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Urothelial bladder cancer represents a heterogeneous disease with divergent pathways of tumorigenesis. Tumor invasion and progression are a multifactorial process promoted by microenvironmental changes that include overexpression of matrix metalloproteinases (MMPs). Recent data clearly challenge the classic dogma that MMPs promote metastasis only by modulating the remodeling of extracellular matrix. Indeed, MMPs have also been attributed as an impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines. Levels of the different MMPs can be measured in several sample types, including tissue, blood (serum and plasma), and urine, and using different methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzymelinked immunosorbent assay, and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with cytology. Although MMP inhibitors have shown limited efficacy, advances in the understanding of the complex physiologic and pathologic roles of MMPsmight permit the development of new MMP-specific and tumor-specific therapies. In this paper we update the understanding of MMPs based on a systematic PubMed search encompassing papers published up to December 2011. [ABSTRACT FROM AUTHOR]

Background: Extracellular matrix metalloproteases (MMPs) have raised an extraordinary interest in cancer research because of their potential role in basal membrane and extracellular matrix degradation, consequently facilitating tumour invasion and metastases development.Methods: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs 1, 2, 7, 9, 11, 13, 14, and their tissue inhibitors, TIMPs 1, 2 and 3. More than 2600 determinations on cancer specimens from 133 patients with clinically localised prostate carcinoma, 20 patients with prostatic intraepithelial neoplasia and 50 patients with benign prostate hyperplasia and controls, were performed.Results: When compared with benign pathologies, prostate carcinomas had higher expression of all MMPs and TIMPs. Dendogram shows a first-order division of tumours into two distinct MMPs/TIMPs molecular profiles, one of them with high MMPs/TIMs expression profile (n=70; 52.6%). Tumours with high expression of MMP-11 or -13, or cluster thereof, were significantly associated with higher probability of biochemical recurrence.Conclusion: The expression of MMPs and TIMPs seems to have an important role in the molecular biology of prostate carcinomas, and their expression by tumours may be of clinical interest to used as indicators of tumour aggressiveness. [ABSTRACT FROM AUTHOR]

An immunohistochemical study was performed using tissue microarrays and specific antibodies against matrix metalloproteinase (MMP)-1, -2, -7, -9, -11, -13 and –14, tissular inhibitors of metalloproteinase (TIMP)-1, -2 and -3. More than 2600 determinations on cancer specimens from 131 patients with primary ductal invasive tumours of the breast were performed. To identify specific groups of tumours with distinct expression profiles the data were analysed by unsupervised hierarchical cluster analysis by each cellular type. We did not find well-defined cluster of cases for tumour cells or fibroblastic cells. However, for mononuclear inflammatory cells the dendogram shows a first-order division of the tumours into two distinct MMP/TIMP molecular profiles, designated group 1 (n=89) and group 2 (n=42). Matrix metalloproteinase-7, -9, -11, -13 and -14, and TIMP-1 and -2, were identified as showing significant high expression in group 2 compared with group 1. Multivariate analysis demonstrated that clustering for mononuclear inflammatory cells was the most potent independent factor associated with distant relapse-free survival (group 2: 5.6 (3.5–9.6), P<0.001). We identify a phenotype of mononuclear inflammatory cells infiltrating tumours, which is associated with the development of distant metastasis. Therefore, this finding suggests that these host inflammatory cells could be a possible target for inhibition of metastasis.British Journal of Cancer (2007) 97, 957–963. doi:10.1038/sj.bjc.6603963 www.bjcancer.com Published online 11 September 2007 [ABSTRACT FROM AUTHOR]

An immunohistochemical study was performed using tissue microarrays and specific antibodies against matrix metalloproteinases (MMPs) 1, 2, 7, 9, 11, 13, 14, and their tisullar inhibitors (TIMPs) 1, 2, and 3. More than 2600 determinations on cancer specimens from 131 patients with primary ductal invasive tumours of the breast (65 with and 66 without distant metastasis) and controls were performed. Staining results were categorised using a score based on the intensity of the staining and a specific software program calculated the percentage of immunostained cells automatically. We observed a broad variation of the total immunostaining scores and the cell type expressing each protein. There were multiple and significant associations between the expression of the different MMPs and TIMPs evaluated and some parameters indicative of tumour aggressiveness, such as large tumour size, advanced tumour grade, high Nottinham prognostic index, negative oestrogen receptor status, peritumoural inflammation, desmoplastic reaction, and infiltrating tumoural edge. Likewise, the detection of elevated immunohistochemical scores for MMP-9, 11, TIMP-1, and TIMP-2, was significantly associated with a higher rate of distant metastases. The expression of MMP-9 or TIMP-2 by tumour cells, MMP-1, 7, 9, 11, 13, or TIMP-3 by fibroblastic cells, and MMP-7, 9, 11, 13, 14, TIMP-1, or TIMP-2 by mononuclear inflammatory cells, was also significantly associated with a higher rate of distant metastases.British Journal of Cancer (2007) 96, 903–911. doi:10.1038/sj.bjc.6603666 www.bjcancer.com Published online 6 March 2007 [ABSTRACT FROM AUTHOR]

Purpose: To determine if collagenase 3 expression is associated with stage progression and prognosis of bladder cancer. Patients and Methods: Immunohistochemical staining for collagenase 3 was carried out on serial sections from specimens of 42 patients (32 males and 10 females) who underwent radical cystectomy for bladder cancer (median follow-up, 67.2 ± 5.99 months). Results: Immunohistochemical expression of collagenase 3 was detected in 13 (31%) patients. Pathological stage was pT2 in 12 (28.57%) patients, pT3a in 7 (16.6%), pT3b in 21 (50%) and pT4 in 2 (4.76%). Four tumours (9.52%) were grade II and 38 (90.47%) were grade III. Stage and tumours >3 cm in size were associated with bladder cancer progression-free survival and overall survival. We did not find any statistical differences with collagenase 3 expression related with stage and size. Conclusions: Immunohistochemical expression of matrix metalloproteinase 13 in invasive bladder cancer is not useful as marker for transformation and invasion. These findings should be evaluated in large multicentre prospective trials. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein D is a protein component of the human plasma lipid transport system but is also associated with a more favorable prognosis in breast cancer and ovarian cancer women. This study was undertaken to examine the tumoral expression of apolipoprotein D in endometrial cancer and to analyze the possible correlation with tumor and patients characteristics as well as androgen receptors and its prognostic significance.Methods: Immunohistochemical evaluation was used to examine apolipoprotein D expression in paraffin blocks from 58 endometrial carcinomas.Results: A total of twenty (34%) tumors stained positively. Staining was localized in tumor cells. No significant correlation was found between apo D expression and patients or tumor characteristics and androgen receptor status. In addition, apolipoprotein D expression was not associated with patient prognosis.Conclusions: Apolipoprotein D is expressed by a significant percentage of endometrial carcinomas without apparent association with other clinicopathologic parameters or with outcome of patients. [ABSTRACT FROM AUTHOR]

Abstract Background Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in breast cancer. Methods The expression levels of TLR3, TLR4 and TLR9 were analyzed on tumors from 74 patients with breast cancer. The analysis was performed by immunohistochemistry. Results Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9. Tumors showed high expression of TLRs expression levels by cancer cells, especially TLR4 and 9. Nevertheless, a significant percentage of tumors also showed TLR4 expression by mononuclear inflammatory cells (21.6%) and TLR9 expression by fibroblast-like cells (57.5%). Tumors with high TLR3 expression by tumor cell or with high TLR4 expression by mononuclear inflammatory cells were significantly associated with higher probability of metastasis. However, tumours with high TLR9 expression by fibroblast-like cells were associated with low probability of metastasis. Conclusions The expression levels of TLR3, TLR4 and TLR9 have clinical interest as indicators of tumor aggressiveness in breast cancer. TLRs may represent therapeutic targets in breast cancer.

Abstract Background To investigate the relationship between the magnetic resonance imaging (MRI) features of breast cancer and its clinicopathological and biological factors. Methods Dynamic MRI parameters of 68 invasive breast carcinomas were investigated. We also analyzed microvessel density (MVD), estrogen and progesterone receptor status, and expression of p53, HER2, ki67, VEGFR-1 and 2. Results Homogeneous enhancement was significantly associated with smaller tumor size (T1: < 2 cm) (p = 0.015). Tumors with irregular or spiculated margins had a significantly higher MVD than tumors with smooth margins (p = 0.038). Tumors showing a maximum enhancement peak at two minutes, or longer, after injecting the contrast, had a significantly higher MVD count than those which reached this point sooner (p = 0.012). The percentage of tumors with vascular invasion or high mitotic index was significantly higher among those showing a low percentage (≤ 150%) of maximum enhancement before two minutes than among those ones showing a high percentage (>150%) of enhancement rate (p = 0.016 and p = 0.03, respectively). However, there was a significant and positive association between the mitotic index and the peak of maximum intensity (p = 0.036). Peritumor inflammation was significantly associated with washout curve type III (p = 0.042). Conclusions Variations in the early phase of dynamic MRI seem to be associated with parameters indicatives of tumor aggressiveness in breast cancer.

Abstract Background In the present study we analyze, in patients with breast cancer, the tumor expression of androgen receptors (AR), its relationship with clinicopathological characteristics and with the expression of several matrix metalloproteases (MMPs) and their inhibitors (TIMPs), as well as with prognosis. Methods An immunohistochemical study was performed using tissue microarrays and specific antibodies against AR, MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. More than 2,800 determinations on tumor specimens from 111 patients with primary invasive ductal carcinoma of the breast (52 with axillary lymph node metastases and 59 without them) and controls were performed. Staining results were categorized using a score based on the intensity of the staining and a specific software program calculated the percentage of immunostained cells automatically. Results A total of 83 cases (74.8%) showed a positive immunostaining for AR, but with a wide variation in the staining score values. There were no significant associations between the total immunostaining scores for AR and any clinicopathological parameters. However, score values for MMP-1, -7 and -13, were significantly higher in AR-positive tumors than in AR-negative tumors. Likewise, when we considered the cellular type expressing each factor, we found that AR-positive tumors had a higher percentage of cases positive for MMP-1, -7, -11, and TIMP-2 in their malignant cells, as well as for MMP-1 in intratumoral fibroblasts. On the other hand, multivariate analysis demonstrated that patients with AR-positive tumors have a significant longer overall survival than those with AR-negative breast carcinomas (p = 0.03). Conclusion Our results confirm that AR are commonly expressed in breast cancer, and are correlated with the expression of some MMPs and TIMP-2. Although we found a specific value of AR expression to be a prognostic indicator in breast cancer, the functional role of AR in these neoplasms is still unclear and further data are needed in order to clarify their biological signification in breast cancer.