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Biomedical subjects

Aasmund Berner

Publications and source records attributed to Aasmund Berner.

At least 19 recordsLinked to original sources
PubMed2007

Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy.

The purpose of this study was to explore whether detection of disseminated tumor cells (DTCs) in bone marrow (BM) of nonmetastatic prostate cancer (PC) was associated with other clinical or histopathological factors at diagnoses or clinical outcome subsequent to definitive radiotherapy (RT). We evaluated BM aspirates from 272 cT(1-4)pN(0)M(0) PC patients by immunocytochemistry employing anticytokeratin antibodies (AE1/AE3). BM-status was compared with clinical and histopathological parameters. Long-term clinical outcome was assessed in 131 of the patients who all had completed definitive RT with or without androgen deprivation (AD), initiating treatment >5 years before cut-off date June 1, 2005. They had at least 1 unfavorable prognostic feature defined as cT(3-4) or Gleason score (GS) >or= 7B or PSA >or= 10 microg/l. Overall death, cause-specific death, distant metastases (DM) as first clinical relapse, local failure as first clinical relapse and biochemical failure were defined as end-points. DTCs were detected in 18% of the patients and were associated with increasing GS (p = 0.04) and percentage of Gleason pattern 4/5 (p = 0.04). The 7-year cumulative risk of DM was 21% for BM-positive patients vs. 6% for BM-negative patients (p = 0.07). In patients receiving RT without AD (n = 75), the 7-year cumulative risk of DM for BM-positive patients was 28% vs. 9% for BM-negative patients (p = 0.03). BM-status did not have impact on other end-points. In conclusion our study shows that presence of DTCs in BM at diagnosis was associated with the histological differentiation of the primary tumor and an increased risk of developing distant metastases after RT.

Aged↗
PubMed2007

Flow cytometric immunphenotyping of epithelial cancer cells in effusions--technical considerations and pitfalls.

BACKGROUND: Data regarding the role of flow cytometry (FCM) in the characterization of malignant effusions are limited to date. In the present study, we optimized the conditions for FCM immunphenotyping of effusions using a four-color analysis and investigated aspects related to the advantages and limitations of this method in this setting. METHODS: FCM analysis optimization for the study of epithelial cells was undertaken using five carcinoma cell lines, and subsequently applied to malignant pleural and peritoneal effusions using antibodies against epithelial and mesothelial markers (Ber-EP4 and EMA), CD138, and integrin subunits. FCM of frozen versus fresh specimens and the performance of FCM compared to immunhistochemistry were evaluated. RESULTS: FCM optimization was achieved and applied to clinical specimens, with resulting detection of epithelial markers and adhesion molecules on cancer cells. Frozen clinical specimens and cell lines showed reduced CD138 expression compared to fresh specimens, with conservation of the remaining epitopes. FCM generally showed comparable performance to immunhistochemistry. CONCLUSIONS: FCM is an effective method for characterization of cancer cells in clinical effusion specimens in both the diagnostic and research setting, and is comparable to immunhistochemistry in terms of sensitivity and specificity, with the additional advantage of providing quantitative data. The majority of epitopes are conserved in frozen cells, but a minority may be lost, suggesting that the thorough testing of each antibody in both conditions is mandatory.

Antibodies↗
PubMed2006

The clinical role of phospholipase A2 isoforms in advanced-stage ovarian carcinoma.

OBJECTIVE: To analyze the expression of phospholipase A2 (PLA2) isoforms and its relationship with matrix metalloproteinase (MMP) expression and clinical parameters in advanced-stage (FIGO III-IV) ovarian carcinoma. METHODS: Seventy-seven fresh frozen effusions from ovarian carcinoma patients were studied for messenger RNA (mRNA) expression of 10 secretory PLA2 (sPLA2) isoforms (IB, IIA/D/E/F, III, V, X, XII and XIII), the PLA2 receptor (sPLA2R), cytoplasmic PLA2 (cPLA2), PLA2-activating protein (PLAP) and MMP-2 using reverse transcription polymerase chain reaction (RT-PCR). Phosphorylated cPLA2 (p-cPLA2) protein expression was studied in 52 effusions using immunohistochemistry. MMP-2 and MMP-9 activity was evaluated in 22 and 20 effusions, respectively, using zymography. Expression was analyzed for correlation with clinicopathologic parameters, chemotherapy status and survival. RESULTS: PLA2 isoforms, sPLA2R, PLAP and MMP-2 mRNA was expressed in >95% of specimens. p-cPLA2 protein was expressed in 46/52 (88%) effusions. MMP-2 activity was found in all specimens, while that of MMP-9 was detected in 19/20 effusions. MMP-2 was found to be co-expressed with p-cPLA2 (p=0.003) and sPLA2-IIA (p=0.021). Lower expression of sPLA2-IIA (p<0.001) and higher expression of sPLA2-V (p=0.038) and sPLA2-XIII (p=0.001) was found in post-chemotherapy effusions. In univariate survival analysis, higher levels of sPLA2-V correlated with better overall (OS, p=0.021) and progression-free (PFS, p=0.025) survival. For patients with post-chemotherapy effusions, FIGO stage IV and higher PLAP mRNA expression correlated with worse OS (p=0.005 for both PLAP and stage), while higher PLAP (p=0.025) and sPLA2-XII (p=0.027) levels and FIGO stage IV (p<0.001) correlated with shorter PFS. In Cox multivariate analysis, PLAP expression (p=0.022) and FIGO stage (p=0.036) independently predicted poor OS, while higher sPLA2-XII levels (p=0.04) and FIGO stage (p=0.003) were independent predictors of shorter PFS. CONCLUSIONS: The present study documents for the first time expression of PLA2 isoforms, sPLA2R and PLAP in ovarian carcinoma. PLA2 isoenzyme expression differs in pre- and post-chemotherapy specimens. PLAP and sPLA2-XII may be independent predictors of poor outcome for patients with post-chemotherapy effusions.

Adenocarcinoma, Clear Cell↗
PubMed2006

Proteomic analysis of malignant ovarian cancer effusions as a tool for biologic and prognostic profiling.

PURPOSE: Malignant epithelial ovarian cancer effusions are important in disease dissemination and clinical outcome. The identification of biochemical events active in effusions may improve our identification and application of targeted therapeutics. EXPERIMENTAL DESIGN: Archival effusion samples for which outcome information was known were studied. Clinical variables were comparable between these groups. Two cohorts of patients with malignant effusion were assessed: those with effusion at presentation (Tap1) or at first recurrence (Tap2). Expression and activated fraction of selected signaling proteins were quantitated on serial protein microarrays using validated antibodies. Proteomic results and clinical variables were analyzed by univariate analysis followed by Cox proportional hazards model analysis. RESULTS: Malignant effusions (>80% malignant cells) were distinguished from benign effusions by higher expression of AKT, activated extracellular signal-regulated kinase, activated (P < or = 0.001) and total cAMP-responsive element binding protein (P = 0.01), and JNK (P = 0.03). Malignant pleural effusions could not be differentiated from ascites by signaling profiles. Both had signal expression clusters for survival, proliferation and metastasis, and injury pathways. Cox proportional hazards model analysis revealed high p38 and pEGFR/EGFR ratio as jointly associated with poor survival in Tap1 cases (both P < or = 0.002). Phospho-JNK quantity was associated with worse outcome in Tap2 patients (P = 0.004), when taking other factors into consideration. CONCLUSIONS: Proliferation, survival, and apoptosis signaling dysregulation can be identified in ovarian cancer effusion samples. Biochemical characterization of clinical effusions may provide either predictive and/or correlative information on patient outcome from which to further understand the mechanisms of effusion development and target clinical intervention.

Apoptosis↗
PubMed2006

Fine-needle aspiration cytology of the thyroid gland: comparative analysis of experience at three hospitals.

Fine-needle cytology is an effective and accurate diagnostic method for the assessment of thyroid lesions. The aim of the present study was to evaluate the role of thyroid cytology at a tertiary where cytopathologists with experience in thyroid cytology participate in the procedure and compare it with results in two community hospitals lacking pathology departments and on-site cytopathologists. A total of 1,770 specimens were diagnosed between 1998 and 2003. Of these, 425 were from the two local hospitals. The fraction of unsatisfactory specimens was 24% for submitted specimens and 9.5% for those taken in the presence of a cytopathologist. The percentage of malignant specimens was 4.1% at the tertiary center compared with 2.2% of submitted cases. These data highlight the need to centralize thyroid fine needle cytology to specialized centers with experienced cytopathologists.

Biopsy, Fine-Needle↗
PubMed2006

The biological differences between ovarian serous carcinoma and diffuse peritoneal malignant mesothelioma.

Recent improvements in immunohistochemistry panels used for differentiating ovarian serous carcinoma/primary peritoneal carcinoma (OC/PPC) from diffuse malignant peritoneal mesothelioma (DMPM) have resulted in improved diagnostic rates for these tumors in both cytological and histological material. However, little is known about the biological characteristics that differentiate these two cancer types. We performed a comparative analysis of cancer-associated molecule expression data for a cohort consisting of up to 270 serous OC/PPC specimens (only peritoneal lesions) and 32 peritoneal MM. The molecules studied were nerve growth factor receptors (p75, p-TrkA), angiogenic factors (VEGF, IL-8, bFGF, heparanase), laminin receptors (the 67-kDa receptor and the alpha 6 integrin subunit), proteases (MMP-2), immune response mediators (HLA-G), and signaling molecules (the MAPK members ERK, JNK, and p38). The methods used were immunohistochemistry, Western blotting, and RT-PCR. DMPM specimens showed significantly higher expression of p75 (P < 0.001), p-TrkA (P < 0.001), and bFGF (P < 0.001), and significantly lower expression of the 67-kDa receptor (P < 0.001), alpha 6 integrin subunit (P = 0.025), VEGF (P < 0.001), IL-8 (P < 0.001), and HLA-G (P = 0.039) compared with OC/PPC. DMPM specimens showed higher activation ratio (phosphorylated/total enzyme ratio) of all three MAPK members (ERK, P = 0.017; JNK, P < 0.001; p38, P = 0.009) compared with OC/PPC. These data document significant differences in the expression of cancer- and metastasis-associated molecules in MM compared with ovarian carcinoma, and suggest that different biological pathways are involved in tumorigenesis and disease progression in these two tumors.

Biomarkers, Tumor↗
PubMed2006

Sentinel node procedure in low-stage/low-grade penile carcinomas.

OBJECTIVE: To optimize the indication for sentinel lymph node (SLN) biopsy according to tumour size in penile carcinoma. MATERIAL AND METHODS: This was a retrospective analysis of 23 consecutive patients (median age 65 years; range 49-85 years) with primary penile carcinoma classified according to the TNM classification as stage T1-T3 who were identified as having SLNs in the groins. SLNs were detected by means of preoperative injection of a 99mTc nanocolloid around the tumour and peroperative use of a gamma detector probe. The average tumour size was 2.9+/-1.3 cm. RESULTS: In 7/25 patients with penile carcinoma examined with the SLN method, metastases to inguinal lymph nodes could be demonstrated. Two out of three patients with primary penile carcinomas classified as T1 according to the TNM classification and tumours > 3 cm in diameter had inguinal lymph node metastases. One of the patients had a micrometastasis, which was detected by means of immunohistochemical analysis. Seven out of eight patients with penile carcinomas > 3 cm in diameter had lymph node metastases. We did not observe any major surgical complications associated with the SLN procedure. CONCLUSION: These data indicate that penile carcinomas with a diameter of >3 cm should be investigated with SLN biopsy regardless of stage. However, multicentre studies are needed in order to obtain the appropriate number of patients.

Aged↗
PubMed2006

NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma.

We studied the clinical role of leukocyte infiltration and chemokine receptor expression in ovarian carcinoma effusions. Expression of leukocyte markers (CD3, CD4, CD8, CD4/CD8 ratio, CD16, CD19, and CD14) and chemokine receptors (CXCR1, CXCR4, CCR2, CCR5, and CCR7) was studied in 73 effusions by using flow cytometry. CXCR4, CCR5, and CCR7 were expressed abundantly on leukocytes, but all receptors were expressed rarely on cancer cells. The presence of natural killer cells (P = .042) and International Federation of Gynecology and Obstetrics (FIGO) stage IV disease (P = .024) predicted worse overall survival (OS). A higher percentage of CD19+ cells (P = .015) and stage IV disease (P = .008) predicted poor survival for patients with postchemotherapy effusions. Only FIGO stage retained significance as a predictor of OS (P = .035) in multivariate analysis. Chemokine receptors are expressed widely on leukocytes but rarely on carcinoma cells in ovarian carcinoma effusions, arguing against an autocrine chemokine pathway in this malignancy. Immune response parameters in ovarian cancer effusions are weak predictors of outcome.

Adenocarcinoma↗
PubMed2005

Differential expression of steroid receptors in prostate tissues before and after radiation therapy for prostatic adenocarcinoma.

The expression, distribution and the role of steroid receptors in benign and malignant untreated prostate tissues is well recognized, however, the status of steroid receptors in prostate after radiotherapy (RT) for adenocarcinoma has not yet been studied fully. Immunohistochemical evaluation of androgen receptor (AR), estrogen receptor-alpha (ER-alpha), estrogen receptor-beta (ER-beta), and progesterone receptor (PR) was carried out in prostate needle biopsies obtained before and after radiotherapy from 60 patients with adenocarcinoma. The ER-beta transcripts were also studied by RT-PCR in LNCaP prostate carcinoma cell line before and 24 hr after gamma-irradiation at 0.5 Gy and 8.0 Gy. Significantly higher level of ER-beta expression was found in post-radiation samples of prostate adenocarcinoma and benign epithelium. After RT, all steroid receptors were upregulated in prostatic stroma. Tumor AR expression did not change significantly. Although a positive association between AR and ER-beta expression was observed in pre-treatment prostate adenocarcinoma, it was lost after RT suggesting that these 2 steroid receptors respond differently to RT. High levels of pretreatment tumor ER-beta were associated with local recurrence after RT and decreased biochemical recurrence-free survival (p = 0.028). LNCaP cell line that expressed no ER-beta mRNA before gamma-irradiation, clearly expressed ER-beta mRNA 24 hr after 0.5 Gy and 8.0 Gy. Upregulation of all steroid receptors in the prostate stroma and upregulation of ER-beta in the tumor epithelium after RT, may represent a protective tissue response to radiation-induced tissue injury. Although stromal AR was doubled after RT, the tumor and benign epithelium expression of AR seemed resistant to change by RT.

Adenocarcinoma↗
PubMed2005

Variation in gene expression patterns in effusions and primary tumors from serous ovarian cancer patients.

BACKGROUND: While numerous studies have characterized primary ovarian tumors, little information is available regarding expression patterns of metastatic sites of this cancer. To define sets of genes that distinguish primary and metastatic ovarian tumors, we used cDNA microarrays to characterize global gene expression patterns in 38 effusions (28 peritoneal, 10 pleural) and 8 corresponding primary ovarian tumors, and searched for associations between expression patterns and clinical parameters. RESULTS: We observed multidimensional variation in expression patterns among the cancers. Coordinate variation in expression of genes from two chromosomal regions, 8q and 19q, was seen in subsets of the cancers indicating possible amplifications in these regions. A set of 112 unique genes of known function was differentially expressed between primary tumors and effusions using supervised analysis. Relatively few differences were seen between effusions isolated from the pleural and peritoneal cavities or between effusions from patients diagnosed with stage III and stage IV cancers. A set of 84 unique genes was identified that distinguished high from lower grade ovarian cancers. The results were corroborated using immunocytochemistry, mRNA in situ hybridization, and immunoblotting. CONCLUSION: The extensive variation in expression patterns observed underscores the molecular heterogeneity of ovarian cancer, but suggests a similar molecular profile for ovarian carcinoma cells in serosal cavities.

Adult↗
PubMed2005

[Actinic keratosis and development of cutaneous squamous cell carcinoma].

BACKGROUND: Actinic keratosis is a common sun-induced skin disease. For many years there has been a great deal of discussion of the term used for the disease and of its classification. Recent molecular studies indicate an association between actinic keratosis and squamous cell carcinoma. MATERIAL AND METHODS: Review of recent reports on histological, molecular, biochemical and clinical findings in actinic keratosis and cutaneous squamous cell carcinoma. RESULTS AND INTERPRETATION: The morphology of atypical cells in both actinic keratosis and squamous cell carcinoma is identical. The risk of progression to squamous cell carcinoma is minimal, but up to 60% of squamous cell carcinoma cases begin as actinic keratosis. Regression of actinic keratosis occurs when sun exposure is decreased. Examination of possible chromosome aberrations and gene mutations in both actinic keratosis and squamous cell carcinoma reveals similar patterns, including the same mutation in the tumour suppressor gene TP53. Recent studies indicate that actinic keratosis is the earliest manifestation of a potentially malignant disease similar to carcinoma in situ in cervix uteri. Thus, actinic keratosis requires careful diagnosis and follow up.

Carcinoma in Situ↗
PubMed2005

Mitogen-activated protein kinase expression and activation does not differentiate benign from malignant mesothelial cells.

BACKGROUND: In vitro studies of malignant mesothelioma (MM) cells have suggested activation of mitogen-activated protein kinase (MAPK) in response to asbestos exposure. The objective of this study was to investigate protein expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), the c-Jun amino-terminal kinase (JNK), and the high-osmolarity glycerol response kinase (p38) in vivo through the analysis of fresh frozen reactive mesothelium (RM) and MM specimens. METHODS: MAPK levels were analyzed in 36 fresh-frozen MM specimens (32 effusions, 4 biopsies) and in 14 RM specimens (all effusions) using immunoblotting with antibodies detecting the total (pan-) and activated (phospho-) fraction (p-) of ERK, JNK, and p38. Values for pan-MAPK and p-MAPK expression and the p-MAPK/pan-MAPK ratio in MM and RM specimens were compared. Results were corroborated using immunocytochemistry for p-ERK, p-JNK, and p-38 in selected specimens. RESULTS: Pan-ERK, pan-JNK, and pan-p38 expression was found frequently in both MM specimens (35 of 36 specimens) and RM specimens (14 of 14 specimens) using immunoblotting, with comparable findings for activated p-p38 (34 of 36 MM specimens, 13 of 14 RM specimens). Activation of p-ERK (27 of 36 MM specimens, 10 of 14 RM specimens) and p-JNK (25 of 36 MM specimens, 10 of 14 RM specimens) was less frequent. Pan-ERK (P = 0.016), pan-JNK (P = 0.004), pan-p38 (P = 0.012), and p-ERK (P = 0.02) expression levels were higher in MM specimens from female patients. Pan-p38 expression levels also were higher in peritoneal MM specimens (P = 0.019). MM and RM showed similar MAPK expression, activation, and activation ratios (Mann-Whitney test; P > 0.05). Immunocytochemistry localized MAPK to MM and RM cells. CONCLUSIONS: The current results provided the first evidence of in vivo activation of MAPK in clinical MM and RM. The similar values in these two cell types suggest that MAPK may not be involved in the transformation of benign to malignant mesothelium, thus bringing into question the validity of using MAPKs as molecular therapeutic targets in patients with MM.

Adult↗
PubMed2005

Quantitative analysis of integrin expression in effusions using flow cytometric immunophenotyping.

We have previously shown that flow cytometric (FCM) immunophenotyping is a useful adjunct to morphology, in the diagnosis of serous effusions. The objective of the present study was to evaluate the possible application of FCM to quantitative analysis of adhesion molecule expression in this clinical setting. Fresh frozen cells from 67 effusions underwent quantitative analysis of alphaV, alpha6, beta1, and beta3 integrin subunit expression, using FCM. Specimens were diagnosed as carcinoma (n = 48), reactive (n = 12), or malignant mesothelioma (MM; n = 7) using morphology and, in selected cases, immunocytochemistry prior to FCM analysis. Antibodies against established epithelial, lymphoid, and mesothelial cell epitopes (Ber-EP4, anti-epithelial membrane antigen; (EMA), anti-CD45, anti-CD14, and anti-CD15) completed the panel. Results (percentage of cells expressing the antigen) were analyzed for relationship with the morphologic diagnosis. Frequent expression of the alphaV, alpha6, and beta1 subunits was seen in all diagnostic groups, with significantly higher expression of the alpha6 subunit in MM (P = 0.029, Kruskal-Wallis H test). The beta3 integrin subunit was not detected in any of the specimens. Ber-EP4 and CD15 expression was significantly higher in carcinomas compared with reactive effusions and MM (P < 0.001 and P = 0.001, Kruskal-Wallis H test), and EMA expression was higher in carcinomas and MM, compared with reactive specimens (P < 0.001, Kruskal-Wallis H test). In conclusion, FCM is an efficient tool for quantitative analysis of adhesion molecules in effusions. The high alpha6 integrin subunit expression in MM suggests involvement of this receptor in tumor attachment to laminin. The frequent expression of the alphaV and beta1 subunits support attachment to fibronectin and vitronectin as the major ECM ligands in body cavities.

Ascitic Fluid↗
PubMed2005

Differential expression of the 67 kilodalton laminin receptor in epithelioid malignant mesothelioma and carcinomas that spread to serosal cavities.

Expression of the 67-kd laminin receptor (67-kd LR) has been reported in a wide range of carcinomas, in many of which it correlated with poor differentiation, metastasis, disease progression, and poor survival. Malignant mesothelioma (MM) is a locally aggressive and highly lethal tumor of serosal cavities that is rarely associated with clinically detectable metastasis to distant organs. The aim of this study was to analyze the expression of the 67-kd LR in epithelioid MM and carcinomas in effusions. Effusions from patients diagnosed with ovarian (=24) and breast (=38) adenocarcinomas and MM (=24) (total = 86) were analyzed for 67-kd LR protein expression, using immunocytochemistry. The 67-kd LR mRNA expression was additionally analyzed in 21 MM effusions using reverse transcription-polymerase chain reaction (RT-PCR). Protein expression of the 67-kd LR was frequently detected in carcinomas (19/24 ovarian tumors, 79%; 15/38 breast tumors, 39%), but was rare in MM (2/24 cases, 8%), despite the presence of mRNA transcripts for the receptor in all 21 specimens studied using RT-PCR. Nine benign effusions that were additionally studied for protein expression were uniformly negative, as were all reactive mesothelial cells in malignant effusions. Our results suggest that the 67-kd LR may aid in the differential diagnosis between metastatic carcinoma, mainly of ovarian origin, and MM. They additionally suggest that the failure of MM to express the 67-kd LR protein, as opposed to the frequent expression in carcinomas with proven metastatic capacity, may be one of the factors contributing to the reduced ability of the former tumor to metastasize to distant organs.

Adenocarcinoma↗
PubMed2005

HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma.

OBJECTIVE: We recently showed that the levels of secreted human leukocyte antigen-G (HLA-G), a nonclassical MHC class I antigen, are significantly elevated in malignant effusions in ovarian carcinoma compared to benign ones. The objective of this study was to evaluate the expression and clinical role of HLA-G in effusions and corresponding solid tumors from patients diagnosed with advanced-stage ovarian carcinoma. METHODS: Effusions (= 148), corresponding primary tumors (= 66), and metastatic lesions (= 122) were analyzed using immunohistochemistry with an anti-HLA-G monoclonal antibody. RESULTS: HLA-G was detected in cancer cells in 49/148 (33%) effusions, 33/66 (50%) primary tumors, and 59/122 (48%) solid metastases. These differences did not reach statistical significance. Expression in effusions and solid metastases significantly correlated (P = 0.029). HLA-G expression in tumor cells was significantly lower in effusions obtained during or following chemotherapy (P = 0.038). The presence of HLA-G-positive tumor cells in effusions obtained prior to the institution of chemotherapy correlated with better overall survival (P = 0.042). HLA-G expression in primary tumors and solid metastases did not correlate with any of the clinicopathologic parameters studied. CONCLUSIONS: HLA-G is expressed in a significant number of ovarian carcinomas at all anatomic sites. The reduced expression of HLA-G in post-chemotherapy effusions and its correlation with improved survival may be related to preferential susceptibility of HLA-G-expressing cells at this site. Our findings suggest a new role for HLA-G as a prognostic indicator in advanced-stage ovarian cancer in effusions.

Adult↗
PubMed2005

Expression of the epidermal growth factor receptor family in normal and malignant urothelium.

OBJECTIVE: To compare the immunohistochemically assessed expression of the epidermal growth factor receptor (EGFR) family in normal and malignant bladder urothelium, and suggest new hypotheses about their function in the development and progression of transitional cell carcinoma (TCC). PATIENTS AND METHODS: EGFR, ERBB2, ERBB3 and ERBB4 were evaluated immunohistochemically in normal urothelium (NU, 15), primary non-metastasized invasive TCC (NMC, 19) and in primary invasive TCCs with corresponding metastases (MC, 51, both specimens). RESULTS: All NU samples expressed ERBB4, none expressed ERBB2 and two expressed EGFR; all staining was uniform throughout all cell layers. ERBB2 expression increased and ERBB4 decreased from normal samples to carcinomas. There was no difference between NMCs and MCs in ERBB2, ERBB3 and ERBB4, but the NMCs expressed more EGFR than both NU and MC samples. There were no associations with T category, grade or survival. All combinations of expression levels for the four receptors were detected, with no dominant profile. CONCLUSION: We hypothesise that: (i) ERBB4 is important for differentiation in NU; (ii) ERBB2 is up-regulated with carcinogenesis in the urinary bladder but does not discriminate between bladder cancer with or without metastases; (iii) EGFR may be a marker of indolent disease. A current hypothesis, that superficial layers of NU do not express EGFR and thus protect the basal cells from the mitogenic effect of urinary EGF, is challenged.

Adolescent↗
PubMed2004

Altered expression of metastasis-associated and regulatory molecules in effusions from breast cancer patients: a novel model for tumor progression.

PURPOSE: The aim of this study was to characterize phenotypic alterations along the progression of breast carcinoma from primary tumor to pleural effusion through analysis of the expression of proteases, laminin receptors (LRs), and transcription factors involved in invasion and metastasis. EXPERIMENTAL DESIGN: The material studied consisted of 60 malignant pleural effusions from breast cancer patients and 68 corresponding solid tumors (37 primary and 31 metastatic tumors). Expression of matrix metalloproteinases [MMPs (MMP-1, MMP-2, MMP-9, and MMP-14)], the MMP inhibitor tissue inhibitor of metalloproteinase-2, the MMP inducer EMMPRIN, the 67-kDa LR, the alpha6 integrin subunit, and the transcription factors AP-2, Ets-1, and PEA3 was studied using immunohistochemistry, mRNA in situ hybridization, reverse transcription-polymerase chain reaction, zymography, and flow cytometry. Hormone receptor (estrogen receptor and progesterone receptor) status and c-erbB-2 status were also studied. RESULTS: Significantly reduced estrogen receptor (P < 0.001) and progesterone receptor (P = 0.001) expression was seen in effusions compared with primary tumors, with opposite findings for c-erbB-2 (P = 0.003). Tumor cell MMP-2 protein expression in effusions was higher than that in primary tumors (P < 0.001) and lymph node metastases (P = 0.01). In situ hybridization demonstrated higher MMP-2 (P = 0.007), PEA3 (P = 0.038), and EMMPRIN (P = 0.026) mRNA expression in effusions. The time to progression from primary tumor to effusion was significantly shorter for patients whose primary tumors expressed MMP-1 (P = 0.016) and who expressed the 67-kDa LR protein in primary tumor (P = 0.007) and effusion (P = 0.015). CONCLUSIONS: Our data provide documented evidence of molecular events that occur during the progression of breast carcinoma from primary tumor to effusion. The coordinated up-regulation of MMP-2 and Ets transcription factors in carcinoma cells in effusions is in full agreement with our previous reports linking these factors to poor prognosis in ovarian cancer. The rapid progression to effusion in cases showing MMP-1 and 67-kDa LR expression in primary tumor cells links aggressive clinical behavior with expression of metastasis-associated molecules in this setting.

Adult↗