E-cadherin and CD10 expression in atypical hyperplastic and malignant endometrial lesions

BackgroundLoss of E-cadherin is a critical step for development and progression of malignant tumors. CD10; a marker of non-neoplastic and neoplastic endometrial stroma, is associated with aggressiveness of many epithelial malignancies.AimsTo evaluate expression and correlation of E-cadherin and CD10 in endometrial lesions and their possible role in differentiating atypical endometrial hyperplasia from endometrial carcinoma. The association of E-cadherin and CD10 expression with clinico-pathological parameters of endometrial carcinoma was also investigated.Materials and methodsFifty four cases including 28 endometrial carcinomas; 19 endometrial hyperplasia and 7 cases of normal endometrial changes were enrolled for this study. The expression of E-cadherin and CD10 was evaluated by immunohistochemistry using the streptavidin–biotin technique. Results: There was a strong association between malignant change of endometrial glands and membrano-cytoplasmic localization of E-cadherin (p < 0.001). Expression of E-cadherin but not CD10 was significantly higher in endometrial carcinomas compared to atypical endometrial hyperplasia (p < 0.01). Expression of E-cadherin was not associated with CD10 expression in different endometrial lesions. High grade tumors expressed low levels of both E-cadherin (p < 0.01) and CD10 (p < 0.05) and serous endometrial carcinoma had low E-cadherin and CD10 expression compared to endometrioid carcinoma (p < 0.01 and <0.05, respectively). Expression of both molecules showed no association with depth of tumor invasion or FIGO stage. Tumors with lower E-cadherin or CD10 expression had higher rates of vascular tumor emboli (p < 0.01 and <0.07, respectively).ConclusionsAlthough expression of E-cadherin and CD10 in endometrial lesions was not correlated, reduced expression of both molecules could be critical for progression of endometrial carcinoma.     

Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial

Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx.Patients (N = 272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome.A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p = 0.02) and disease-specific survival (92% versus 77% p = 0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p = 0.009).In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON.     

Endo180 expression with cofunctional partners MT1-MMP and uPAR–uPA is correlated with prostate cancer progression

Endo180 (CD280; MRC2; uPARAP) regulates collagen remodelling and chemotactic cell migration through cooperation with membrane type-1 matrix metalloproteinase (MT1-MMP), urokinase-type plasminogen activator receptor (uPAR) and urokinase-type plasminogen activator (uPA). One hundred and sixty nine prostate tissue sections clinically graded as benign prostatic hyperplasia (BPH) (n = 29) or prostate cancer (PCA) with Gleason scores indicating low (?7(3 + 4); n = 26), intermediate (7(4 + 3)–8; n = 96) or high (9–10; n = 19) clinical risk were immunofluorescently stained for Endo180, pan-cytokeratin (pCk), vimentin, MT1-MMP and uPAR–uPA. Quantification of % Endo180⁺/pCk^– and Endo180⁺/pCk⁺ cells in entire tissue cores revealed stromal (p = 0.0001) and epithelial (p = 0.0001) upregulation of Endo180 in PCA compared to BPH. Epithelial Endo180 expression was significantly different between the three clinical risk groups of PCA (p < 0.05). Correlations with MT1-MMP and uPAR–uPA confirmed the functionality of Endo180 during PCA progression. This molecular evaluation is the first step in the exploration of Endo180 in PCA diagnosis and therapy.     

Associations of sexual dysfunction symptoms with PSA-detected localised and advanced prostate cancer: A case-control study nested within the UK population-based ProtecT (Prostate testing for cancer and Treatment) study

BackgroundSexual dysfunction might be symptomatic of cancer spreading beyond the prostate by local invasion, a mechanism of tumour progression associated with prognosis. Conversely, among men with raised prostate-specific antigen (PSA) levels, a negative association might be expected if sexual dysfunction was symptomatic of benign, rather than malignant, prostatic disease.Patients and methodsCases and controls were selected from among men recruited to the UK population-based ProtecT (Prostate testing for cancer and Treatment) study. Men aged 50–69 years were invited for PSA testing and those with a PSA level ?3.0 ng/ml were invited for biopsy. We investigated whether symptoms of sexual dysfunction, determined by self-completed questionnaire prior to biopsy, were associated with prostate cancer.ResultsOf the 8924 men who had a PSA level ?3.0 ng/ml (11% of the men who had a PSA test), 6585 underwent biopsy of whom 2813 and 421, respectively, were subsequently diagnosed with localised and advanced prostate cancer and 3351 had a negative biopsy result. No individual symptom of sexual dysfunction was associated with risk of prostate cancer. The symptom score was associated with advanced (odds ratio (OR) per one unit increase in score = 1.06; 1.00–1.12; P = 0.07) but not with localised (OR = 1.00; 0.97–1.02; P = 0.9) prostate cancer (P = 0.05 for heterogeneity).ConclusionsOur study provides weak evidence that sexual dysfunction may be associated with PSA-detected advanced, but not localised, prostate cancer among men with raised PSA levels.     

Prognostic significance of neuroendocrine components in gastric carcinomas

BackgroundGastric neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs) are aggressive tumours but the prognostic significance of a neuroendocrine component in <30% of the tumour remains unclear. Here, the implication of neuroendocrine components in gastric carcinomas was assessed according to proportion.MethodsSurgically resected primary gastric carcinomas with neuroendocrine morphology (NEM; n = 88) from 2000 to 2012 at Asan Medical Center were retrospectively reviewed. Neuroendocrine differentiation (NED) was defined as immunopositivity for one of three neuroendocrine markers (synaptophysin, chromogranin or CD56) within the NEM area. To validate the prognostic significance of NED, these cases were compared with 650 randomly selected gastric adenocarcinomas without NEM from the same time period.ResultsGastric carcinomas with NEM were reclassified as NEC (⩾70% NED, n = 47), MANEC (30–70% NED, n = 10), gastric carcinoma with 10–30% NED (GCNED, n = 8) and carcinoma with <10% NED (n = 23). The survival rates of patients with ⩾10% NED were significantly poorer than those with <10% NED but no survival difference was observed between NEC and MANEC. In univariate analyses, older age (⩾60 years), larger tumour size (⩾4 cm), advanced stage group, ⩾10% NED and lymphovascular or perineural invasion were indicative of a poor prognosis. Stage group and ⩾10% NED remained as independent prognostic factors by multivariate analysis.ConclusionsA minor proportion (10–30%) of NED should not be overlooked in gastric carcinomas with NEM. NED should be carefully evaluated to predict patient outcomes and plan optimal additional therapies.     

High RNA-binding motif protein 3 expression is an independent prognostic marker in operated prostate cancer and tightly linked to ERG activation and PTEN deletions

BackgroundThe RNA-binding motif protein 3 (RBM3) has recently been suspected as a prognostic biomarker in several cancers.MethodsRBM3 expression was analysed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers.ResultsRBM3 expression was more often detectable in malignant compared to benign prostate. RBM3 immunostaining was found in 64% of the interpretable prostate cancers and was considered strong in 25.6%. High RBM3 expression was linked to advanced tumour stage, high Gleason score, positive nodal involvement and positive surgical margin status (p < 0.0001 each). There was a remarkable accumulation of strong RBM3 expression in v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) positive prostate cancers and tumours harbouring PTEN deletions (p < 0.0001 each). Moreover, RBM3 staining was tightly related to early biochemical recurrence if all tumours or subgroups of ERG negative and ERG positive cancers were analysed (p < 0.0001 each). In multivariate analysis, including RBM3 staining, Gleason grade, pT stage, prostate-specific antigen (PSA), surgical margin status, and nodal status, the prognostic impact of RBM3 staining retained statistically significance (p = 0.0084).ConclusionOur observations indicate that high RBM3 expression is an independent prognostic marker in prostate cancer. The tight link to ERG activation and PTEN deletions suggest interaction with key molecular pathways in prostate cancer.     

Familial transmission of prostate,breast and colorectal cancer in adoptees is related to cancer in biological but not in adoptive parents: A nationwide family study

AimFamilial clustering of prostate, breast and colorectal cancer is well established, but the familial risk of these cancers has not been determined among adoptees. The aim was to disentangle the contributions of genetic and environmental factors to the familial transmission of prostate, breast and colorectal cancer.MethodsThe Swedish Multi-Generation Register was used to follow all adoptees born between 1932 and 1969 (n = 70,965) for prostate, breast and colorectal cancer from January 1958 up to December 2010. The risk of prostate, breast and colorectal cancer was estimated in adoptees with at least one biological parent with the same cancer type compared with adoptees without a biological parent with the same cancer type. The risk of cancer was also determined in adoptees with at least one adoptive parent with cancer compared with adoptees with an adoptive parent without cancer.ResultsAdoptees with at least one biological parent with prostate, breast or colorectal cancer were more likely to have cancer of the same type than adoptees with biological parents not affected by these respective cancer types (standardised incidence ratio = SIR: 1.8 [95% confidence interval 1.2–2.7], 2.0 [1.6–2.5] and 1.9 [1.2–2.9], respectively). In contrast, adoptees with at least one adoptive parent with prostate, breast or colorectal cancer were not at an increased risk of these respective cancer types (SIR = 1.2 [0.94–1.6], 0.97 [0.71–1.3], and 1.1 [0.71–1.5], respectively).ConclusionsThe findings of the study support the importance of genetic/biological factors in the familial transmission of prostate, breast and colorectal cancer.     

Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer

BackgroundThere is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs.Patients and methodsWe reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied.ResultsThe study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6–27) and 41% (95% CI: 30–47) in patients with TTCRPC of under and over 12 months respectively (p = 0.005). Median PFS was 2.8 months (95% CI: 2.1–3.9) and 5.8 (95% CI: 4.6–7.8; HR: 0.58, p = 0.002). In patients treated with post-docetaxel enzalutamide (n = 57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR) = 3.1; 95% CI: 1.6–5.8, p = 0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n = 27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0–38) and 58% (95% CI: 42–73) in patients with a TTCRPC of under and over 12 months respectively (p < 0.001).ConclusionThe previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.     

Oxidative stress-induced antioxidant enzyme expression is an early phenomenon in ovarian carcinogenesis

Oxidative stress and antioxidant enzymes have been widely investigated in various carcinomas. However, there is only some information about their role in ovarian carcinogenesis or in ovarian carcinomas in vivo. We studied immunohistochemical nuclear and/or cytoplasmic expression of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine, as well as major antioxidative enzymes peroxiredoxins (PRDX) I–VI and thioredoxin (TXN) in ovarian tumours. The material consisted of 20 benign (10 serous, 10 mucinous) and 51 borderline (33 serous, 18 mucinous) epithelial ovarian tumours. The markers of oxidative stress, 8-OHdG and nitrotyrosine, were seen already in benign tumours (in 20% and 45% of the tumours, respectively) and their expression patterns were similar in benign and borderline tumours. The levels of PRDX II, III, IV, V and VI were significantly higher in borderline than in benign tumours (p < 0.02 for all). Specifically for PRDX II (for both nuclear and cytoplasmic expression, p < 0.00005) and PRDX VI (for cytoplasmic expression, p = 0.0003 and for nuclear expression, p = 0.0005) the difference between benign and borderline tumours was remarkable. In general, serous benign and borderline tumours expressed higher antioxidant enzyme levels than mucinous ones. Nuclear TXN was expressed more strongly in benign than in borderline tumours (p = 0.003). Oxidative stress occurs already in benign ovarian tumours and the levels are comparable to borderline tumours. However, some of the antioxidant enzymes, especially PRDX II and VI, are more profoundly induced in borderline ovarian tumours, reflecting their possible role as cancer preventers. This difference could also offer a potential tool for differential diagnosis between benign and borderline epithelial ovarian tumours.     

Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients

BackgroundThe purpose of this study is to investigate the prognostic role of insulin-like growth factor receptor 1 (IGF1R) expression in surgically resected non-small-cell lung cancer (NSCLC).Patient characteristics and methodsThis retrospective study was conducted in 369 stage I–II–IIIA, surgically resected, NSCLC patients. Patients exposed to anti-epidermal growth factor receptor (EGFR) agents were excluded. IGF1R expression was evaluated by immunohistochemistry in tissue microarray sections.ResultsA positive IGF1R expression (score ≥ 100) was observed in 282 cases (76.4%) and was significantly associated with squamous cell histology (P = 0.04) and with grade III differentiation (P = 0.02). No difference in survival was observed between the positive and negative group when score 100 was used as cut-off for discriminating a positive versus a negative IGF1R result (52 versus 48 months, P = 0.99) or when median value of IGF1R expression was used (45 versus 55 months, P = 0.36). No difference in survival was observed between IGF1R-positive and -negative patients in a subgroup of stage I–II adenocarcinoma (n = 137) with known EGFR mutation and copy number status.ConclusionsIGF1R expression does not represent a prognostic factor in resected NSCLC patients. Patients with squamous cell carcinoma overexpress IGF1R more frequently than patients with nonsquamous histology, justifying the different sensitivity to anti-IGF1R agents observed in clinical trials.     

MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer

BackgroundMSR1 repeats are a 36–38 bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV).Patients and methodsBioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer.ResultsMSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1 and H3K4me3). MSR1-regulated genes were found to have specific molecular roles, such as serine-protease activity (P = 4.80 × 10⁻⁷) and ion channel activity (P = 2.7 × 10⁻⁴). The kallikrein locus was found to contain a large number of MSR1 clusters, and at least six of these showed CNV. An MSR1 cluster was identified within KLK14, with 9 and 11 copies being normal variants. A significant association with the 9-copy allele and non-familial breast cancer was found in two independent populations (P = 0.004; P = 0.03). In the white British population, the minor allele conferred an increased risk of 1.21–3.51 times for all non-familial disease, or 1.7–5.3 times in early-onset disease. The 9-copy allele was also found to be associated with increased risk of prostate cancer in an independent population (odds ratio = 1.27–1.56; P =0.009).ConclusionsMSR1 repeats act as molecular switches that modulate gene expression. It is likely that CNV of MSR1 will affect risk of development of various forms of cancer, including that of breast and prostate. The MSR1 cluster at KLK14 represents the strongest risk factor identified to date in non-familial breast cancer and a significant risk factor for prostate cancer. Analysis of MSR1 genotype will allow development of precise stratification of disease risk and provide a novel target for therapeutic agents.     

Clinico-pathological significance of the molecular alterations of the SPOP gene in prostate cancer

AimsSpeckle-type POZ protein (SPOP) is an E3 ubiquitin ligase adaptor recently described to be mutated in prostate cancer (PCa). Hence, studying the gene expression profile and the presence of SPOP mutations in PCa and understanding its clinico-pathological significance as prognostic and therapeutic biomarker are important to further understand its role in PCa development.Patients and methodsA cohort of 265 paraffin-embedded PCa samples from patients with more than 5 years of follow-up and treated with radical prostatectomy were collected at our institution for SPOP evaluation. RT-qPCR analysis was performed for expression studies while mutations were assessed by next generation sequencing. Relationship with prognosis was analysed using log-rank analysis and multivariable Cox regression.ResultsSPOP was found to be strongly down-regulated in PCa (median = 0.24; range = 0.04–9.98) and its expression was associated with both, biochemical (p = 0.003) and clinical progression free survival (p = 0.023), the very low SPOP expression levels being associated to the worst prognosis. Multivariate analysis demonstrated that low levels of SPOP independently predicted a worse prognosis for both, biochemical (Hazard ratio (HR) = 0.5; confidence interval (CI) 95% [0.4–0.9], p = 0.011) and clinical progression (HR = 0.6; IC 95% [0.4–1], p = 0.046). SPOP mutations were found in 10% of TMPRSS2-ERG (T2E)-negative cases. Log-rank tests showed that mutations were significantly associated with biochemical progression free survival (BPFS) (p = 0.009) and also were significant in the multivariable analysis (HR = 3.4; IC 95% [1.5–7.6], p = 0.004).ConclusionsThe present study demonstrates that prognosis varies depending on SPOP expression and mutational status, hence, defining a new biotype of PCa associated with a worse prognosis.     

Elevated expression of T-lymphoma invasion and metastasis inducing factor 1 in squamous-cell carcinoma of the head and neck and its clinical significance

PurposeT-lymphoma invasion and metastasis inducing factor 1 (Tiam1) overexpression has been reported in a variety of human cancers. However, the investigation of Tiam1 in squamous-cell carcinoma of the head and neck (SCCHN) is extremely rare. The aim of the present study is to assess Tiam1 expression and to explore its role in SCCHN.MethodsTiam1 expression in 119 primary SCCHN tissue specimens was analysed by immunohistochemistry and correlated with clinicopathological parameters and patients’ survival. Additionally, 12 paired SCCHN tissues were evaluated for Tiam1 expression by Western blotting.ResultsWestern blotting indicated that Tiam1 expression levels in SCCHN carcinomas were significantly higher than those in the corresponding paraneoplastic tissues (P < 0.001). Immmunohistochemistry staining revealed that Tiam1 was detected in all primary tumour samples, moreover, Tiam1 overexpression was significantly correlated with lymph node metastasis (P < 0.001), clinical stage (P < 0.001), histological grade (P = 0.001) and recurrence (P < 0.001). Survival analysis demonstrated that high Tiam1 expression was significantly correlated with shorter disease-free survival and overall survival (both P < 0.001). When combining the Tiam1 expression and lymph node status, Kaplan–Meier survival showed that patients with Tiam1 overexpression/lymph node metastasis (+) had both shorter disease-free and overall survival than others (both P < 0.001). Multivariate Cox proportional hazards model analysis confirmed that lymph node metastasis, histological grade and Tiam1 overexpression were statistically significant, independent predictor of prognosis for patients with SCCHN.ConclusionTiam1 may contribute to SCCHN progression, and represent as a novel prognostic indicator as well as a potential therapeutic target for SCCHN.     

High subcutaneous adipose tissue predicts the prognosis in metastatic castration-resistant prostate cancer patients in post chemotherapy setting

BackgroundCancer studies have shown that body mass index (BMI), skeletal muscle mass (SMM) and adipose tissue indexes are linked to overall survival (OS) and progression-free survival (PFS). New treatments (abiraterone acetate, enzalutamide cabazitaxel, radium-223, sipuleucel-T) have improved patient outcomes in metastatic castration-resistant prostate cancer (mCRPC). Our objective was to analyse whether body composition parameters exert a prognostic role in mCRPC patients treated with next generation of androgen receptor (AR) axis inhibitors (abiraterone and enzalutamide).MethodsAll mCRPC patients from our institution who were enrolled in two prospective trials, assessing the efficacy of abiraterone acetate and the efficacy of enzalutamide, were selected. SMM, visceral and subcutaneous adipose tissue (SAT) indexes were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues.ResultsIn the 120 patients with available data, median OS and PFS were respectively: 16 months (95% confidence interval [CI] = 12–19) and 4 months (95% [CI] = 3–6). OS was associated with the SAT index: median survival was 15 months (95% [CI] 9–18) for patients with a SAT index < median value and 18 months (95% [CI] 13–30) for patients with a SAT index above (P = 0.008). In multivariate analyses, only the occurrence of visceral metastasis (P = 0.004), pain (P = 0.015) and SAT index (P = 0.036) were statistically significant predictors of OS. From baseline to 3 months, the SMM index loss was 2.49 ± 0.44 cm²/m² (P < 0.001) corresponding to nearly 3.4 kg of muscle loss.ConclusionsHigh volume of SAT is independently associated with overall survival in mCRPC patients treated with next generation AR axis inhibitors.     

A novel panel of biomarkers predicts radioresistance in patients with squamous cell carcinoma of the head and neck

PurposeGlobal gene expression analysis was performed on pre-treatment biopsies from patients with squamous cell carcinoma of the head and neck (SCCHN) to discover biomarkers that can predict outcome of radiation based therapy.MethodsWe initially evaluated RNA expression using cDNA microarray analysis of 38 patients that received radiotherapy (RT). The five strongest candidates (VEGF, BCL-2, CLAUDIN-4, YAP-1 and c-MET) were then analysed in pre-treatment biopsies in a second group of 86 patients who received radiation based treatment using immunohistochemical staining (IHC), prepared by tissue microarray.ResultsIn the first population, 13 of 38 (34%) had no (NR) or partial response (PR) to RT. cDNA microarrays revealed 60 genes that were linked to response to therapy. In the second series, 12 of 86 patients (14%) experienced NR or PR to CRT. Cause specific survival (CSS) and recurrence free survival (RFS) at 2 years was 85% and 90% and at 3 years 81% and 84%, respectively. Biomarkers predictive for NR/PR were increased expression of vascular endothelial growth factor (VEGF) (p = 0.02), Yes-associated protein (YAP-1) (p < 0.01), CLAUDIN-4 (p < 0.01), c-MET (p < 0.01) and BCL-2 (p = 0.02). Biomarkers predictive of poor RFS were YAP-1 (p = 0.01) and BCL-2 (p < 0.01). Biomarkers predictive of poor CSS were YAP-1 (p = 0.04), VEGF (p = 0.03) and CLAUDIN-4 (p = 0.03). Furthermore, when YAP-1 and c-MET expression levels were combined the prediction of radio-resistance was increased.ConclusionAll five biomarkers were predictive of poor response to radiation based therapy. In particular, YAP-1 and c-MET have synergistic power and could be used to make treatment decisions.     

Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells – Associations with histopathology and patients outcome

AimTo elucidate cellular features accountable for colorectal cancers’ (CRC) capability to invade normal tissue and to metastasize, we investigated the level of the collagenase matrix metalloproteinase 9 (MMP-9) and its physiological inhibitor tissue inhibitor of metalloproteinases 1 (TIMP-1) in cancer cells and supporting stroma cells of CRC.MethodsImmunoreactivity of MMP-9 and TIMP-1 by carcinoma cells, lymphocytes and fibroblasts in archival specimens of paraffin-embedded primary tumours were retrospectively associated with outcome in 340 consecutive patients completely resected for CRC stages II–IV and subsequently treated with adjuvant 5-fluorouracil.ResultsExpression of MMP-9 by carcinoma cells was demonstrated in 9% of specimens without association to recurrence free survival (RFS) (HR = 1.0; 95% CI: 0.6–1.8; P = 0.9) or overall survival (OS) (HR = 0.9; 95% CI: 0.5–1.6; P = 0.6). TIMP-1 expression by carcinoma cells, which appeared in 64% of the specimens, was inversely related with RFS (HR = 1.3; 95% CI: 0.9–1.8; P = 0.08) and OS (HR = 1.5; 95% CI: 1.1–2.1; P = 0.02). Expression of TIMP-1 by fibroblasts at the invasive border was directly related to RFS (HR = 0.7; 95% CI: 0.6–0.9; P = 0.02) and OS (HR = 0.7; 95% CI: 0.6–1.0; P = 0.05). Expression of MMP-9 by lymphocytes correlated significantly with the degree of peritumoural inflammation (P = 0.02) but not with RFS (HR = 0.9; 95% CI: 0.7–1.1; P = 0.2) or OS (HR = 0.8; 95% CI: 0.7–1.0; P = 0.07).ConclusionTIMP-1 in cancer cells is associated with poor prognosis independent of its function as inhibitor of MMP-9. MMP-9 and TIMP-1 are important mediators of the host–cancer cell interaction in the tumour microenvironment with significant influence on the histopathology and on prognosis of CRC.     

CXC chemokine receptor 2 is associated with postoperative recurrence and survival of patients with non-metastatic clear-cell renal cell carcinoma

BackgroundAberrant CXC chemokine receptor 2 (CXCR2) expression has been shown to promote angiogenesis and proliferation in renal cell carcinoma (RCC). Our current study aims to evaluate the prognostic significance of CXCR2 in patients with non-metastatic clear-cell renal cell carcinoma (ccRCC).MethodsWe retrospectively enrolled 375 patients with non-metastatic ccRCC undergoing nephrectomy at Zhongshan Hospital, Fudan University between 2003 and 2008. The cohort was split into a training set (n = 184) and a validation set (n = 191). CXCR2 expression was assessed by immunohistochemical staining and its association with clinicopathologic features and prognosis were evaluated.ResultsCXCR2 expression was significantly associated with tumour size (P = 0.036 and P = 0.016, respectively) and Fuhrman grade (P = 0.009 and P = 0.001, respectively) in the training and validation sets. Moreover, high CXCR2 expression indicated poor overall survival (OS) (P < 0.001 and P = 0.001, respectively) and recurrence-free survival (P < 0.001 and P < 0.001, respectively) in the training and validation sets. The incorporation of CXCR2 into the T stage and Fuhrman grade would help to refine individual risk stratification. Furthermore, CXCR2 expression was identified as an independent adverse prognostic factor for survival (P < 0.001) and recurrence (P < 0.001). A predictive nomogram was generated with identified independent prognosticators to assess patient recurrence-free survival at 5 and 10 years.ConclusionsCXCR2 is a potential independent adverse prognostic biomarker for recurrence and survival of patients with non-metastatic ccRCC after nephrectomy.