8-prenylnaringenin and tamoxifen inhibit the shedding of irradiated epithelial cells and increase the latency period of radiation-induced oral mucositis : cell culture and murine model.

PURPOSE: The major component in the pathogenesis of oral radiation-induced mucositis is progressive epithelial hypoplasia and eventual ulceration. Irradiation inhibits cell proliferation, while cell loss at the surface continues. We conceived to slow down this desquamation by increasing intercellular adhesion, regulated by the E-cadherin/catenin complex. We investigated if 8-prenylnaringenin (8-PN) or tamoxifen (TAM) decrease the shedding of irradiated human buccal epithelial cells in vitro and thus delay the ulcerative phase of radiation-induced mucositis in vivo. MATERIALS AND METHODS: In vitro, aggregates of buccal epithelial cells were irradiated and cultured in suspension for 11 days. 8-PN or TAM were investigated regarding their effect on cell shedding. In vivo, the lower tongue surface of mice was irradiated with graded single doses of 25 kV X-rays. The incidence, latency, and duration of the resulting mucosal ulcerations were analyzed after topical treatment with 8-PN, TAM or solvent. RESULTS: 8-PN or TAM prevented the volume reduction of the irradiated cell aggregates during the incubation period. This was the result of a higher residual cell number in the treated versus the untreated irradiated aggregates. In vivo, topical treatment with 8-PN or TAM significantly increased the latency of mucositis from 10.9 to 12.1 and 12.4 days respectively, while the ulcer incidence was unchanged. CONCLUSION: 8-PN and TAM prevent volume reduction of irradiated cell aggregates in suspension culture. In the tongues of mice, these compounds increase the latency period. This suggests a role for these compounds for the amelioration of radiation-induced mucositis in the treatment of head and neck tumors.

Direct effects of delta opioid receptor agonists on invasion-associated activities of HCT-8/E11 colon cancer cells.

BACKGROUND: Opioids and opioid receptors are an integral part of the tumour microenvironment and hence may influence tumour progression. Studies on direct effects of opioids on invasion-associated cellular activities are equivocal. We wanted to clarify these differences. MATERIALS AND METHODS: The direct effects of the delta opioid receptor (DOR) agonists [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE), leu-enkephalin and [D-Ala(2), D-Leu(5)]-enkephalin (DADLE) on invasion-associated activities of HCT-8 myc-DOR and HCT-8 FLAG-DOR colon cancer cells stably overexpressing DOR were studied. RESULTS: The opioids showed a trend to stimulate invasion of single cells in collagen in one clone, while they did not influence invasion of the other clone. In other invasion assays, no effects were observed. They did not affect cell growth and homotypical cell-cell adhesion. DPDPE at 0.1 muM inhibited directional migration; the other opioids and concentrations tested were inefficient. CONCLUSION: Opioids differently influence invasion-associated cellular activities, depending on the expression level of DOR, experimental set-up, type and concentration of opioid.

Intensity-modulated radiotherapy for recurrent and second primary head and neck cancer in previously irradiated territory.

PURPOSE: To evaluate re-irradiation using IMRT for recurrent and second primary head and neck cancer in previously irradiated territory. MATERIALS AND METHODS: Between 1997 and 2008, 84 patients with recurrent and second primary head and neck cancer were treated with IMRT to a median dose of 69 Gy. Median time interval between initial radiotherapy and re-irradiation was 49.5 (5.2-298.3) months. Salvage surgery preceded re-irradiation in 19 patients; 17 patients received concurrent chemotherapy. RESULTS: Median follow-up of living patients was 19.8 (1.9-76.1) months. Five-year locoregional control and overall survival were 40% and 20%, respectively. Five-year disease-specific survival and disease-free survival were 29% and 15%, respectively. Stage T4 (p=0.015), time interval between initial treatment and re-irradiation (p=0.011) and hypopharyngeal cancer (p=0.013) were independent prognostic factors for worse overall survival in multivariate analysis. Twenty-six and 11 patients developed Grade 3 acute and late toxicity, respectively. No Grade 5 acute toxicity was encountered. There were 2 fatal vascular ruptures during follow-up. CONCLUSIONS: High-dose IMRT for recurrent and second primary head and neck cancer in previously irradiated territory leads to approximately 20% long-term survival in a non-selected patient population. Identification of patients who would benefit most of curative IMRT is warranted.

Intensity-modulated radiotherapy for sinonasal tumors: Ghent University Hospital update.

PURPOSE: To report the long-term outcome of intensity-modulated radiotherapy (IMRT) for sinonasal tumors. METHODS AND MATERIALS: Between July 1998 and November 2006, 84 patients with sinonasal tumors were treated with IMRT to a median dose of 70 Gy in 35 fractions. Of the 84 patients, 73 had a primary tumor and 11 had local recurrence. The tumor histologic type was adenocarcinoma in 54, squamous cell carcinoma in 17, esthesioneuroblastoma in 9, and adenoid cystic carcinoma in 4. The tumors were located in the ethmoid sinus in 47, maxillary sinus in 19, nasal cavity in 16, and multiple sites in 2. Postoperative IMRT was performed in 75 patients and 9 patients received primary IMRT. RESULTS: The median follow-up of living patients was 40 months (range, 8-106). The 5-year local control, overall survival, disease-specific survival, disease-free survival, and freedom from distant metastasis rate was 70.7%, 58.5%, 67%, 59.3%, and 82.2%, respectively. No difference was found in local control and survival between patients with primary or recurrent tumors. On multivariate analysis, invasion of the cribriform plate was significantly associated with lower local control (p = 0.0001) and overall survival (p = 0.0001). Local and distant recurrence was detected in 19 and 10 patients, respectively. Radiation-induced blindness was not observed. One patient developed Grade 3 radiation-induced retinopathy and neovascular glaucoma. Nonocular late radiation-induced toxicity comprised complete lacrimal duct stenosis in 1 patient and brain necrosis in 3 patients. Osteoradionecrosis of the maxilla and brain necrosis were detected in 1 of the 5 reirradiated patients. CONCLUSION: IMRT for sinonasal tumors provides low rates of radiation-induced toxicity without blindness with high local control and survival. IMRT could be considered as the treatment of choice.

Intensity-modulated radiotherapy for cervical lymph node metastases from unknown primary cancer.

PURPOSE: To compare the effectiveness of intensity-modulated radiotherapy (IMRT) and conventional (two-dimensional) radiotherapy in the treatment of cervical lymph node metastases from unknown primary cancer (UPC). METHODS AND MATERIALS: Between February 2003 and September 2006, 23 patients with UPC of squamous cell carcinoma were treated with IMRT. Extended putative mucosal and bilateral nodal sites were irradiated to a median dose of 66 Gy. In 19 patients, IMRT was performed after lymph node dissection, and in 4 patients primary radiotherapy was given. The conventional radiotherapy group (historical control group) comprised 18 patients treated to a median dose of 66 Gy between August 1994 and October 2003. RESULTS: Twenty patients completed treatment. As compared with conventional radiotherapy, the incidence of Grade 3 acute dysphagia was significantly lower in the IMRT group (4.5% vs. 50%, p = 0.003). By 6 months, Grade 3 xerostomia was detected in 11.8% patients in the IMRT group vs. 53.4% in the historical control group (p = 0.03). No Grade 3 dysphagia or skin fibrosis was observed after IMRT but these were noted after conventional radiotherapy (26.7%, p = 0.01) and 26.7%, p = 0.03) respectively). With median follow-up of living patients of 17 months, there was no emergence of primary cancer. One patient had persistent nodal disease and another had nodal relapse at 5 months. Distant metastases were detected in 4 patients. The 2-year overall survival and distant disease-free probability after IMRT did not differ significantly from those for conventional radiotherapy (74.8% vs. 61.1% and 76.3% vs. 68.4%, respectively). CONCLUSIONS: Use of IMRT for UPC resulted in lower toxicity than conventional radiotherapy, and was similar in efficacy.

Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer.

PURPOSE: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. METHODS AND MATERIALS: A Phase I clinical trial was designed to escalate the dose limited to the [(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy. RESULTS: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p = n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted (18)F-FDG-PET-delineated region. CONCLUSIONS: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.

Intensity-modulated radiation therapy for prostate cancer: late morbidity and results on biochemical control.

PURPOSE: To report on late morbidity and biochemical relapse-free survival (bRFS) after intensity-modulated radiation therapy (IMRT) for prostate cancer. METHODS: Between 1998 and 2005 133 patients were treated with IMRT for T(1-4) N0 M0 prostate cancer. The median follow-up time was 36 months. In a first cohort, patients received a median planning target volume (PTV) dose of 74 Gy with a hard constraint on maximum rectum dose of 72 Gy (74R72, n=51). Later, median PTV and maximum rectum dose were increased to 76 and 74 Gy, respectively (76R74; n=82). We defined low-risk (n=20), intermediate-risk (n=70) and high-risk (n=43) groups. Androgen deprivation was given to patients in the intermediate- and high-risk group. Late gastro-intestinal (GI) and genito-urinary (GU) morbidity and biochemical relapse, in accordance with the ASTRO consensus, were recorded. RESULTS: We observed grade 2 GI (17%) and GU (19%), grade 3 GI (1%) and GU (3%) late toxicities. Except for hematuria, the median duration of side-effects was 6 months. Biochemical relapse-free survival (bRFS) at 3 and 5 years was 88% and 83%, respectively, with a significantly better 3-year bRSF for the 76R74 than for the 74R72 group (p=0.01). Five-year bRFS for patients in the low-risk, intermediate-risk and high-risk group was 100%, 94% and 74%, respectively (p<0.01). CONCLUSION: IMRT for localized or locally advanced prostate cancer combines low morbidity with excellent biochemical control.

Systemic NO production during (septic) shock depends on parenchymal and not on hematopoietic cells: in vivo iNOS expression pattern in (septic) shock.

Septic shock is the leading cause of death in noncoronary intensive care units and the 10th leading cause of death overall. Several lines of evidence support an important role for the vasodilator NO in hypotension, a hallmark of septic shock. However, NO may also positively or negatively regulate inflammation, apoptosis, and oxidative stress. These dual effects of NO may relate to its isoform specific production but also to differences in cellular and/or temporal expression. Via bone marrow transplantations, we examined the contribution of hematopoietic cells to the dramatically elevated NO levels seen in (septic) shock. Surprisingly, hematopoietic cells are not responsible at all for the production of circulating NO after systemic tumor necrosis factor or lipopolysaccharide challenge and contribute only marginally in a bacteremic (Salmonella) model of septic shock. Immunohistochemistry identified the nonhematopoietic sources of NO as hepatocytes, paneth cells, and intestinal and renal epithelial cells. In contrast, during granulomatous Bacillus Calmette-Guérin inflammation, the hematopoietic cell population represents the sole source of systemic NO. These mouse data demonstrate that, in contrast to the general conjecture, the dramatically elevated levels of NO during (septic) shock are not produced by hematopoietic cells such as monocytes/macrophages but rather by parenchymal cells in liver, kidney and gut.

Interobserver delineation variation using CT versus combined CT + MRI in intensity-modulated radiotherapy for prostate cancer.

PURPOSE: To quantify interobserver variation of prostate and seminal vesicle delineations using CT only versus CT + MRI in consensus reading with a radiologist. MATERIAL AND METHODS: The prostate and seminal vesicles of 13 patients treated with intensity-modulated radiotherapy for prostatic adenocarcinoma were retrospectively delineated by three radiation oncologists on CT only and on CT + MRI in consensus reading with a radiologist. The volumes and margin positions were calculated and intermodality and interobserver variations were assessed for the clinical target volume (CTV), seminal vesicles, prostate and three prostatic subdivisions (apical, middle and basal third). RESULTS: Using CT + MRI as compared to CT alone, the mean CTV, prostate and seminal vesicle volumes significantly decreased by 6.54%, 5.21% and 10.47%, respectively. More importantly, their standard deviations significantly decreased by 63.06%, 62.65% and 44.83%, respectively. The highest level of variation was found at the prostatic apex, followed by the prostatic base and seminal vesicles. CONCLUSION: Addition of MRI to CT in consensus reading with a radiologist results in a moderate decrease of the CTV, but an important decrease of the interobserver delineation variation, especially at the prostatic apex.

Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients.

BACKGROUND: Carcinoma of the paranasal sinuses is rare. Standard therapeutic modalities consist of surgery and radiotherapy (RT). Because of the often advanced stage and the vicinity of optic structures, RT-induced ocular toxicity is a feared side effect of conventional RT. Intensity-modulated radiotherapy (IMRT) is a relatively new technique, which is implemented with the hypothesis that, compared with conventional RT, it would result in a lower rate of ocular toxicity for an equal local control (LC). METHODS: Between 1998 and 2003, 39 consecutive patients received postoperative irradiation by means of IMRT for an adenocarcinoma (n = 31) or squamous cell carcinoma (n = 8) of the paranasal sinuses (n = 36) or nasal cavity (n = 3). T-classification was T2 in 41%, T3 in 15%, T4a in 23%, and T4b in 21% of patients. Invasion through the cribriform plate was seen in 11 patients. Orbital invasion was present in 36% of patients. The median delivered dose was 70 gray (Gy) (range, 60-70 Gy). The authors compared the overall survival (OS) and LC of the patients with a historic cohort (HC) (n = 30), treated with conventional or 3-dimensional conformal RT. RESULTS: The median follow-up was 31 months. The actuarial OS rates were 68% at 2 years and 59% at 4 years. The actuarial LC rates were 73% at 2 years and 68% at 4 years. Invasion through the cribriform plate was a significant prognostic factor for LC and OS, with a median time to local disease recurrence of 7 months if present, and a 2-year LC rate of 90% if not present. In the comparison between the IMRT and HC groups, no significant differences were found for LC and OS. Acute toxicity was mild. Two patients developed decreased vision after RT. No RT-induced blindness was observed. CONCLUSIONS: Postoperative IMRT for sinonasal carcinoma resulted in good LC, with a low acute toxicity and no RT-induced blindness.

Automatic generation of a plan optimization volume for tangential field breast cancer radiation therapy.

BACKGROUND AND PURPOSE: Dose homogeneity is one of the objectives during computer planning of postoperative radiotherapy of the conserved breast. For three-dimensional (3-D) optimization of the dose distribution using serial CT scan images, suitable volumes have to be delineated. The purpose of this study was to develop a computer-generated delineation of a plan optimization volume (POV) and an irradiated volume (IV) and to automate their use in a fast dose homogeneity optimization engine. PATIENTS AND METHODS: Simulation was performed according to our standard procedure which involves the positioning of a lead collar around the palpable breast to facilitate the definition of gantry angle, collimator angle and field aperture for tangential wedged photon beams. In a change to the standard procedure an anterolateral radiograph was taken with its axis orthogonal to the central plane of the two tangential half-beams. Images from a serial CT scan were acquired in treatment position, and the geometric data of the three simulated beams were used by a computer program to generate the POV and IV. For each patient, weights of wedged and unwedged beams were optimized by either human heuristics using only the central slice (2-D), the whole set of CT slices (3-D), or by a computer algorithm using the POV, IV and lung volume with constrained matrix inversion (CMI) as optimization method. The resulting dose distributions were compared. RESULTS: The total planning procedure took, on average, 44 min of which < 7 min were needed for human interactions, compared to about 52 min for the standard planning at Ghent University Hospital, Belgium. The simulation time is increased by 2-3 min. The method provides 3-D information of the dose distribution. Dose homogeneity and minimum dose inside the POV and maximum dose inside the IV were not significantly different for the three optimization techniques. CONCLUSION: This automated planning method is capable of replacing the contouring of the clinical target volume as well as the trial-and-error procedure of assigning weights of wedged and unwedged beams by an experienced planner.

Intensity-modulated radiotherapy as primary treatment for prostate cancer: acute toxicity in 114 patients.

INTRODUCTION: Dose escalation improves local control in prostate cancer. At Ghent University Hospital, intensity-modulated radiotherapy (IMRT) is used to increase the dose to the prostate and/or seminal vesicles. We report on acute toxicity in 114 patients who received IMRT for prostate cancer. METHODS AND MATERIALS: Intensity-modulated radiotherapy was initiated after approval of our ethics committee. A class solution was used to plan all cases. Three beams (gantry 0 degrees , 116 degrees , and 244 degrees ) and anatomy-based segmentation were used to create an intensity-modulated dose distribution. Maximal rectal dose was set at 2 Gy per fraction. Detailed dose-volume histograms for all relevant structures were present. For all patients, we determined the pretreatment morbidity by a detailed preradiotherapy, in-house developed symptom scale. All patients were treated with 18 MV photons of an Elekta linear accelerator. Patients were seen on a weekly basis during treatment, and 1 month (M1) and 3 months (M3) thereafter. The registration of acute toxicity was standardized by a fixed questionnaire. The Radiation Therapy Oncology Group (RTOG) toxicity scale served as a basis, but additional symptoms, such as rectal blood loss, urgency, and incontinence, were scored as well. RESULTS: All 114 IMRT plans were delivered successfully without any interruption or technical problem. Daily treatment time was always less than 8 min and less than 6 min in 90% of the cases. Grade 1 and Grade 2 gastrointestinal (GI) toxicities were observed in 44% and 29% of the patients, respectively, during the whole period. If only the RTOG scale was used, Grade 1 and Grade 2 GI toxicities were noted in 39% and 27% of the patients, respectively, leaving 34% free of acute RTOG-scaled toxicity. Grade 3 genitourinary (GU) toxicity was seen in 8 patients (7%), all but 1 during treatment. Grade 2 and Grade 1 GU toxicities were seen in 36% and 47% of the patients, respectively, leaving only 10% free of acute GU toxicity. DISCUSSION: Anatomy-based IMRT to treat prostate cancer is incorporated into our daily routine without any problem. Acute toxicity is very low. Most of the recorded symptoms decrease over time, except for GI urgency and incontinence. The incorporation of additional symptoms makes the scoring more detailed.

The incidence of inclusion of the sigmoid colon and small bowel in the planning target volume in radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: In radiotherapy for prostate cancer, the rectum is considered the dose-limiting organ. The incidence of overlap between the sigmoid colon and/or small bowel and the planning target volume (PTV) as well as the dose to sigmoid colon and small bowel were investigated. PATIENTS AND METHODS: The CT data of 75 prostate cancer patients were analyzed. The clinical target volume (CTV) consisted of prostate and seminal vesicles. The PTV was defined as a three-dimensional expansion of the CTV with a 10-mm margin in craniocaudal and a 7-mm margin in the other directions. All patients were planned to a mean CTV dose of at least 76 Gy. Minimum CTV dose was set at 70 Gy. Dose inhomogeneity within the CTV was kept between 12% and 17%. Sigmoid colon was defined upward from the level where the rectum turned in a transverse plane. Contrast-filled small bowel was contoured on all slices where it was visible. The presence of sigmoid colon and/or small bowel in close vicinity to or overlapping with the PTV was recorded. For each case, the dose to the sigmoid colon and small bowel was calculated. RESULTS: The PTV was found to overlap with the sigmoid colon in 60% and with the small bowel in 19% of the cases. In these patients, mean maximum dose to the sigmoid colon was 76.2 Gy (5th-95th percentile: 70.0-80.7 Gy). Mean maximum dose to the small bowel was 74.9 Gy (5th-95th percentile: 68.0-80.0 Gy). CONCLUSION: When systematically investigating the anatomic position of sigmoid colon and small bowel in patients accepted for prostate irradiation, parts of both organs were often observed in close vicinity to the PTV. Apart from the rectum, these organs may be dose-limiting in prostate radiotherapy.

Pain control by ionizing radiation of bone metastasis.

Pain treatment due to cancer is a large fraction of the care in a radiotherapy department. While radiation treatment is very effective in reducing pain, the pathophysiology of bone metastases remains very complex. Reducing the number of tumour cells by radiation will reduce the pressure in bone marrow, but the very rapid response to radiation treatment seen in some patients is probably related to the presence of highly radiosensitive inflammatory cells. In this review we give an overview of the pathophysiological mechanisms which lead to pain associated with bone metastasis and the impact of radiation treatment and other treatments on this mechanism.

Direct segment aperture and weight optimization for intensity-modulated radiotherapy of prostate cancer.

BACKGROUND AND PURPOSE: To describe the implementation and to evaluate the results of direct segment aperture optimization using the segment outline and weight adapting tool (SOWAT) in intensity-modulated radiotherapy (IMRT) for prostate cancer. PATIENTS AND METHODS: 14 consecutive, unselected patients with localized prostate cancer were entered in a planning study comparing IMRT without and with the use of SOWAT. The clinical target volume (CTV) consisted of the prostate and seminal vesicles in all cases. To create the planning target volume (PTV), a three-dimensional anisotropic margin (10 mm in craniocaudal direction, 7 mm in both other directions) was used. To compare both plans, physical as well as biological endpoints were considered. RESULTS: Considering the CTV, SOWAT resulted in a significantly higher minimal dose together with a higher dose to 95% (D(95)) and 90% (D(90)) of the CTV volume (p < 0.05; Figure 2). Target dose homogeneity was significantly improved (p < 0.001). Tumor control probability (TCP) was significantly increased (p < 0.05). Considering the PTV, D(90) was significantly increased (p < 0.05). Target dose homogeneity was significantly improved (p < 0.05; Figure 1). For rectum, the volumes receiving 50 Gy (R(vol50)), 60 Gy (R(vol60)), or 65 Gy (R(vol65)) as well as the mean dose were significantly lowered after SOWAT (p = 0.0001; Figure 3). Rectal normal tissue complication probability (NTCP) was significantly lower after SOWAT (p = 0.005). Probability of uncomplicated local control (P+) was significantly higher after SOWAT (p < 0.0001). CONCLUSION: SOWAT is a powerful planning tool to increase the therapeutic ratio of IMRT for prostate cancer. It leaves the delivery time unchanged, so that treatments can still be delivered within a time slot of 8 min.

G-protein alpha(olf) subunit promotes cellular invasion, survival, and neuroendocrine differentiation in digestive and urogenital epithelial cells.

The heterotrimeric G-protein subunits Galpha and Gbetagamma are involved in cellular transformation and tumor development. Here, we report the expression of Galpha(olf) in human digestive and urogenital epithelial cells using RT-PCR and Western blot. When the constitutively activated form of Galpha(olf)Q214L (AGalpha(olf)) was stably transfected in canine kidney MDCKts.src and human colonic HCT-8/S11 epithelial cells, it induced cellular invasion in collagen gels. AGalpha(olf)-mediated invasion was abrogated by agonists of platelet activating factor receptors (PAF-R) and protease-activated receptors -1 (PAR-1), pharmacological inhibitors of PI3'-Kinase (wortmannin), protein kinase C (Gö6976 and GF109203X), Rho GTPase (C3T exoenzyme), but was independent of protein kinase A. Accordingly, the invasive phenotype induced by AGalpha(olf) in HCT-8/S11 cells was reversed by the RhoA antagonist RhoD (G26V). Although AGalpha(olf) protected MDCKts.src cells against serum starvation-mediated apoptosis via a Rho-independent pathway, both AGalpha(olf) and Rho inhibition by C3T induced neuroendocrine-like differentiation linked to extensive neurite outgrowth and parathyroid hormone-related protein expression in human prostatic LNCaP-AGalpha(olf) cells. Since prostate tumors with a larger neuroendocrine cell population display increased invasiveness, persistent activation of the G-protein alpha(olf) may exert convergent adverse effects on cellular invasion and survival in solid tumors during the neoplastic progression towards metastasis. doi:10.1038/sj.onc.1205498