[show abstract][hide abstract] ABSTRACT: Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.
[show abstract][hide abstract] ABSTRACT: Urinary bladder squamous cell carcinoma and urothelial carcinoma with squamous differentiation are often high-grade and high-stage tumors that are thought to be associated with a poorer prognosis and response to therapy compared with urothelial carcinoma without divergent differentiation. Therefore, recognition of a squamous component is increasingly important in guiding prognosis and therapy. We investigated the expression of MAC387, desmoglein-3, and TRIM29 in pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation to determine whether they have utility as diagnostic biomarkers for squamous differentiation. Eighty-four cases were retrieved from participating institutions including 51 pure urinary bladder squamous cell carcinomas and 33 urothelial carcinomas with squamous differentiation. MAC387, desmoglein-3, and TRIM29 antibodies demonstrated positive staining in pure squamous cell carcinoma in 51 (100%), 46 (90%), and 48 (93%) cases, respectively. Urothelial carcinoma with squamous differentiation showed reactivity for MAC387, desmoglein-3, and TRIM29 in the squamous component for 32 (97%), 26 (79%), and 32 (97%) cases, respectively. MAC387 demonstrated a sensitivity of 99% and a specificity of 70% for squamous differentiation, whereas desmoglein-3 yielded a sensitivity of 86% and a specificity of 91%. No urothelial component showed greater than 10% labeling for desmoglein-3. TRIM29 labeling showed a sensitivity of 95%, but a poorer specificity of 33%. In summary, MAC387 and desmoglein-3 are reliable diagnostic markers for supporting the morphologic impression of squamous differentiation in urinary bladder carcinoma. Desmoglein-3 shows high specificity, whereas TRIM29 was most likely to demonstrate labeling in areas without light microscopically recognizable squamous differentiation.
[show abstract][hide abstract] ABSTRACT: Tissue transglutaminase (TG2) is a multifunctional protein that binds to fibronectin and exerts protein transamidating activity in the presence of Ca(2+). We previously reported that TG2 is upregulated in ovarian tumors and enhances intraperitoneal (i.p.) metastasis. TG2 is secreted abundantly in ovarian cancer (OC) ascites as an active enzyme, yet its function in the extracellular compartment remains unknown. To study the distinct functions of secreted TG2, we used recombinant His6-tagged TG2 and catalytically inactive enzyme in vitro and in vivo. By using i.p. and orthotopic ovarian xenografts, we show that extracellular transglutaminase promoted OC peritoneal metastasis. The main pathway activated by extracellular TG2 was noncanonical nuclear factor-kappa B (NF-κB) signaling, and the enzymatic function of the protein was required to induce phosphorylation of IκB kinase α and processing of the precursor protein p100 into the active p52 subunit. A specific target of TG2-activated p52/RelB complex is the hyaluronan receptor, CD44. Noncanonical NF-κB activation by extracellular TG2 induced CD44 up-regulation and epithelial-to-mesenchymal transition, contributing to increased cancer cell invasiveness and OC peritoneal dissemination. Taken together, our data support that noncanonical NF-κB activation is the pathway through which extracellular TG2 promotes OC metastasis.
Neoplasia (New York, N.Y.) 06/2013; 15(6):609-19. · 5.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inverted papilloma of the urinary bladder is rare, accounting for <1% of all bladder neoplasms. Although there is general consensus that inverted papilloma is benign in nature, little is known about its pathogenesis. Some have suggested that human papillomavirus (HPV) plays an etiologic role in the development of this neoplasm. These claims have not been adequately substantiated, and there is controversy as to the role of HPV in other urinary bladder neoplasms as well. To further investigate a possible etiologic role of HPV in urothelial neoplasia, we evaluated 27 inverted papillomas of the urinary bladder for the presence of HPV. Both immunohistochemical and in situ hybridization (ISH) studies for HPV and immunohistochemical analysis for p16, a surrogate marker for HPV infection, were used to assess HPV infection status. In the urinary bladder inverted papillomas of these 27 patients (age range, 35 to 78 y; M:F ratio, 11:1), no HPV was detected by HPV immunohistochemistry or by ISH. Immunoreactivity to p16 was detected in 11/27 (41%) of the cases. Expression of p16 is seen inconsistently within these neoplasms and does not correlate with the presence of HPV antigens or genes by immunohistochemistry or ISH, respectively. Therefore, p16 is not a reliable surrogate marker for HPV infection in urothelial inverted papilloma. Our findings indicate the absence of HPV in urothelial inverted papillomas. HPV testing should not be used as a diagnostic adjunct for inverted papilloma cases.
The American journal of surgical pathology 05/2013; · 4.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: There has been great progress in the understanding of the molecular events involved in normal germ cell maturation and testicular tumour pathobiology. Identification of the molecules involved in these processes has provided a number of new immunohistochemical markers for intratubular germ cell neoplasia, unclassified (IGCNU) and germ cell tumours. OCT4, the most important of the newer markers, is highly sensitive and specific for IGCNU and is superior to older immunohistochemical markers for this purpose. However, germ cell maturation delay is a potential pitfall in the application of this marker. In contrast to the type II testicular germ cell tumours, relatively little is known about premalignant lesions of testicular sex cord-stromal tumours, malignancies of the rete testis and epididymis, and paratesticular malignancies.
[show abstract][hide abstract] ABSTRACT: Glandular neoplasms involving the urinary bladder carry a challenging differential diagnosis including primary and secondary processes. We investigated the potential diagnostic utility of cadherin-17 and GATA3 in 25 primary adenocarcinomas of the urinary bladder, as compared with other commonly used markers including β-catenin and p63. Urothelial carcinoma with glandular differentiation (11), colorectal adenocarcinoma secondarily involving the bladder (25), and primary colorectal adenocarcinoma (22) were also analyzed and the results were compared using a Fisher exact test. Cadherin-17 was expressed in 23/25 primary bladder adenocarcinomas (92%), 23/25 colorectal adenocarcinomas involving the bladder (92%), 21/22 primary colorectal adenocarcinomas (95%) and entirely negative (0/11) in both components of urothelial carcinoma with glandular differentiation (P<0.001). In urothelial carcinoma with glandular differentiation, positive nuclear staining for GATA3 was evident in the urothelial component for 18% (2/11) and the glandular component for 9% (1/11) with additional tumors showing only cytoplasmic staining. Nuclear reactivity for GATA3 was not present in primary bladder adenocarcinoma and primary/secondary colorectal adenocarcinoma (P<0.05). Positive nuclear and cytoplasmic immunostaining for β-catenin was evident in 21/22 primary colorectal adenocarcinomas (95%) and 23/25 cases of secondary involvement by colorectal adenocarcinoma (92%). In contrast, positive membranous and cytoplasmic staining for β-catenin was observed in 23/25 primary bladder adenocarcinomas (92%) and 11/11 urothelial carcinomas with glandular differentiation (100%, P<0.001). p63 was expressed only in the urothelial component of urothelial carcinoma with glandular differentiation and not in the glandular component (P<0.001). In summary, cadherin-17 is a relatively specific and sensitive marker for primary adenocarcinoma of the urinary bladder, distinguishing it from urothelial carcinoma with glandular differentiation. However, it does not distinguish primary bladder adenocarcinoma from secondary involvement by colorectal adenocarcinoma. The pattern of reactivity for β-catenin remains the most useful marker for distinguishing these two tumors.Modern Pathology advance online publication, 25 January 2013; doi:10.1038/modpathol.2012.229.
[show abstract][hide abstract] ABSTRACT: Flat bladder lesions comprise a spectrum of morphologic changes ranging from reactive atypia to carcinoma in situ (CIS). Differentiating these lesions is important because of differences in patient management and clinical outcome. The precise nature of precursor lesions of bladder cancer remains incompletely understood. Urothelial CIS is the most definitely characterized precursor lesion of high grade bladder cancer. Atypia of unknown significance (AUS) is somewhat controversial. For practical purposes, AUS and reactive urothelial changes should be considered a single entity, since neither lesion has established preneoplastic potential. Simple hyperplasia and papillary hyperplasia are recently identified putative preneoplastic lesions. More recent molecular data also support the precursor nature of intestinal metaplasia and keratinizing squamous metaplasia. In this review, we also discuss the utility of molecular ancillary studies in establishing premalignant lesions, diagnosis, and differential diagnosis of flat bladder lesions.
[show abstract][hide abstract] ABSTRACT: Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway. The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone. In summary, IGF-1 activation represents an important mechanism of adaptive escape during anti-VEGF therapy in ovarian cancer. This study provides the rationale for designing bevacizumab-based combination regimens to enhance antitumor activity.
Molecular Cancer Therapeutics 06/2012; 11(7):1576-86. · 5.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a well-established association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.Modern Pathology advance online publication, 8 June 2012; doi:10.1038/modpathol.2012.103.
[show abstract][hide abstract] ABSTRACT: Data on the utility of endoscopic ultrasound-guided Trucut biopsy (EUS-TCB) for suspected gastrointestinal mesenchymal tumor (GIMT) are limited. This study aimed to determine the diagnostic yield and complications from EUS-TCB for GIMT.
Consecutive patients with suspected upper gastrointestinal or rectal GIMT from the muscularis propria with a maximal diameter of 20 mm or more were enrolled in a prospective, single-center cohort. An EUS-TCB was performed when on-site fine-needle aspiration (FNA) cytology review of the lesion was deemed suboptimal. Gastrointestinal stromal tumor (GIST) and leiomyoma were defined by the presence or absence of positive immunochemistry (IC) for c-kit, respectively. All GIMTs with a nondiagnostic IC were considered as unspecified. The outcomes assessed included diagnostic pathologic and IC yield (when tested) and procedural complications.
In this study, 38 patients (24 women; median age, 62 years) with suspected GIMT (median maximal diameter, 42 mm; range, 20-120 mm) in the esophagus (n=6), stomach (n=28), duodenum (n=3), or rectum (n=1) underwent EUS-TCB without complications. Final diagnoses included GIST for 20 patients, leiomyoma for 13 patients, unspecified GIMT for 3 patients, and unknown disorder for 2 patients. An EUS-FNA was performed for 33 (87%) of the 38 patients, a diagnostic final cytology for 25 (76%) of 33 patients, and an FNA-IC for 12 (50%) of 24 patients. The EUS-TCB (median, 3 passes; range, 1-8 passes) obtained a visible tissue specimen in 37 (97%) of the 38 patients, with a median overall maximal fragment length of 3.5 mm (range, 0-15 mm). The diagnostic final TCB histology and TCB-IC were obtained, respectively, in 79 and 97% of the samples tested.
In this cohort, EUS-TCB provided diagnostic histology and IC for 79 and 97% of the patients, respectively. For the initial biopsy of GIMT, EUS-TCB may be considered an acceptable alternative to EUS-FNA.
[show abstract][hide abstract] ABSTRACT: Urothelial carcinomas demonstrate diverse morphologic and immunologic features that frequently lead to diagnostic challenges. Recent advances have identified a number of immunohistochemical stains that, when used in the context of a panel, can be a valuable tool in properly classifying primary urothelial carcinoma and carcinomas secondarily involving the urinary bladder. In addition, new biomarkers prove helpful in the staging of bladder carcinoma. In this article, we review the clinical utility of immunohistochemistry in a series of diagnostic scenarios, including flat urothelial lesions with atypia, rare variants of urothelial carcinoma, primary adenocarcinoma versus secondary colorectal tumors, distinguishing prostate from urothelial carcinoma, and the utility of smoothelin in staging bladder carcinoma. Emphasis is placed on panels of commonly used biomarkers to establish diagnoses.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 10/2010; 18(5):401-10. · 1.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent advances in the understanding of the molecular pathology of testicular tumours have led to the identification of several new immunohistochemical markers for invasive and in situ germ cell neoplasms. OCT3/4 and NANOG are nuclear stains that have high sensitivity and specificity for the identification of intratubular germ cell neoplasia as well as seminoma and embryonal carcinoma. A potential pitfall in their application to the detection of intratubular germ cell neoplasia, as in other markers that represent oncofetal antigens, is their expression in non-neoplastic germ cells with 'delayed maturation'. SALL4, another nuclear stain, is positive for most germ cell tumours as a group and may be especially helpful in the distinction of these tumours from somatic carcinomas in non-testicular sites. Glypican 3 is a more sensitive marker for yolk sac tumour than alpha-fetoprotein. SOX2 and SOX17 may be useful for differentiating seminoma and embryonal carcinoma, especially following chemotherapy as embryonal carcinoma may lose CD30 expression in this setting. This article reviews the application of these immunohistochemical markers and others to the diagnosis of germ cell neoplasia with reference to older immunohistochemical stains when appropriate. Suggested immunohistochemical panels are described for individual tumour types.
[show abstract][hide abstract] ABSTRACT: ThinPrep is often used for endoscopic ultrasound fine-needle aspiration (EUS-FNA) samples but the sensitivity of this method is unknown. The objective of the study was to compare sensitivity and accuracy of ThinPrep versus the smear method in pancreas and lymph node samples obtained by EUS-FNA.
Patients with suspected malignancy in the pancreas or lymph node underwent EUS-FNA. On-site rapid assessment of all aspirates using the smear method was performed. After rapid assessment, three additional passes from each site were submitted into ThinPrep liquid medium. Cytopathologists interpreting the smear method and ThinPrep slides were blinded to each other. The gold standard was final cytology or pathology results.
A total of 130 patients (36 % women, mean age 63 years) underwent EUS-FNA of 139 sites (50 pancreas, 89 lymph node). Malignancy was confirmed in 47 pancreas samples (94 %) and 48 lymph node samples (54 %). Mean +/- SD number of passes made for the smear method was 2.6 +/- 1.3. For pancreatic cancer, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the ThinPrep versus the smear method were: 62 % versus 98 %, 100 % versus 100 %, 100 % versus 100 %, 14 % versus 75 %, and 64 % versus 98 %, respectively. For lymph nodes the values were 67 % versus 92 %, 100 % versus 98 %, 100 % versus 98 %, 72 % versus 72 %, and 82 % versus 94 %, respectively.
The smear method is more sensitive and accurate than ThinPrep in detecting malignancy from EUS-FNA samples of the pancreas and lymph nodes. Smear method with on-site rapid assessment should be favored over ThinPrep in suspected malignancy.
[show abstract][hide abstract] ABSTRACT: The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) with flow cytometry for the diagnosis of primary pancreatic lymphoma (PPL) has not been previously described. Our aims were to describe the EUS features of PPL and the role of EUS-FNA with and without flow cytometry in the diagnosis of 16 patients. When EUS-FNA with flow cytometry was compared with EUS-FNA without flow cytometry, the sensitivities for diagnosing non-Hodgkin's lymphoma were 84.6 % versus 30.8 %, respectively ( P = 0.01). EUS-FNA with flow cytometry is a valuable tool to diagnose PPL. Flow cytometry analysis complements traditional assessment by standard cytology.
[show abstract][hide abstract] ABSTRACT: Each major histologic category of testicular tumor includes hormonally functional neoplasms. Testicular germ cell tumors,
sex cord-stromal tumors, and tumors of neuroendocrine origin are all capable of producing one or more hormones that may result
in the clinical presentation of the tumor, be useful for diagnosis of the tumor, or serve as a tumor marker for guiding treatment
or determining prognosis. Pathology and clinical endocrine syndromes associated with testicular tumors are reviewed in this
KeywordsTestis-Germ cell tumor-Leydig cell tumor-Genetic syndrome
[show abstract][hide abstract] ABSTRACT: Anaplastic carcinoma of the pancreas (ACP) is an aggressive variant of ductal adenocarcinoma. The aim of this study was to describe a single-center experience with the use of endoscopic ultrasound (EUS) with or without fine-needle aspiration (FNA) for the diagnosis of ACP.
The cytology and surgical pathology databases were searched for a diagnosis of ACP between 1992 and 2008. Demographic, clinical,surgical, radiographic, pathological, and EUS data were abstracted.
Thirteen patients with ACP were identified, which represented 0.8% of all pancreatic cancers diagnosed during the study period. Six of 13 patients had EUS. Features of these 6 tumors: median diameter of 42 mm (range, 20-100 mm), hypoechoic (n = 6), solid (n = 3) or mixed solid and cystic (n = 3), heterogeneous (n = 5) or homogeneous (n = 1),and well defined (n = 2) or poorly defined (n = 4) borders. Five underwent EUS-FNA of a pancreatic mass, and cytology demonstrated ACP in 4 and ductal adenocarcinoma in 1. The diagnosis of ACP was confirmed after surgical resection in 2 of these 5, including one in whom cytology demonstrated only adenocarcinoma. The sixth patient had EUS without FNA, and surgical pathology after distal pancreatectomy found ACP.
Anaplastic carcinoma of the pancreas has variable endosonographic features. Endoscopic ultrasound-FNA may assist in the cytological diagnosis of these tumors.
[show abstract][hide abstract] ABSTRACT: The use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) +/- flow cytometry (FC) for the diagnosis of suspected lymphoma remains controversial. We report our experience and diagnostic yield for EUS +/- FC for suspected lymphoma.
Databases were queried for those who underwent EUS-FNA +/- FC for suspected lymphoma. Hospital charts were reviewed to confirm the final cytological diagnosis, follow up and FC results if obtained. The final diagnosis was confirmed by the results of EUS-FNA +/- FC, other biopsy and/or follow up.
In total, 54 patients underwent EUS-FNA of 72 lesions. The final diagnosis of lymphoma was made in 38 of the 54 (70%) patients, and 33 of the 54 (61%) patients relied on EUS-FNA. Cytopathology in 41 patients using EUS-FNA + FC showed lymphoma in 24 patients, atypical lymphoid cells in six and reactive lymph node in 11. In 9 of the 24 with lymphoma by EUS + FC, the diagnosis was confirmed by another diagnostic modality, like surgery, bone marrow biopsy and computed tomography-guided biopsy. Of the six with atypical lymphoid cells, additional diagnostic methods confirmed lymphoma in three. The remaining 13 of the 54 patients underwent EUS-FNA without FC due to insufficient sample (n = 5) or operator choice (n = 8). Cytopathology in these 13 patients without FC showed lymphoma (9), atypical lymphoid cells (3) and reactive node (1). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of EUS-FNA for lymphoma in all 54 patients ranged from 80% to 87%, 92% to 93%, 97%, 60% to 75% and 83% to 89%, respectively.
EUS-FNA is sensitive and specific for the diagnosis of suspected lymphoma. Confirmatory or further testing should be performed when EUS-FNA with or without FC is indeterminate and or non-diagnostic.
Journal of Gastroenterology and Hepatology 10/2009; 24(12):1826-33. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tissue transglutaminase 2 (TG2) is overexpressed in epithelial ovarian cancer (EOC) and promotes intraperitoneal metastasis. How TG2 facilitates the spread of EOC is unknown. Here, we show that TG2 regulates the expression and function of matrix metalloproteinase-2 (MMP-2), a critical mediator of tissue invasiveness. TG2 knockdown down-regulates MMP-2 protein and mRNA expression in SKOV3, IGROV-1, MDA-MB-436, and PC-3 cancer cells. TG2 knockdown or inhibition of TG2 activity using KCC009 decreases MMP-2 gelatinase activity in cancer cells. MMP-2 expression and function are regulated by TG2 at transcriptional level, as demonstrated by quantitative PCR and reporter assays. We used bioinformatics and chromatin immunoprecipitation to identify a CREB binding site in the MMP-2 promoter. Binding of CREB to the MMP-2 promoter was diminished in cells that expressed decreased TG2 levels. TG2 knockdown decreased CREB phosphorylation, and CREB knockdown decreased MMP-2 expression. The effect of TG2 on CREB activity and MMP-2 transcription is mediated by TG2-dependent degradation of protein phosphatase 2 (PP2A-alpha). We show that PP2A-alpha complexes with and is targeted for degradation by TG2. In addition to their related in vitro expression levels, TG2 and MMP-2 expression were significantly correlated in vivo, as shown by concordant immunostaining in peritoneal xenografts and in human ovarian tumors. The capacity of TG2 to regulate MMP-2 expression in vitro and in vivo identifies a mechanism that may facilitate tissue invasion and the spread of EOC. The demonstration that TG2 induced degradation of PP2A-alpha activates CREB, and thereby increases MMP-2 transcription, provides novel mechanistic insight into the pro- metastatic function of TG2.
Journal of Biological Chemistry 04/2009; 284(23):15390-9. · 4.65 Impact Factor