05.01.2016

Journal article colorectal cancer

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The different classes of prostaglandins (PGs) exert their effects by binding to a G-protein-coupled cell-surface receptor, leading to changes in the cellular levels of cyclic AMP and Ca2+. Isaacson PG, Berger F, Müller-Hermelink HK, Nathwani BN, Piris MA, Swerdlow SH, et al. Figure 3: Representative cadherin-mediated intercellular interactions that are involved in cancer. Three cell types are partially depicted: a cancer cell, an endothelial cell and a non-endothelial stromal cell, which could be an osteoblast at the site of bone metastasis. Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.The Inflammation Research Center, VIB, B-9052 Ghent, Belgium. Frans van RoyFrans van Roy is Full Professor of molecular cell biology at Ghent University, Belgium, and Senior Group Leader at the Flanders Interuniversity Institute of Biotechnology (VIB), Flanders, Belgium. Epithelia occur as sheets of one layer thickness (simple epithelia) or as multiple layers (stratified epithelia), in which the basal layer rests on the basement membrane and is proliferative, whereas the suprabasal layers rest on the basal layer or on each other and undergo terminal differentiation. Adhesion can occur between cells of the same type (homotypic) or of different types (heterotypic); both binding modes can occur via molecules of the same type (homophilic) or of different types (heterophilic).
A member of a family of cadherins that comprises single-pass transmembrane proteins, which are characterized by tandem repeats of extracellular cadherin-specific domains, and by intracellular domains with two highly conserved binding sites for armadillo proteins, p120-catenin and β-catenin. Spot-like junction types, which tether the intermediate filament cytoskeleton to the plasma membrane and provide strong force-resistant mechanical properties to particular tissues such as epidermis and heart muscle.
Used in this article to indicate that a particular cadherin is causally involved in processes of formation and organization of ordered tissues and organs. Classical cadherins that phylogenetically form a distinct branch from the type I cadherins.
Multiprotein complex consisting of five proteins, including a member of the Wiskott–Aldrich syndrome protein (WASP) family and NCK-associated protein 1 (NAP1). There is increasing evidence that PGs can also modulate cellular pathways by acting directly within the nucleus. Gastric MALT lymphomas positive for the API2-MALT1 fusion gene do not respond to Helicobacter pylori–eradication therapy, but otherwise, the incidence and clinicopathological behavior of colorectal MALT lymphoma with this genetic abnormality are unclear. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The upregulation of CDH2 (also known as neuronal cadherin (N-cadherin)), CDH11 (also known as osteoblast-cadherin (OB-cadherin)) and CDH5 (also known as vascular endothelial cadherin (VE-cadherin)) in cancer cells will increase heterotypic cadherin-mediated interactions (bidirectional arrows) with endothelial and other stromal cells.
The role of intercellular junctions in cancer and other pathologies is the major focus of his research team.
A small cadherin family with two members (cadherin 16 (CDH16) and CDH17), each of which comprises seven extracellular cadherin repeats and a short cytoplasmic domain that is unable to bind to armadillo proteins.
A complex biological process in which genetic and epigenetic events lead to epithelial cells acquiring a mesenchymal gene activity signature and phenotype, which are often concomitant with increased cell migration. A glycolipid that can be attached by posttranslational modification to the carboxyl terminus of particular extracellular proteins; this structure anchors those proteins to the exterior leaflet of the apical plasma membrane. Morphogenesis implicates spatially and temporally regulated dynamical interactions of cells with their environment (or microenvironment), including neighbouring cells.
Compared to type I cadherins, their more deviating structure also results in more distant functions.
It results in de novo formation of vascular networks by tumour cells, which thereby contribute to perfusion of rapidly growing tumours.
Various WAVE complexes function as scaffolds for numerous regulatory proteins that synergistically regulate the actin cytoskeleton and the plasma membrane shape and thus mediate outward cell protrusions and intracellular vesicular trafficking.
GSK3 phosphorylates -catenin, allowing it to be recognized by an SCF complex containing the F-box protein -TrCP.
COX-2 has been localized to the perinuclear envelope, and both PGI2 and metabolites of PGD2 can transactivate members of the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors.
We examined the API2-MALT1 fusion by multiplex RT-PCR method in 47 cases of MALT lymphoma and 13 cases of diffuse large B-cell lymphoma and evaluated the relevance of API2-MALT1 positivity to the clinical and pathological features. MALT lymphoma affects various organs, among which the stomach is the most frequently involved (1, 2, 3). Besides various members of the cadherin superfamily, his research has covered α-catenins and members of the armadillo protein families.
The molecular mechanisms of cadherin-mediated morphogenesis are complex and partly unresolved. Interpretations from in vitro data (in italics) require further examination in clinical studies. HCT116 cells were infected with retrovirus containing CHI3L1 or pMXs-IRES-Puro vector control.
Other proteins in the SCF complex catalyse the addition of a polyubiquitin chain to -catenin, allowing -catenin to be recognized and degraded by the proteasome.
Moreover, the PGE2 receptor EP1 has been localized to the nuclear envelope in certain cell types, and activation of the receptor leads to changes in nuclear levels of Ca2+. Interestingly, the majority of gastric low-grade MALT lymphoma cases, those proven to be neoplastic by detection of monoclonal rearrangement in immunoglobulin (Ig) genes, regress after eradication of H. CDH5 is the predominant cadherin in normal endothelium with positive and negative influences on signalling pathways, as indicated. Protein level of CHI3L1 was upregulated by CHI3L1 overexpression as compared with control vector. Consequently, -catenin cannot reach the nucleus, and cannot co-activate TCF-responsive genes. API2-MALT1 fusion genes were detected in seven cases (15%) of MALT lymphoma and one case (8%) of diffuse large B-cell lymphoma.
In tumour-associated endothelial cells, induction of CDH13 (also known as truncated cadherin (T-cadherin)) expression leads to increased proliferation and survival.
Mice were inoculated subcutaneously with 5 × 106 HCT116 cells in the left (vector control) and right (CHI3L1) flank.
Groucho, a corepressor, also prevents the activation of TCF-responsive genes in the absence of -catenin.


API2 contains three sets of baculovirus inhibitor of apoptosis repeats (BIRs), a caspase recruitment domain (CARD), and a RING finger domain. Upregulated endothelial CDH2 functions antagonistically on endothelial CDH5, which stimulates ERK signalling and endothelial cell migration, and thereby promotes angiogenesis and tumour growth. API2 is thought to suppress apoptosis by inhibiting caspases and activation of NF-B (12, 13). This leads to a poorly understood signalling cascade in which Dishevelled activates GBP — an inhibitor of GSK3. Its cytoplasmic domain interacts with various proteins that regulate cell growth, polarity and migration, including β-catenin. Overexpression of CHI3L1 significantly enhanced xenograft tumor growth as compared with control vector. This cytoplasmic sequestration of β-catenin inhibits its nuclear transcription stimulating role.
The related FAT4 (not shown) and possibly FAT1 can stimulate the Hippo signalling pathway, which by inhibition of the YES-associated protein (YAP) transcription factor, downregulates the transcription of cancer-promoting genes. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Only a few reports have described the regression of colorectal MALT lymphomas to antibiotic treatments that are generally found to be successful for gastric tumors (22, 23). Eradication of Helicobacter pylori and stability of remissions in low-grade gastric B-cell lymphomas of the mucosa-associated lymphoid tissue: results of an ongoing multicenter trial. All cases were reviewed to confirm the histological diagnosis according to the criteria of the World Health Organization Classification for Tumors of Hematopoietic and Lymphoid Tissues (1). Lymphoepithelial lesions in colorectal MALT lymphoma were not as obvious as those of gastric tumors were (representative histologies were shown in Fig.
As summarized in Table 1, the number of MALT lymphomas was 47 (17 from males and 30 from females), and that of diffuse large B-cell lymphoma was 13 (7 from males and 6 from females).
D, plasmacytoid differentiation of the API2-MALT1–negative MALT lymphoma (arrowhead, Dutcher body).
E and F, histology of the API2-MALT1–positive diffuse large B-cell lymphoma with low-grade MALT lymphoma component (Case 8 in Fig. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Bcl10 and MALT1, independent targets of chromosomal translocation in MALT lymphoma, cooperate in a novel NF-B signaling pathway.
The MALT lymphoma cells were positive for CD20 and CD79a and negative for CD5, CD10, and cyclin D1.Immunostaining for the BCL10 protein was also performed. In brief, 3-m-thick tissue sections were heat retrieved in 10 mm citric acid buffer (pH 6.0) in a microwave oven for 30 minutes. Translocation t(11;18) absent in early gastric marginal zone B-cell lymphoma of MALT type responding to eradication of Helicobacter pylori infection.
Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. In brief, amplification of IgH genes was performed by semi-nested PCR, using primers directed to the Framework 2 or Framework 3 region and to the joining region. At least two DNA samples were extracted from each paraffin block and separately subjected to PCR reaction.
The determination as "clonal" was made only when a single or dominant discrete band was consistently reproduced from different specimens.Detection of the API2-MALT1 Fusion GeneAP12-MALT1 fusion genes were detected using the multiplex RT-PCR method as described previously (29). Primary gastrointestinal non-Hodgkin's lymphoma: a review of 175 British National Lymphoma Investigation cases.
Reverse transcription was performed using SuperscriptII (Invitrogen Japan) at 42° C for 30 minutes. With regard to clinical stages, 61% of the patients with MALT lymphoma and 30% of the patients with diffuse large B-cell lymphoma remained at Stage I. Regression of colonic low grade B cell lymphoma of the mucosa associated lymphoid tissue type after eradication of Helicobacter pylori. Regression of mucosa-associated lymphoid-tissue lymphoma of rectum after eradication of Helicobacter pylori. Extranodal involvement was seen as follows; 3 cases in the stomach, 3 in the small intestine, and 1 in the thyroid, bone marrow, and lungs, respectively.
In all cases, the main organ was colorectum, and clinical records showed colorectal origin. API2-MALT1 chimeric transcripts involved in mucosa-associated lymphoid tissue type lymphoma predict heterogeneous products. Cases that were thought to be secondary involvement or primary organ undetermined were not included in the present series.According to International Prognostic Index, the risk was found to be low in 71% of patients with MALT lymphoma and in 63% of patients with diffuse large B-cell lymphoma. Approximately one half of the patients received only resection (surgical or endoscopic) therapy. Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas. Detection of AP12-MALT1 chimaeric gene in extranodal and nodal marginal zone B-cell lymphoma by reverse transcription polymerase chain reaction (PCR) and genomic long and accurate PCR analyses.
Relapse of lymphoma occurred in 6% of MALT lymphoma cases and in 15% of diffuse large B-cell lymphoma cases.
Clinical, histopathological, and immunogenetic analysis of ocular adnexal lymphoproliferative disorders: characterization of MALT lymphoma and reactive lymphoid hyperplasia.
The patients with diffuse large B-cell lymphoma also demonstrated a respectively good survival rate (80%).
In MALT lymphomas, 27 cases arose in the rectum, followed by 7 cases in multiple sites (5 cases involving the rectum) and 5 cases in the cecum. API2-MALT1 fusion transcripts involved in mucosa-associated lymphoid tissue lymphoma: multiplex RT-PCR detection using formalin-fixed paraffin-embedded specimens. Diffuse large B-cell lymphoma cases did not seem to have such a predilection, with cases almost equally involving the cecum, ascending colon, rectum, and multiple sites.Elevated lesions (polyp or submucosal tumor) were formed in 89% of MALT lymphoma cases and 31% of diffuse large B-cell lymphoma. Ulcerative lesions were formed much more frequently in diffuse large B-cell lymphoma (62%) than MALT lymphomas (6%).The average sizes of MALT lymphomas and diffuse large B-cell lymphomas were 31 mm and 62 mm, respectively.


About half of the MALT lymphomas were localized in the submucosa, whereas 80% of the diffuse large B-cell lymphoma cases involved the subserosa or deeper tissues. Histologically, plasmacytic differentiation was found in seven MALT lymphomas often associated with Dutcher bodies (Fig. A histopathological and immunohistochemical analysis of 45 cases with clinicopathological correlations. Three of 13 cases of diffuse large B-cell lymphoma included low-grade MALT lymphoma components (Fig. 1).Clinical Outcome and Therapeutic WaysClinical outcome, therapeutic methods, and responses were summarized in Table 3. In 35 MALT lymphoma cases of Clinical Stage I or II, 29 cases (83%) achieved complete remission, and 6 (17%) were partial response or refractory. In contrast, in nine Stage IV cases, two (22%) were complete remission, and seven (78%) were partial response or refractory. In eight cases of diffuse large B-cell lymphoma at Clinical Stage I or II, seven cases were complete remission and one case was partial response or refractory. A clinicopathological and immunohistochemical study of 61 cases with an evaluation of prognostic parameters. In the resected group, 30 cases achieved complete remission, and 9 cases were partial response or refractory. In the unresected group, 1 was complete remission, and 4 were partial response or refractory. For diffuse large B-cell lymphomas, seven were in the resected group, and all achieved complete remission. As for the MALT1 gene on 18th chromosome, 5 cases had the M814 breakpoint, 1 had the M1123 breakpoint, and 2 had the M1150 breakpoint (Fig. Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALTlymphoma-associated protein. Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways. The positive nuclear immunostaining pattern for BCL 10 was observed in 9 cases of MALT lymphoma and 4 cases of diffuse large B-cell lymphoma. In the API2-MALT1–positive diffuse large B-cell lymphoma, the positive nuclear pattern for BCL 10 was detected in the proliferating large cells (Fig. A and B, BCL 10 immunostaining in API2-MALT1–positive diffuse large B-cell lymphoma with MALT lymphoma component (Case 8).
The patients with MALT lymphoma negative for API2-MALT1 fusion gene exhibited a female predominance (occurrence approximately three times more commonly than in males), but diffuse large B-cell lymphoma cases did not show such a tendency. This might be related to the fact that MALT lymphomas are often associated with an autoimmune state (1, 30), which is known to occur more frequently in females. In contrast, the API2-MALT1–positive cases actually demonstrated a male predominance in our series. As the number of API2-MALT1–positive cases was rather small, it may be difficult to form a conclusion.
In most cases, tumor cell infiltrates were mainly confined to the submucosa, forming elevated lesions (polypoid lesions or submucosal tumors) as previously reported (31).
We did not observe significant differences in tumor shapes between API2-MALT1 positive and negative cases as reported in the gastric case (16). In contrast, most diffuse large B-cell lymphoma formed ulcerative lesions (similar to those in advanced cancers), were larger in diameter, and infiltrated more deeply than MALT lymphomas.There was a good correlation between API2-MALT1 positivity and clinical stages in MALT lymphomas.
Advanced tumor stage at diagnosis (including regional lymph node infiltration) is one of the predictive prognostic factors of gastrointestinal lymphomas (31, 32, 33, 34, 35). In our cases, however, there was no significant difference in prognosis between API2-MALT1 –positive and negative cases of MALT lymphoma. In MALT lymphoma cases, 42 patients were alive for the follow-up period, and only 1 patient died of lymphoma; the patient in the other case died of urothelial carcinoma.
It is said that MALT lymphomas demonstrate indolent progression and result in a good prognosis.
For patients diagnosed in the early stage of the gastric lymphoma, the 5-year survival rate is >90%, and 10-year survival is about 70% (32, 34).
However, it has been reported that MALT lymphomas in the advanced stage are resistant to chemotherapy and have a rather poor prognosis (34, 35). Therefore, the API2-MALT1–positive group might have a poor prognosis if longer follow-up data are examined.
As shown in Table 3, achievement of complete remission was closely related to lower clinical stage. Most patients were treated with surgery or endoscopic resection, and being in the unresected group may result in failure of remission, though such cases were rather small in number.
In the present study, most cases positive for the API2- MALT1 fusion gene displayed nuclear immunostaining with BCL10, which is compatible with a previous report (38).
BCL10 binds to the Ig-like domains of MALT1, and the complex functions in the inhibition of apoptosis (39). The API2-MALT1 fusion gene was detected in one of the 13 diffuse large B-cell lymphoma cases.
In this case, which contained a low-grade MALT lymphoma component, nuclear staining of BCL10 was observed in large lymphoma cells as well as MALT lymphoma cells. We checked BCL-6 expression and found that large cells of this case expressed BCL-6 (data not shown). This is compatible with previous reports that t(11;18) is not detectable in diffuse large B-cell lymphoma (43, 44, 45, 46). Interestingly, we also have a similar case in ocular adnexa lymphomas that has recently been published in this journal(47).In summary, most colorectal MALT lymphomas demonstrate indolent progression, and therefore, partial resection is thought to be the first line of therapy.



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