Expression and prognostic significance of thymidylate synthase (TS) in pancreatic head and periampullary cancer

Background

Pancreatic cancer has a dismal prognosis. Attempts have been made to improve outcome by several 5-FU based adjuvant treatment regimens. However, the results are conflicting. There seems to be a continental divide with respect to the use of 5-FU based chemoradiotherapy (CRT). Furthermore, evidence has been presented showing a different response of pancreatic head and periampullary cancer to 5-FU based CRT. Expression of thymidylate synthase (TS) has been associated with improved outcome following 5-FU based adjuvant treatment in gastrointestinal cancer. This prompted us to determine the differential expression and prognostic value of TS in pancreatic head and periampullary cancer.

Patients and methods

TS protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 212 patients following microscopic radical resection (R0) of pancreatic head (n = 98) or periampullary cancer (n = 114). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS), and conventional prognostic factors.

Results

High cytosolic TS expression was present in 26% of pancreatic head tumours and 37% of periampullary tumours (p = .11). Furthermore, TS was an independent factor predicting favourable outcome following curative resection of pancreatic head cancer (p = .003, .001 and .001 for RFS, CSS and OS, respectively). In contrast, in periampullary cancer, TS was not associated with outcome (all p > .10).

Conclusion

TS, was found to be poorly expressed in both pancreatic head and periampullary cancer and identified as an independent prognostic factor following curative resection of pancreatic head cancer.     

Angiogenesis: a prognostic determinant in pancreatic cancer?

Angiogenesis has been associated with disease progression in many solid tumours, however the statement that tumours need angiogenesis to grow, invade and metastasise seems no longer applicable to all tumours or to all tumour subtypes. Prognostic studies in pancreatic cancer are conflicting. In fact, pancreatic cancer has been suggested an example of a tumour in which angiogenesis is less essential for tumour progression. The aim of the present study was therefore to measure angiogenesis in two anatomically closely related however prognostically different types of pancreatic cancer, pancreatic head and periampullary cancer, and investigate its relation with outcome. Vessels were stained by CD31 on original paraffin embedded tissue from 206 patients with microscopic radical resection (R0) of pancreatic head (n=98) or periampullary cancer (n=108). Angiogenesis was quantified by microvessel density (MVD) and measured by computerised image analysis of three randomly selected fields and investigated for associations with recurrence free survival (RFS), cancer specific survival (CSS), overall survival (OS) and conventional prognostic factors. MVD was heterogeneous both between and within tumours. A higher MVD was observed in periampullary cancers compared with pancreatic head cancers (p<.01). Furthermore, MVD was associated with lymph node involvement in pancreatic head (p=.014), but not in periampullary cancer (p=.55). Interestingly, MVD was not associated with RFS, CSS or with OS. In conclusion, angiogenesis is higher in periampullary cancer and although associated with nodal involvement in pancreatic head cancer, pancreatic cancer prognosis seems indeed angiogenesis independent.     

Valeur pronostique des sous-types moléculaires et du Ki67 pour les cancers du sein indemnes d’envahissement ganglionnaire après mastectomie : expérience de l’institut Curie–hôpital René-Huguenin et revue de la littérature

PurposeTo evaluate the prognostic value of Ki67 expression, breast cancer molecular subtypes and the impact of postmastectomy radiotherapy in breast cancer patients with pathologic negative lymph nodes (pN0) after modified radical mastectomy.Patients and methodsSix hundred and ninety-nine breast cancer patients with pN0 status after modified radical mastectomy, treated between 2001 and 2008, were identified from a prospective database in a single institution. Tumours were classified by intrinsic molecular subtype as luminal A or B, HER2+, and triple-negative using estrogen, progesterone, and HER2 receptors. Multivariate Cox analysis was used to determine the risk of locoregional recurrence associated with intrinsic subtypes and Ki67 expression, adjusting for known prognostic factors.ResultsAt a median follow-up of 56 months, 17 patients developed locoregional recurrence. Five-year locoregional recurrence-free survival and overall survival in the entire population were 97%, and 94.7%, respectively, with no difference between the postmastectomy radiotherapy (n = 191) and no-postmastectomy radiotherapy (n = 508) subgroups. No constructed subtype was associated with an increased risk of locoregional recurrence. A Ki67 above 20% was the only independent prognostic factor associated with increased locoregional recurrence (hazard ratio, 4.18; 95% CI, 1.11 to 15.77; P < 0.0215). However, postmastectomy radiotherapy was not associated with better locoregional control in patients with proliferative tumours.ConclusionKi67 expression but not molecular subtypes are predictors of locoregional recurrence in breast cancer patients with negative lymph nodes after modified radical mastectomy. The benefit of adjuvant radiotherapy in patients with proliferative tumours should be further investigated in prospective studies.     

Nuclear S100A4 is a novel prognostic marker in colorectal cancer

Current staging classifications in colorectal cancer are not able to accurately predict patient outcome, and the need for novel prognostic markers is evident. S100A4 is a Ca²⁺-binding protein which promotes metastasis in several tumour types, and the aim of the present study was to investigate the prognostic impact of S100A4 expression in colorectal cancer. Two hundred and forty two patients with curatively resected adenocarcinoma of the colon or rectum were prospectively included in the study at the time of surgery. S100A4 expression was analysed by immunohistochemistry, and associations with clinicopathological variables and patient outcome were investigated. Nuclear expression of S100A4 was observed in 29% and cytoplasmic expression was observed in 64% of the tumours. In univariate analysis, nuclear S100A4 was a negative predictor of metastasis-free (P = 0.006) and overall survival (P = 0.01), whereas cytoplasmic S100A4 was not associated with patient outcome. In multivariate analysis, nuclear localisation was inversely associated with metastasis-free (P = 0.03) and overall survival (P = 0.02). Interestingly, the prognostic impact was largely confined to TNM stage II, and stage II patients with tumours expressing nuclear S100A4 had a similar prognosis as stage III patients. In conclusion, nuclear expression of S100A4 is a novel prognostic marker in colorectal cancer, and the prognostic value in TNM stage II suggests that nuclear S100A4 could be used in the stratification of stage II patients for adjuvant treatment.     

Loss of Plexin B1 is highly prognostic in low proliferating ER positive breast cancers – Results of a large scale microarray analysis

Plexins, cell-surface receptors for semaphorins, are involved in cell adhesion and migration. In the previous work, we demonstrated that the loss of Plexin B1 expression is associated with poor outcome in breast cancer patients. The goal of the present study was a validation of Plexin B1 expression in a large scale microarray dataset from n = 1086 breast cancer patients. Plexin B1 correlates with ER status (p < 0.001) and is of prognostic significance only in ER positive (p = 0.024) but not in ER negative samples (p = 0.85). Among ER positive tumours, the loss of Plexin B1 expression is associated with a positive ErbB2 status (p = 0.05) and a high Ki67 expression (p = 0.016) in univariate analysis. Multivariate Cox regression including all standard parameters among ER positive tumours revealed that Plexin B1 (HR 1.59, 95% confidence interval (CI) 1.03–2.47, p = 0.036) remains a significant prognostic marker besides tumour size (HR 2.27, 95% CI 1.33–3.89, p = 0.0028) and Ki67 (HR 1.78, 95% CI 1.12–2.84, p = 0.0149). Interestingly, the prognostic value of Plexin B1 was pronounced in low proliferating ER positive tumours otherwise characterised by a low risk of recurrence. In conclusion, this study confirms our previous observations suggesting Plexin B1 as a new prognostic marker in ER positive breast cancers.     

HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome

AimTo evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases.Patient and methodsHER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed.ResultsHER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p = 0.026) and in the subgroup of patients with colon cancer stage II (p = 0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r = 0.9, p < 0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r = 0.6, p < 0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis.ConclusionA high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.     

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

IntroductionAkt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER–) breast cancer with long-term follow-up.Material and methodsThe expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model.ResultsThe risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. The prognostic value of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER– tumours to 68% risk reduction for the group with high ER-levels (P for trend = 0.042). Akt1 showed no significant prognostic information.ConclusionOur results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.     

Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma

BackgroundPrognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients.Patients and methodsA total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-β receptor, CXCR4, and LKB1.ResultsHigh CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002).ConclusionsCXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.     

Molecular prediction of early recurrence after resection of hepatocellular carcinoma

The prognosis of hepatocellular carcinoma (HCC) remains poor. Vascular invasion, tumour multiplicity and large tumour size are the conventional poor prognostic indicators related to early recurrence. However, it is difficult to predict prognosis of each HCC in the absence of these indicators. The purpose of this study is to predict early recurrence of HCC after radical resection based on whole human gene expression profiling. Microarray analyses were performed in 139 HCC primary tumours. A total of 88 cases lacking the conventional poor prognostic indicators were analysed to establish a molecular prediction system characteristic for early recurrence in 42 training cases with two polarised prognoses, and to test its predictive performance in 46 independent cases (group C). Subsequently, this system was applied to another 51 independent cases with some poor prognostic indicators (group D). The molecular prediction system accurately differentiated HCC cases into poor and good prognoses in both the independent group C (disease-free survival [DFS]: p = 0.029, overall survival [OS]: p = 0.0043) and independent group D (DFS: p = 0.0011, OS, p = 0.035). Multivariate Cox regression analysis indicated that the clinical value of molecular prediction system was an independent prognostic factor (p < 0.0001, hazard ratio = 3.29). Gene expression pattern related to early intrahepatic recurrence inherited in the primary HCC tumour can be useful for the prediction of prognosis.     

Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer

AimsEpidermal growth factor receptor (EGFR) is expressed by over 70% of muscle-invasive bladder tumours and is associated with diminished overall survival. In model tumour systems, ionising radiation has been shown to activate EGFR, leading to cellular proliferation and is therefore a possible mechanism of underlying radioresistance. We carried out an immunohistochemical study relating the clinical outcome of patients receiving radical radiotherapy for muscle-invasive bladder cancer to tumour EGFR status.Materials and methodsArchived paraffin-embedded tumours from 110 consecutive patients receiving radical radiotherapy for muscle-invasive bladder cancer between 1991 and 1997 were immunohistochemically stained for EGFR. Data were collected concerning the tumour stage and grade, the presence of ureteric obstruction, the response to radiotherapy at 3 months, local recurrence rates, metastatic spread and survival. Multivariate analysis of potential independent prognostic factors of impaired bladder cancer-specific survival was carried out using Cox's regression.ResultsOf 110 tumours, 79 (72%) stained positively for EGFR. Of 87 patients undergoing the 3-month check cystoscopy, 60 (69%) had a positive response to radiotherapy. A positive response to radiotherapy correlated significantly with a negative EGFR status (χ² test, P = 0.05). Kaplan–Meier survival analysis revealed a trend towards improved bladder cancer-specific survival in EGFR-negative patients (Log-rank, P = 0.10). A lack of response to radiotherapy at 3 months, local recurrence, metastatic spread and the presence of ureteric obstruction were all independent prognostic factors for diminished bladder cancer-specific survival (Cox's regression: P = 0.009, P = 0.001, P = 0.04 and P = 0.005, respectively).ConclusionsEGFR status predicts the local response to radiotherapy but does not provide prognostic utility in relation to overall or bladder cancer-specific survival. As EGFR status seems to be linked to the initial response to radiotherapy, its inhibition may be a means of enhancing the radio-responsiveness of these poor prognosis tumours.     

Malignant pancreatic neuroendocrine tumour: lymph node ratio and Ki67 are predictors of recurrence after curative resections

IntroductionMalignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs.MethodsThe prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed.ResultsFifty-seven patients (male/female ratio = 1) with a median age of 58 years (33–78) entered in the study. Twenty-nine (51%) patients underwent pancreaticoduodenectomy and 28 (49%) distal pancreatectomy. Postoperative mortality was nil with a 37% morbidity rate. There were 36 (63%) patients with lymph node metastases (N1). Of these, 23 (64%) had a lymph node ratio (LNR) >0 and ⩽0.20 and 13 (36%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80 months, respectively. Recurrent disease was identified in 24 patients (42%) with a 2 and 5-year DFS rate of 82% and 49%, respectively. On multivariate analysis, LNR >0.20 (HR = 2.75) and a value of Ki67 >5% (HR = 3.39) were significant predictors of recurrence (P < 0.02).ConclusionsAfter resection for malignant PNETs, LNR and a Ki67 >5% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials.     

Elevated expression of HMGB1 in squamous-cell carcinoma of the head and neck and its clinical significance

PurposeHMGB1 overexpression has been reported in a variety of human cancers. However, the role of HMGB1 in squamous-cell carcinoma of the head and neck (SCCHN) remains unclear. The aim of the present investigation was to analyse HMGB1 protein expression in both SCCHN tissue and cell levels and to assess its prognostic significance in SCCHN.MethodsHMGB1 protein expression in 103 primary SCCHN tissue specimens was analysed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Additionally, HMGB1 protein expression was evaluated in cell level by Western blotting.ResultsBy Western blotting analysis, all the 5 SCCHN cell lines overexpressed HMGB1 protein, whereas the non-transformed immortalised cell line NP-69 had relatively weak HMGB1 protein expression. Immunohistochemical staining revealed that HMGB1 protein was detected in 91 (91/103, 88.3%) primary tumour samples, but only in 7 (7/16, 43.75%) adjacent non-carcinoma samples (p < 0.001); moreover, HMGB1 overexpression was significantly associated with T classification (p = 0.001), clinical stage (p < 0.001), recurrence (p < 0.001) and lymph node metastasis (p < 0.001). Survival analysis demonstrated that high HMGB1 expression was significantly associated with shorter disease-free and overall survival (both p < 0.001), especially in late patients with SCCHN. When HMGB1 expression and lymph node status were combined, patients with HMGB1 overexpression/lymph node (+) had both poorer disease-free and overall survival than others (both p < 0.001). Multivariate analysis further demonstrated that HMGB1 was an independent prognostic factor for patients with SCCHN.ConclusionsHMGB1 protein may contribute to the malignant progression of SCCHN, and present as a novel prognostic marker and a potential therapeutic target for patients with SCCHN.     

A high cannabinoid CB1 receptor immunoreactivity is associated with disease severity and outcome in prostate cancer

In the light of findings indicating that cannabinoids can affect the proliferation of a number of cancer cell types and that cannabinoid receptor expression is higher in prostate cancer cell lines than in non-malignant cells, we investigated whether the level of cannabinoid 1 receptor immunoreactivity (CB₁IR) in prostate cancer tissues is associated with disease severity and outcome. Formalin-fixed paraffin-embedded non-malignant and tumour tissue samples from patients who were diagnosed with prostate cancer at a transurethral resection for voiding problems were used. CB₁IR, which was scored in a total of 399 cases, was associated with the epithelial cell membranes, with little staining in the stroma. Patients with a tumour CB₁IR score greater or equal to the median (2) had a significantly higher proportion of Gleason scores 8–10, metastases at diagnosis, tumour size and rate of cell proliferation at diagnosis than patients with a score < 2. For 269 cases, tumour CB₁IR was measured for patients who only received palliative therapy at the end stages of the disease, allowing the influence of CB₁IR upon the disease outcome to be determined. Receiver operating characteristic (ROC) curves showed an area under the curve of 0.67 (95% confidence limits 0.59–0.74) for CB₁IR in the tumour. CB₁IR in non-malignant tissue was not associated with disease outcome. A tumour CB₁IR score ? 2 was associated with a significantly lower disease specific survival. A Cox proportional hazards regression indicated that the tumour CB₁IR score and the Gleason score were independent prognostic variables. It is concluded that a high tumour CB₁IR score is associated with prostate cancer severity and outcome.     

Wnt1 overexpression promotes tumour progression in non-small cell lung cancer

BackgroundThe Wnt gene family is involved in embryogenesis and tumourigenesis. We investigated the clinical significance of Wnt1 expression in non-small cell lung cancer (NSCLC).MethodWe studied 216 NSCLC patients. Immunohistochemistry was performed to investigate the Wnt1 expression in relation to the expression of β-catenin and Wnt-targets, including c-Myc, Cyclin D1, VEGF-A and MMP-7. The Ki-67 proliferation index and the intratumoural microvessel density (IMD) were also evaluated.ResultsThe ratio of tumours with an aberrant β-catenin expression was significantly higher in Wnt1-positive tumours than in Wnt1-negative tumours (p < 0.0001). The Wnt1 expression significantly correlated with the expression of c-Myc (p < 0.0001), Cyclin D1 (p < 0.0001), VEGF-A (p = 0.0160), MMP-7 (p < 0.0001), the Ki-67 index (p = 0.0048) and the IMD (p = 0.0267). Furthermore, the Wnt1 status was a significant prognostic factor for NSCLC patients (p = 0.0127).ConclusionsThe Wnt1 overexpression is associated with the expression of tumour-associated Wnt-targets, tumour proliferation, angiogenesis and a poor prognosis in NSCLCs.     

ENO1, a potential prognostic head and neck cancer marker,promotes transformation partly via chemokine CCL20 induction

The success of using glycolytic inhibitors for cancer treatment depends on studying the individual role of frequently deregulated glycolytic genes in cancer. This report aims to study the prognostic implication, and determine the cellular role and action mechanism of glycolytic ENO1 overexpression in head and neck cancer. The relationship of ENO1 mRNA expression in 44-pair clinical specimens with patient clinicopathologic characteristics was analysed by semi-quantitative RT-PCR, Kaplan–Meier survival curve and Cox model analyses. Following ectopic ENO1 expression or knockdown, we studied the proliferative, migratory, invasive, colony-forming and tumourigenic abilities of ENO1-genetically altered cells. DNA microarray analysis was used to identify downstream targets responsible for the ENO1 action in the cells. The expression of ENO1 mRNA was increased in 68% of tumour (T) specimens when compared to their normal (N) counterparts, and positively associated with clinical progression (p < 0.05). High ENO1 expression (T/N ? 2) was frequently observed in the patients with large primary tumours, late clinical stages or advanced neck metastasis. Moreover, high ENO1 patients had significantly poorer clinical outcomes than low expressers (T/N < 2). Ectopic ENO1 expression stimulated cell transformation, invasion and tongue tumour formation. ENO1 knockdown abrogated the stimulation. Suppression of ENO1-induced proinflammatory CCL20 chemokine expression significantly attenuated its stimulatory effects on cell transformation and invasion. A concordant expression of ENO1 and CCL20 was validated both in ENO1-expresing cells and in clinical specimens. Together, we demonstrate a prognostic role of ENO1 overexpression in head and neck cancer and ENO1-mediated promotion of cell transformation and invasion partly via induced CCL20 expression.     

17ß-Hydroxysteroid dehydrogenase type 1 as predictor of tamoxifen response in premenopausal breast cancer

17ß-Hydroxysteroid dehydrogenases (17HSDs) are involved in the local regulation of sex steroids. 17HSD1 converts oestrone (E1) to the more potent oestradiol (E2) and 17HSD2 catalyses the reverse reaction. The aim of this study was to investigate the expression of these enzymes in premenopausal breast cancers and to analyse if they have any prognostic or tamoxifen predictive value. Premenopausal patients with invasive breast cancer, stage II (UICC), were randomised to either 2 years of adjuvant tamoxifen (n = 276) or no tamoxifen (n = 288). The median follow-up was 13.9 years (range 10.5–17.5). The expression of 17HSD1 and 17HSD2 was analysed with immunohistochemistry using tissue microarrays. The enzyme expression level (–/+/++/+++) was successfully determined in 396 and 373 tumours, respectively. Women with hormone-receptor positive tumours, with low levels (–/+/++) of 17HSD1, had a 43% reduced risk of recurrence, when treated with tamoxifen (Hazard Ratio (HR) = 0.57; 95% confidence interval (CI), 0.37–0.86; p = 0.0086). On the other hand high expression (+++) of 17HSD1 was associated with no significant difference between the two treatment arms (HR = 0.91; 95% CI, 0.43–1.95; p = 0.82). The interaction between 17HSD1 and tamoxifen was significant during the first 5 years of follow-up (p = 0.023). In the cohort of systemically untreated patients no prognostic importance was observed for 17HSD1. We found no predictive or prognostic value for 17HSD2. This is the first report of 17HSD1 in a cohort of premenopausal women with breast cancer randomised to tamoxifen. Our data suggest that 17HSD1 might be a predictive factor in this group of patients.     

Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens

PurposeSphingosine kinase-1 (SphK1) was shown in preclinical models and non-genitourinary cancers to be instrumental in cancer progression, adaptation to hypoxia and in tumour angiogenesis. No data were available in human prostate cancer. The present study was designed to assess SphK1 expression and activity in radical prostatectomy specimens and to research correlations with clinical features.Materials and methodsTransverse section of fresh tissue was obtained from 30 consecutive patients undergoing laparoscopic prostatectomy. SphK1 enzymatic activities of tumour and normal counterpart were determined. Relationships with PSA, Gleason sum, pathological stage, resection margin status and treatment failure were researched. SphK1 pattern of expression was then assessed on tissue microarray.ResultsA significant 2-fold increase in SphK1 enzymatic activity(11.1 ± 8.4 versus 5.9 ± 3.2 (P < 0.04)) was observed in cancer. The upper quartile of SphK1 activity was associated with higher PSA (16.7 versus 6.4 ng/ml, P = 0.04), higher tumor volumes (20.7 versus 9.8, P = 0.002), higher rates of positive margins (85.7% versus 28.6%, P = 0.01) and surgical failure (71.4% versus 9.5%, P = 0.003) than the lower three quartiles. Odds ratios (OR) for treatment failure showed a strong relationship with SphK1 activity (OR: 23.7, P = 0.001), positive resection margins (OR: 15.0, P = 0.007) and Gleason sum (?4 + 3, OR: 8.0, P = 0.003). Tissue microarrays showed discrete epithelial expression that varied with Gleason sum with significant relationship between SphK1 expression and higher Gleason sum.ConclusionIn complement to preclinical literature, the demonstrated relationships between SphK1-increased activity in cancer and relevant clinical features confirm a central role for SphK1 in prostate cancer that herald promising avenues in risk-assessment and treatment.     

Metastasis suppressor 1 (MTSS1) demonstrates prognostic value and anti-metastatic properties in breast cancer

Metastasis suppressor 1 (MTSS1) may play an important role in cancer metastasis. Firstly, this study assessed MTSS1 expression levels within breast cancer patients to reveal any clinical relevance. Secondly, we aimed to clarify the cellular function of MTSS1 in breast cancer cells. MTSS1 expression levels were assessed in a cohort of breast cancer specimens (normal n = 33; cancer n = 127), through quantitative PCR analysis and immuno-histochemical techniques. The influence of MTSS1 was further examined via biological overexpression and knockdown within breast cancer cell lines. We report that patients with tumours expressing reduced levels of MTSS1 had a poorer prognosis (p = 0.042). High levels of MTSS1 correlated with an increased patient overall survival (p = 0.0108) and disease-free survival (p = 0.012). Furthermore, overexpression of MTSS1 significantly suppressed (p < 0.01) the invasive, migratory, growth and adherence properties of a human breast cancer cell line. In contrast, knockdown of MTSS1 dramatically enhanced these properties. We conclude that MTSS1 is a prognostic indicator of disease-free survival in breast cancer patients and demonstrates the ability to play a role in governing the metastatic nature of breast cancer cells.