, which was the C-terminal of pancreastatin, enhanced the invasive potential of PC-3 Nagakawa et al.

    and DU-145 PCa cells in vitro. CGA (286301) also increased the haptotactic migration of these cells and the production of urokinase-type

    49plasminogen activator. The same group also analyzed the effect of prostatic neuropeptides on migration of prostate cancer cells. Using invasion assay, it was shown that gastrin-releasing peptide, calcitonin gene-related peptide, and parathyroid hormone-related protein increased

    invasive capacity of PCa cells.

    50,5152In addition, Uchida et al. revealed the role of NE cells in metastasis of PCa. The allograft of NE-10, mouse NE cancer model, promoted

    pulmonary metastasis of subcutaneously inoculated LNCaP cells by facilitating cell invasion without any change in proliferation of LNCaP.

    Secretions from NE cells upregulated the expression of gelsolin, which is an actin-binding protein, resulting in acceleration of the migration of

    LNCaP cells. These results indicate that NE products affect proliferation, invasion and metastasis of PCa cells. Jump to…

    Immunohistochemical staining of NE markers in prostate cancer

    53An IHS study by Allen reported that NE cells were more common in higher grade and stage disease, but 5-year survival did not differ significantly between patients with NE cell-positive and -negative tumors using 160 consecutive patients with PCa. On the other hand,

    54McWilliam et al. found NED in 52% of prostate cancer tissues by IHS for CGA and NSE. They also demonstrated a significant correlation of

    55NED with worsening tumor differentiation, the presence of bone metastasis and with poor patient survival. Weinstein et al. reported that NED

    defined by IHS using CGA was an independent prognostic factor for biochemical progression in clinical organ-confined PCa treated by radical

    56prostatectomy. Kokubo et al. showed that 22% of stage D2 prostate cancer overexpressed CGA by IHS, and that CGA positivity was related to shorter time to recurrence after hormone therapy. CGA expression was not correlated with age, PSA level, Gleason score, extent of bone

    11metastasis, clinical T stage nor N stage. Most recently, Kamiya et al. demonstrated that the cause-specific survival was significantly poorer after hormone therapy in stage D2 PCa with strongly positive staining for independent CGA and combined CGA with NSE. Furthermore,

    multivariate analysis of cause-specific survivals in patients with stage D2 PCa demonstrated that IHS of strong staining for NE markers were

    considered as independent variables associated with greater risk of death. From these results, NED detected by IHS can predict the prognosis

    of PCa patients.

    Jump to…

Serum neuroendocrine markers in prostate cancer

    Instead of IHS, the measurement of serum NE markers constitutes a more representative indicator and more objective quantification of

    19significant NED of tumors, as it corresponds to the entire primary tumor cell population and its associated metastases. The majority of NE

    products can be released into the blood stream and measured using immunoassay techniques. Out of the NE markers, CGA and NSE are

    commonly expressed in neuroendocrine prostatic carcinoma. Recently, we and others reported that pretreatment serum NE markers such as

    12,57CGA, NSE and Pro-GRP were potentially prognostic markers for metastatic PCa patients hormonally treated.

    It is known that serum CGA is elevated in various types of endocrine neoplasms, including pheochromocytoma, pancreatic islet cell tumors,

    carcinoid tumors and medullar carcinoma of the thyroid. It was also reported that other diseases or drugs, such as renal impairment or proton

    958607pump inhibitors, could influence CGA levels. In recent years CGA has been recognized as a useful marker of these tumors. Angelsen et al.

    noted that 91% of prostate glands had NE cells and PCa patients with CGA-positive tumor cells had elevated serum CGA, although

    immunohistochemical findings and serum levels of other NE markers, such as NSE, chromogranin B, thyroid stimulating hormone and

    pancreastatin, did not correlate, suggesting that CGA should be a useful marker for predicting the extent of NED in prostatic tumors. Due to

    improved measuring techniques, it has become easier to measure serum or plasma CGA and the results have become more reliable. Wu

    61et al. reported that CGA should be used as a marker for NED and an early elevated serum level indicates resistance to hormone therapy.

    16Kadmon et al. reported that 48% of patients with stage D2 PCa had elevated serum CGA and the level in some closely paralleled the clinical

    61course. Wu et al. noted that serum CGA was elevated in patients who did not undergo hormone therapy and the serum level enabled the early

    detection of hormone therapy resistance in PCa, although the serum concentration in those with BPH overlapped considerably with that of men

    12with PCa. Isshiki et al. have shown that mean serum CGA in PCa and benign prostatic hyperplasia cases was 59.4 and 59.3 ng/mL,

    respectively (no significant difference); however, poorly differentiated adenocarcinoma was associated with higher CGA than well differentiated

    disease (P = 0.044). More importantly in the same study, of the stage D cases with a median PSA of 172.1 ng/mL or less, those with higher

    CGA had a poorer prognosis than those with lower CGA. Therefore, CGA in combination with PSA may effectively predict a poor prognosis

    after hormone therapy in stage D2 PCa.

    Circulating NSE in PCA was also studied as CGA. A few have failed to demonstrate any clinical significance of serum NSE level in the

    15pathogenesis of prostate cancer. Tarle et al. examined serum concentrations of NSE in PCa patients and suggested that NED, as reflected by

    an increase in serum concentrations of these NE secretory products, correlated with androgen independence and poor prognosis. In addition,

    another study reported that elevated NSE and CGA levels were predictors for poor prognosis in patients with hormone-refractory prostate

    10cancer, whereas CGA appears to reflect the NE activity of PCa rather than NSE. Kamiya et al. demonstrated that poor survival in metastatic patients with higher NSE level and no significant correlation among serum levels of PSA, NSE and CGA. Multivariate analysis of cause-specific

    survival in patients with metasitatic PCa, serum NSE showed the highest risk (18.3, P = 0.0064) for poor survival after hormone therapy among

    62other variables including extent of disease of bone metastasis (relative risk 10.3, P = 0.029), serum CGA (8.72, P = 0.024), serum PSA,

    histological grade, response to hormone therapy (latter three were not significant). Therefore, serum NSE can be the strongest prognostic

    factor for metastatic prostate cancer hormonally treated. When both of the serum levels of NSE and CGA were combined, patients with

    elevated NSE as well as CGA had the worst survival as compared with the others. Their survival was less than 27 months (Fig. 2).

    Figure 2. Cause-specific survival curves in patients with stage D prostate cancer according to the serum levels of neuron-specific enolase (NSE)

    and chromogranin A (CGA) (unpublished data). ?: higher than median level of NSE or CGA. ?: lower than or equal to median level of NSE or

    CGA. P < 0.0004.

Gastrin-releasing peptide (GRP), a mammalian homolog of the amphibian peptide bombesin, is composed of 27 amino acids and is widely

    22distributed throughout the mammalian nervous system, gastrointestinal tract, pulmonary tract, and prostatic neuroendocrine cells. GRP is

    initially synthesized as amino acids 127 of a 125-residue precursor, ProGRP, and is subsequently cleaved and amidated to form GRP18-27.

ProGRP has a longer half-life than GRP and is detectable in serum at levels similar to those of GRP itself. This enables detection by means of a

    6364,65clinically applicable ELISA kit. Serum levels of ProGRP is extensively measured in the studies of lung cancer patients. From the finding of

    6657recent reports, serum ProGRP is also thought to be a useful diagnostic and therapeutic marker for PCa. Nagakawa et al. and Yashi et al.

    measured its level in patients with PCa. The mean serum levels of ProGRP in patients with distant metastasis and hormone-resistant PCa were

    67significantly elevated compared with those in patients with organ-confined disease. Yashi et al. demonstrated that elevated serum ProGRP level is a predictor of short response duration after hormonal therapy in metastatic PCa. A weak positive correlation between serum PSA and

    ProGRP values was found (rs = 0.268, P = 0.0311) when patients with pure NE carcinoma were excluded. Jump to…

    Changes in serum NE markers during androgen deprivation therapy in PCa CGA and NSE

    As described above, among many NE markers, CGA and NSE serum levels are most frequently reported. Furthermore, longitudinal changes in

    68the CGA serum levels are described in recent published reports. Sciarra et al. reported increasing CGA serum levels in continuous androgen deprivation therapy in pT3 PCa with PSA progression after radical prostatectomy. It was described that the CGA slope was 0.60 ng/mL per

    month with castration therapy, whereas it was 0.29 in bicalutamide monotherapy in pT3 patients. CGA velocity was not shown among patients

    undergoing combined androgen blockade in their study. Their follow-up period was 24 months and their findings did not include hormone

    refractory PCa. A few studies have reported the progress of serum NE markers. Changing levels of CGA and NSE were shown among the

    69hormone refractory patients undergoing palliative radiation therapy to bone metastases by Hvamstad et al. Serum NSE value was decreased,

    70whereas CGA and PSA were increased after radiation. Terle et al. observed 15 months of PCa, and revealed statistically significant

    31CGA-positivity in the last 6 months in hormonally treated patients when compared with the untreated group (P < 0.001). Sasaki et al.

    evaluated the changing levels of CGA including hormone refractory PCa for the average follow-up period of 4 years. During hormone therapy in

    metastatic PCa patients, serum CGA values were not related to serum PSA levels. Serum CGA increased as intervals of hormone therapy

    became longer with positive correlation (P < 0.05). Its velocity was higher in patients with PSA failure than in those without it (6.98 vs.

    2.09 ng/mL per month, P = 0.011). It is suggested that CGA velocity has the potential to predict androgen independent progression after

    hormone therapy. On the other hand, NSE serum levels showed no significant change during hormone therapy using the same cohort with

    Sasaki et al. (unpublished data).

    Table 1 summarizes the results from peer-reviewed journals about the changes in CGA during hormone therapy in PCa. When comparing

    these findings, it seems that NED progresses more rapidly if androgen deprivation is carried out more intensively. Defined by serum CGA levels,

    NED does not progress without treatment (watchful waiting/active surveillance) or during intermittent hormone therapy. On the other hand,

    maximal androgen blockade induced NED the most rapidly, especially in the more advanced cases. Table 1. Summary of changes in CGA serum value during hormone therapy in prostate cancer

    CGA change (ng/mL per Follow-up Pre-Tx Pre-Tx Authors Patients n Treatment month) (months) CGA PSA

    BPH, benign prostatic hypertrophy; CGA, chromogranin A; LH-RH, luetenizing hormone-releasing hormone; MAB, maximal androgen blockade; PSA, prostate-specific antigen; RP, radical prostatectomy; Tx, treatment.

    Stage C-D1 67 None ? (0) 15 38 14 70Tarle et al. 2002

    BPH 20 None ? (0) 15 41 5

    Sciarra et al. PSA failure after RP Anti-androgen 24 ? (0.29) 24 36 6 682004 (pT3) monotherapy

Table 1. Summary of changes in CGA serum value during hormone therapy in prostate cancer

    CGA change (ng/mL per Follow-up Pre-Tx Pre-Tx Authors Patients n Treatment month) (months) CGA PSA

    PSA failure after RP LH-RH agonist 24 ? (0.60) 24 33 6 (pT3) monotherapy

    PSA failure after RP 20 MAB ? (0.83) 24 38 1.3 (pT3) Sciarra et al.

    712003 Stage D2 20 MAB ? (1.00) 24 73 41

    Stage D2 20 Intermittent ? (0)

    Stage D2 All 38 MAB ? (4.04) 47.1 108 1941

    Sasaki et al. Stage D2 17 ? (6.97) 312004

    CR,PSA failure


    57In the study by Yashi et al., change in serum ProGRP was analyzed. During hormone therapy, the decrease in ProGRP value after hormonal

    treatment was observed in serial measurements of the marker in patients with Stage D disease when compared between the initial value and

    values obtained 4 months after hormonal treatment. Longitudinal change in serum ProGRP had no certain patterns and did not parallel the

    serum levels of PSA.

    Jump to…

    Neuroendocrine-targeted therapy

    Somatostatin analogs

    It was shown that somatostatin is likely to counteract NE and other growth regulatory systems through somatostatin receptors (SSTR)

    expressed on secretory, NE, stromal and endothelial prostatic cells. The potential mechanisms of SSTR antitumor effects include inhibition of

    72angiogenesis, proliferation and promotion of apoptosis. Moreover, somatostatin analogs have a wide therapeutic index and they are

    73apparently free of major side effects. Most reported side effects are gastrointestinal in nature, including minor nausea, diarrhea and constipation. Somatostatin is the only NE substance to inhibit NE activity. There are two somatostatin analogs available in clinical use.

    7477Octreotide has no satisfying results in published reports. Hormone-refractory prostate cancer (HRPC) had minor response to Lanreotide

    78,79monotherapy. In combination with dexamethasone, Koutsilieris et al. reported PSA and symptomatic response in 90% of studied HRPC

    80,81patients with 7 months progression-free survival. By using Lanreotide therapy with ethinylestradiol, Di Sillverio and Sciarra demonstrated

    82PSA and symptomatic response in 90% of studied HRPC patients with 18.5 months progression-free survival. During this treatment or even after treatment failure, serum CGA is decreased and kept in the normal range. Somatostatin analog in combination with other agents has a

    83certain role in the treatment of hormone-refractory prostate cancer.

    Bombesin antagonists

    The physiologic effects of bombesin/Gastrin-releasing peptide (GRP) are related to androgen-dependent growth, invasiveness, metastatic

    8489potential and the presence of its receptor and intracellular signal pathways in PCa tissues. Most human prostate cancers (91%) express the

    90mRNA of the GRP receptor, suggesting that bombesin/GRP plays a significant role in conventional prostate cancer progression. Jungwirth

    et al. tested bombesin/GRP antagonist RC-3940-II and revealed its marked inhibitory effect on the growth of the androgen-independent PC-3

    91human prostate cancer cell line xenografted into nude mice. Stangelbergere et al. developed a powerful cytotoxic analog of bombesin AN-215,

    92which was able to decrease the ratio of Bcl-2/Bax in DU-145 and the expression of antiapoptotic Bcl-2 in LuCaP-35 tumors. Therefore,

    93,94bombesin-like antagonists could become an effective treatment option in the future.

    Serotonin antagonists

    Neuroendocrine cells produce and secrete 5-HT, a biogenic amine, neurotransmitter and potent mitogen associated with prostate cancer

    95growth. It has been demonstrated that 5-HT receptors (5-HTR) are overexpressed in HRPC tissues and in PCa cell lines. Recent

    18,93,9698investigations show promising results using 5-HTR antagonists. Dizeyi et al. demonstrated that 5-HTRs were present at various tumor

    99stages and that antagonists to these receptors could inhibit the proliferative activity of androgen-independent PCa cell lines, Du-145.

    mTOR inhibitor

    The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth, and apoptosis. Alterations in the pathway regulating mTOR occur in many solid malignancies including prostate, bladder, and kidney cancer; in vitro and in vivo models of

    100prostate have established the importance of the mTOR pathway in the control of cancer progression and metastasis. As described above, NED is activated via the PI3K-AKT-mTOR pathway, and rapamycin, an inhibitor of mTOR, significantly inhibited the expression of NSE in

    41LNCaP cells under androgen suppression. Growth and clonogenic survival of Du-145 and PC-3 cell lines were inhibited in a dose-dependent

    101manner by the rapamycin analog CCI-779. This agent also inhibited the growth of xenografts derived from both cell lines with greater effects

    against PC-3 than DU145 tumors.

    Chemotherapy to small cell carcinoma of the prostate Small-cell neuroendocrine carcinoma has been recognized as a rare histological variant occurring in only 0.5% to 2.0% of prostatic primary tumors. However, recent autopsy studies suggest development to this phenotype in up to 10% to 20% of the cases with hormone-refractory

    102 In approximately 50% of the cases, the tumors are mixed small-cell carcinoma and adenocarcinoma of the prostate. Most small-cell state.

    tumors of the prostate lack clinically evident hormone production. However, this type of tumor accounts for the majority of clinically evident

    35,103adrenocorticotropic hormone or antidiuretic hormone production in prostatic tumor Small-cell carcinomas of the prostate are thought to be

    104identical to small-cell carcinomas of the lung. Therefore, similar cisplatin-based cytotoxic agents to small-cell carcinoma of the lung are

    105usually applied such as irinotecan (CPT-11) + cisplatin (CDDP), or etoposide (VP-16) + cicplatin (CDDP).Figure 3 shows a case of small cell carcinoma of the prostate treated at Chiba University Hospital.

    Figure 3. A case of small-cell carcinoma of the prostate. 53-year-old Japanese man with initial prostate-specific antigen (PSA) of 1.02 ng/mL and neuron-specific enolase (NSE) of 13.38 ng/mL was treated with four cycles of irinotecan (CPT-11) + cisplatin (CDDP). (a) Change in serum NSE levels, which normalized after the second cycle. (b) An initial image of magnetic resonance imaging (MRI) (T2). Most of the prostate was replaced by tumor. (c) MRI after the fourth cycle. Nearly complete remission was attained.

    106,107Cisplatin-based chemotherapy was reported to have significant activity in patients with poorly differentiated NE tumors other than prostate.

    On the other hand, chemotherapy using docetaxel and CDDP for conventional androgen-independent PCa had limited response for NE marker;

    108serum CGA and/or NSE decrease was observed in 13/41 cases (33%) with a median duration of 4 months. Two studies described NE response rates for assessing treatment efficacy in patients with metastatic androgen-independent PCa who received oral estramustine;

    8,109however, response rates were below 20%.

    Jump to…

    Future prospects

    When treating prostate cancer with androgen deprivation therapy, one should evaluate NED especially in those with advanced stage but with relatively lower serum PSA. It is important to keep in mind that the NE pathway is one of the key mechanisms of hormone-refractory prostate cancer and hormone therapy itself induces NED. Pretreatment measurement of serum CGA, NSE and ProGRP can predict prognosis after hormone therapy. IHS of CGA remains a useful tool because it is easy to access and available in most hospitals, even in Japan. It can be recommended to measure serial CGA serum levels to predict treatment failure during hormone therapy. If intensive NED is identified, one

    110,111should consider milder androgen deprivation therapy like intermittent androgen deprivation or antiandrogen monotherapy to slower NED

    and/or NE targeted therapy. Although NE-targeted therapies such as serotonin, or bombesin analogs are still under development, combination therapies with somatostatin analog are promising.

    Jump to…



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