Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroendocrine differentiation and subsequent excretion of neuropeptides have been demonstrated to be associated with progression of human prostate cancer. Among neuropeptides found to exist in the prostate, bombesin/gastrin-releasing peptide has been shown to upregulate matrix metalloproteinase-9 (MMP-9) in human prostate cancer cell lines. Expression levels of bombesin, MMP-9, and neuron-specific enolase were examined by immunohistochemistry in 41 cases of clinically organ-confined prostate cancers including 9 with microscopic lymph node metastases. Twenty-seven (64%) of the 41 radical prostatectomy specimens were positive for both MMP-9 and bombesin. Expression of these molecules was observed in almost the same population of the cancer cells. The remaining 14 cases were negative for both MMP-9 and bombesin. High-grade tumors (Gleason sum > or = 7) were more likely to express MMP-9 and bombesin (21/24:88%) than low-grade tumors (Gleason sum > or = 6) (7/17:41%). In eight of the nine cases with pathological lymph node metastases, expression of MMP-9 and bombesin was also noted in metastatic sites. Neuron-specific enolase was positive in 16 cases (39%) and not always associated with the expression of bombesin. Expression of bombesin and expression of MMP-9 are common in human prostate cancers and may be related to an aggressive phenotype.
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PMID:Expression of matrix metalloproteinase-9 and bombesin/gastrin-releasing peptide in human prostate cancers and their lymph node metastases. 1219 49

Bombesin (BN) and its mammalian homologue gastrin-releasing peptide (GRP) have been shown to play an important role in human cancer as autocrine and paracrine growth factors. Prostatic neuroendocrine cells are thought to secrete these regulatory peptides and they may therefore interact with their specific, aberrantly expressed GRP receptor (GRP-R) in prostate cancer. In this study, we investigated the effect of BN on immediate early gene expression in two androgen-independent prostate cancer cell lines DU-145 and PC-3 with functional GRP receptor. We found that BN induced c-fos mRNA expression in both cell lines in a time-dependent manner. In contrast, c-jun mRNA was only modestly induced in DU-145 cells but not at all in PC-3 cells. On the protein level, we detected BN-induced stimulation of the c-fos gene product but not of c-jun protein. Sustained increase of the c-myc gene product was detectable in PC-3 but not in DU-145 cells. Concurrently, we demonstrated BN-dependent activation of the transcription factor Elk-1 and significant increase of cell proliferation in both prostate cancer cell lines. Taken together, these data suggest that BN acts as a mitogen in prostate cancer and this might be associated with the activation of the transcription factor Elk-1 and the immediate early gene c-fos.
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PMID:GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells. 1240 26

The majority of deaths from prostate cancer occur in patients with androgen-insensitive metastatic disease. An important early event in the development of the metastatic phenotype is the induction of genes that promote angiogenesis, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), which are released from tumor cells into their microenvironment. Coincident with progression from prostatic carcinoma in situ to metastatic disease is an increase in the number of tumor cells exhibiting neuroendocrine (NE) differentiation. NE cells express a variety of peptide hormones, including the bombesin (BBS)-like peptide, gastrin-releasing peptide (GRP), and its cognate receptor, GRP-R. Although there is a strong positive correlation between the degree of NE differentiation and the metastatic potential of prostate cancers, a mechanistic link between increased expression of peptide hormone receptors, such as GRP-R, and proangiogenic gene expression has not been established. Here we report that BBS stimulates nuclear factor kappa B (NF kappa B) activation and proangiogenic gene expression in the androgen-insensitive prostate cancer cells lines, PC-3 and DU-145. In PC-3 cells, BBS stimulation of GRP-R resulted in the up-regulation of IL-8 and VEGF expression through a NF kappa B-dependent pathway. We show that BBS treatment induced inhibitor of NF kappa B degradation, NF kappa B translocation to the cell nucleus, increased NF kappa B binding to its DNA consensus sequence, and increased IL-8 and VEGF mRNA expression and protein secretion. Treatment with the proteasome inhibitor, MG-132, blocked BBS-stimulated NF kappa B DNA binding, and IL-8 and VEGF expression and secretion. Finally, media collected from PC-3 cell cultures, after BBS treatment, stimulated an NF kappa B-dependent migration of human umbilical vascular endothelial cells in vitro. Together, our data demonstrate a role for BBS and GRP-R in the NF kappa B-dependent up-regulation of proangiogenic gene expression, and suggest a possible molecular mechanism linking NE differentiation and the increased metastatic potential of androgen-insensitive prostate cancers.
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PMID:Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells. 1283 33

Bombesin and its mammalian homologue gastrin-releasing peptide have been shown to be highly expressed and secreted by neuroendocrine cells in prostate cancer, and are thought to be related to the carcinogenesis and progression of this disease. We found, in this study, bombesin specifically induced mitogen-activated protein (MAP) kinase activation as shown by increased extracellular regulated kinase (ERK) phosphorylation and epidermal growth factor (EGF) receptor transactivation in prostate cancer cells, which express functional gastrin-releasing peptide receptor. The transactivation of EGF receptor was required for bombesin-induced ERK phosphorylation. Furthermore, non-receptor tyrosine kinase Src and cellular Ca2+ were shown to be involved in bombesin-induced EGF receptor transactivation and ERK phosphorylation. Inhibition of either EGF receptor transactivation or ERK activation blocked bombesin-induced DNA synthesis in these cells. Taken together, these data suggest bombesin may act as a mitogen in prostate cancer by activating MAP kinase pathway via EGFR transactivation.
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PMID:Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. 1287 8

Gastrointestinal (GI) hormones are chemical messengers that regulate the physiological functions of the intestine and pancreas, including secretion, motility, absorption, and digestion. In addition to these well-defined physiological effects, GI hormones can stimulate proliferation of the nonneoplastic intestinal mucosa and pancreas. Furthermore, in an analogous fashion to breast and prostate cancer, certain GI cancers possess receptors for GI hormones; growth can be altered by administration of these hormones or by blocking their respective receptors. The GI hormones that affect proliferation, either stimulatory or inhibitory, include gastrin, cholecystokinin, gastrin-releasing peptide, neurotensin, peptide YY, glucagon-like peptide-2, and somatostatin. The effects of these peptides on normal and neoplastic GI tissues will be described. Also, future perspectives and potential therapeutic implications will be discussed.
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PMID:Role of gastrointestinal hormones in the proliferation of normal and neoplastic tissues. 1457 Jul 43

Small neuropeptides, labeled with gamma- and/or beta-emitting radionuclides, are currently being investigated for their ability to bind to cell-surface receptors, overexpressed in a wide variety of malignant tissues being, thus, potentially useful for radionuclide detection and/or therapy for tumors. Particular attention has been focused on the amphibian peptide, bombesin (BN), and the molecularly related gastrin-releasing peptide (GRP). These peptides act as neurotransmitters and endocrine cancer cell-growth factors on normal tissues as well as on neoplastic cells of various origin. In recent investigations, modification of the native peptide structure has been attempted in order to obtain derivatives, which might easily be labeled with radionuclides. Thus, iodinated (I-125) BN derivatives, as well as Indium (In-111) labeled BN analogs are currently being investigated, presenting satisfactory tumor localization. Also, some new BN analogs containing a 6-carbon linker have been prepared and labeled with Rhenium-188, resulting in positive in vitro binding to prostate cancer cells. More recent studies refer to the Technetium-99m labeling of BN, performed either directly, after attaching proper technetium-chelating groups onto the BN sequence, or indirectly, by coupling BN to a preformed 99mTc-tagging ligand. Both types of conjugates were found to have a high in vitro affinity for cells with BN receptors, also presenting satisfactory in vivo uptake in experimental tumor models. Pilot clinical studies of a new BN-derived, 99mTc-labeled pentadecapeptide indicated significant uptake by breast cancer and invaded lymph nodes, as well as by prostate cancer, small-cell lung carcinoma, gastro-entero-pancreatic tumors, and others, Further studies of this new GRP derivative, as well as of other new BN-like peptides, are intensively performed internationally today.
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PMID:Gastrin-releasing peptide (GRP) analogues for cancer imaging. 1518 3

Work on cytotoxic analogs of luteinizing hormone-releasing hormone (LH-RH), somatostatin and bombesin, designed for targeting chemotherapy to peptide receptors on various cancers, is reviewed here as the project is at advanced stages of development and clinical trials are pending. Cytotoxic analogs of LH-RH, AN-152 and AN-207, containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201), respectively, target LH-RH receptors and can be used for the treatment of prostatic, breast, ovarian and endometrial cancers and melanomas. AN-201 was also incorporated into the cytotoxic analog of somatostatin, AN-238, which can be targeted to receptors for somatostatin in prostatic, renal, mammary, ovarian, gastric, colorectal and pancreatic cancers as well as glioblastomas and lung cancers, suppressing the growth of these tumors and their metastases. A cytotoxic analog of bombesin AN-215, containing 2-pyrrolino-DOX, was likewise synthesized and successfully tested in experimental models of prostate cancer, small cell lung carcinoma, gastrointestinal cancers and brain tumors expressing receptors for bombesin/gastrin-releasing peptide. This new class of targeted cytotoxic peptide analogs might provide a more effective therapy for various cancers.
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PMID:Chemotherapy targeted to cancers through tumoral hormone receptors. 1535 Jun 1

The bombesin (BN)/gastrin-releasing peptide (GRP) receptor is expressed in high density on the cell surface of a variety of tumors. This makes the receptors accessible as a molecular target for the detection of lesions in which they are expressed. In this study, we describe a high affinity hydrophilic (99m)Tc-labeled BN analogue, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN, having diethylenetriaminepentaacetic acid (DTPA), as a build-in pharmacokinetic modifier, to direct its excretion through the urinary system in order to lower abdominal background activity. In vitro binding studies using [(125)I-Tyr(4)]BN (K(d), 0.1 nM) and human prostate cancer PC-3 cell membranes showed that the inhibition constant (K(i)) of [DTPA(1), Lys(3)((99)Tc-Hx-DADT), Tyr(4)]BN was 19.9 +/- 8.0 nM. Biodistribution studies in normal mice showed fast blood clearance (0.15 +/- 0.01% ID/g, 4 h postinjection), low intestinal accumulation (9.16 +/- 2.35% ID/g, 4 h postinjection), and significant uptake in BN/GRP receptor rich tissues such as the pancreas (21.83 +/- 2.88% ID/g, 15 min postinjection). The pancreas/blood, pancreas/muscle, and pancreas/liver ratios were highest at 2 h postinjection at 23, 74, and 8.4, respectively. The uptake in the pancreas could be blocked by BN (11.96 +/- 1.17 vs 0.65 +/- 0.16% ID/g), partially blocked by neuromedin B (11.96 +/- 1.17 vs 6.66 +/- 0.51% ID/g), but not affected by somatostatin (11.96 +/- 1.17 vs 12.91 +/- 2.53% ID/g), indicating that the binding of [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN to the receptors was specific. Scintigraphic imaging of human PC-3 prostate cancer xenografts in SCID mice gave a high target to nontarget ratio on the image. Thus, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN has the potential for imaging BN/GRP receptor-positive lesions.
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PMID:A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier. 1554 10

99mTc-labeled bombesin analogues have shown promise for noninvasive detection of many tumors that express bombesin (BN)/gastrin-releasing peptide (GRP) receptors. 99mTc-labeled peptides, however, have a tendency to accumulate in the liver and intestines due to hepatobiliary clearance as a result of the lipophilicity of the 99mTc chelates. This makes the imaging of lesions in the abdominal area difficult. In this study, we have synthesized a new high affinity 99mTc-labeled BN analogue, [DTPA1, Lys3(99mTc-Pm-DADT), Tyr4]BN, having a built-in pharmacokinetic modifier, DTPA, and labeled with 99mTc using a hydrophilic diaminedithiol chelator (Pm-DADT) to effect low hepatobiliary clearance. In vitro binding studies using human prostate cancer PC-3 cell membranes showed that the inhibition constant (Ki) for [DTPA1, Lys3(99Tc-Pm-DADT), Tyr4]BN was 4.1 +/- 1.4 nM. Biodistribution studies of [DTPA1, Lys3(99mTc-Pm-DADT), Tyr4]BN in normal mice showed very low accumulation of radioactivity in the liver and intestines (1.32 +/- 0.13 and 4.58 +/- 0.50% ID, 4 h postinjection, respectively). There was significant uptake (7.71 +/- 1.37% ID/g, 1 h postinjection) in the pancreas which expresses BN/GRP receptors. The uptake in the pancreas could be blocked by BN, partially blocked by neuromedin B, but not affected by somatostatin, indicating that the in vivo binding was BN/GRP receptor specific. Scintigraphic images showed specific, high contrast delineation of prostate cancer PC-3 xenografts in SCID mice. Thus, the new peptide has a great potential for imaging BN/GRP receptor-positive cancers located even in the abdomen.
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PMID:A new high affinity technetium-99m-bombesin analogue with low abdominal accumulation. 1565 74

Neuroendocrine (NE) cells are found in prostate tumors, and their incidence is considered a promising prognostic indicator for the development of androgen-independent disease. NE cells are derived from non-NE prostate cancer cells and secrete factors that can act in a paracrine manner to stimulate the survival, growth, motility, and metastatic potential of prostatic carcinoma cells. Factors such as IL-6, epinephrine, and forskolin induce NE differentiation in prostate cancer cells; the mechanisms involve increases in intracellular cAMP, protein kinase A (PKA) activation and reduced intracellular calcium levels. Transcription factors implicated in the acquisition of NE characteristics by prostate cancer cells include STAT3, CREB, EGR1, c-fos, and NF-kappaB. Expression of Chromogranin A, neuron-specific enolase, bcl-2, and the androgen receptor are modulated during NE differentiation and serve as molecular markers for NE cells. Most importantly, NE cells secrete neuropeptides, such as bombesin, neurotensin, PTHrP, serotonin, and calcitonin, which trigger growth and survival responses in androgen-independent prostate cancer cells. Prostate cancer cell receptors that play a role in these processes include the gastrin-releasing peptide (GRP) receptor, neurotensin receptors, and the epidermal growth-factor receptor (EGFR). Signal-transduction molecules activated by these neuropeptides include Src, focal adhesion kinase (FAK), ERK, and PI3K/Akt, with subsequent activation of Elk-1, NF-kappaB, and c-myc transcription factors. A multitude of genes are then expressed by prostate cancer cells, which are involved in proliferation, anti-apoptosis, migration, metastasis, and angiogenesis. Targeting of these pathways at multiple levels can be exploited to inhibit the process by which NE cells contribute to the progression of androgen-independent, treatment-refractory prostate cancer.
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PMID:Neuroendocrine cells in prostate cancer. 1566 58


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