Intestinal-type Gastric Cancer Research Articles

Adhesion of Gastric Cancer Cells to the Enteric Nervous System: Comparison between the Intestinal Type and Diffuse Type of Gastric Cancer.

Simple SummaryGastric cancer is one of the leading cause of cancer-related deaths worldwide. The role of the enteric nervous system, a component of the tumor micro-environment in digestive cancers is of growing interest, since enteric neurons may be a route for cancer dissemination. The aim of this study was to investigate the adhesion of the gastric cancer cells to the neurons of the enteric nervous system. We showed that enteric neurons were a privileged site of gastric cancer cell adhesion, particularly in diffuse-type gastric cancer cell lines. We showed that this phenomenon was partially mediated by N-Cadherin, an adhesion protein whose blockade resulted in a dramatic decrease in adhesion ability. These results support the role of enteric neurons as a potential route for cancer cells dissemination, particularly in diffuse-type gastric cancer.Background: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. The enteric nervous system (ENS) has been suggested to be involved in cancer development and spread. Objective: To analyze the GC cell adhesion to the ENS in a model of co-culture of gastric ENS with GC cells. Methods: Primary culture of gastric ENS (pcgENS), derived from a rat embryo stomach, was developed. The adhesion of GC cells to pcgENS was studied using a co-culture model. The role of N-Cadherin, a cell-adhesion protein, was evaluated. Results: Compared to intestinal-type GC cells, the diffuse-type GC cancer cells showed higher adhesion to pcgENS (55.9% ± 1.075 vs. 38.9% ± 0.6611, respectively, p < 0.001). The number of diffuse-type GC cells adherent to pcgENS was significantly lower in neuron-free pcgENS compared to neuron-containing pcgENS (p = 0.0261 and 0.0329 for AGS and MKN45, respectively). Confocal microscopy showed that GC cells adhere preferentially to the neurons of the pcgENS. N-Cadherin blockage resulted in significantly decreased adhesion of the GC cells to the pcgENS (p < 0.01). Conclusion: These results suggest a potential role of enteric neurons in the dissemination of GC cells, especially of the diffuse-type, partly through N-Cadherin.

Clinicopathological differences, risk factors and prognostic scores for western patients with intestinal and diffuse-type gastric cancer

BACKGROUNDIn the molecular era, the Laurén system is still a cost-effective and widely implemented classification for gastric cancer (GC) and it has been recently associated with clinical, histological and molecular features of these tumors. Despite recent advances in the understanding of the molecular biology of GC, there is a need to develop new prognostic tools for patient stratification in clinical practice. Thus, the identification of easily available prognostic factors in patients with intestinal and diffuse-type tumors can significantly improve risk assessment and patient stratification in GC.AIMTo identify clinicopathological differences, risk factors, and to develop cost-effective prognostic scores for patients with intestinal and diffuse-type GC.METHODSRetrospective study of all patients undergoing surgery for GC at a tertiary referral center from 2001 to 2019. 286 cases met inclusion criteria (intestinal: 190, diffuse: 96). Clinical data and gross findings were collected. All specimens were reviewed by two independent pathologists and a detailed protocol for histologic evaluation was followed. Five tissue microarrays (TMAs) were constructed and sections of the TMA block were immunostained for HERCEPTEST, MSH2, MSH6, MLH1 and PMS2. Statistical analyses were performed and prognostic scores were developed based on hazard ratios.RESULTSIntestinal and diffuse-type GC showed different epidemiological, clinicopathological and prognostic features. Diffuse tumors were significantly associated with younger age, less symptomatology, flat morphology, deeper invasion, perineural infiltration, advanced stage at diagnosis, administration of adjuvant therapy and poorer prognosis. Intestinal lesions were fungoid or polypoid, showed necrosis, desmoplasia, microsatellite instability and HERCEPTEST positivity and were diagnosed at earlier stages. Tumor depth, desmoplasia, macroscopic type and lymph node involvement were independently related to the Laurén subtype. Furthermore, intestinal and diffuse GC were associated with different risk factors for progression and death. Vascular invasion, perineural infiltration and growth pattern were important prognostic factors in intestinal-type GC. On the contrary, tumor size and necrosis were significant prognosticators in diffuse-type GC. Our recurrence and cancer-specific death scores for patients with intestinal and diffuse-type GC showed an excellent patient stratification into three (diffuse GC) or four (intestinal) prognostic groups.CONCLUSIONOur findings support that Laurén subtypes represent different clinicopathological and biological entities. The development of specific prognostic scores is a useful and cost-effective strategy to improve risk assessment in GC.

Dynamic change of circulating innate and adaptive lymphocytes subtypes during a cascade of gastric lesions

According to the Correa model, the intestinal-type gastric cancer (GC) is preceded by premalignant lesions, including chronic gastritis, intestinal metaplasia and dysplasia. However, the dynamic change of innate and adaptive immune response during this process has not been studied comprehensively. In this study, we performed a comprehensive and trajectory analysis of circulating innate lymphoid cells (ILCs) and adaptive Th lymphocytes subtypes in patients spanning a cascade of gastric lesions. Increased circulating ILC2s frequency was found in the gastritis, premalignant stage and GC group, whereas further decreased ILC2s were detected in the GC group compared with the premalignant group. Moreover, ILC3s level was higher in both gastritis, premalignant lesion and GC stage, compared with healthy controls. Furthermore, up-regulated T follicular helper (Tfh) cell proportions were detected in the gastritis and premalignant process. In conclusion, by analyzing the circulating ILCs and Th cells frequency and the key cytokine production or immunoglobulin level, we demonstrated the potential involvement of ILC3 and Tfh in the gastric diseases. These findings will help to understand the immunologic mechanisms in both GC and the premalignant process and contribute to serve potential therapeutic targets to prevent the GC development.

Prognostic role of tumor stroma ratio, tumor-infiltrating lymphocytes, and tumor budding in patients with intestinal-type gastric cancer after radical resection.

4055 Background: Tumor microenvironmental (TME) features including tumor stroma ratio (TSR), tumor infiltrating lymphocytes (TILs) and tumor budding (TB), may be associated with tumor metastatic potential. We sought to identify the association of these features with prognosis of patients with resectable intestinal-type gastric cancer. Methods: Radical resection of gastric carcinoma (&gt; 15 LNs removed) was performed in 493 patients (stage I, n=225; stage II, n=119; stage III, n=149) at two university hospitals between 2010 and 2016. Cutpoints were as follows: TSR (50%), TILs (median), and TB (Bd0-Bd3). TME features and their association with clinicopathological characteristics, time-to-recurrence (TTR) and overall survival (OS) were analyzed by univariate and multivariate Cox methods.. Results: Among 493 patients, high TSR, low TILs and high TB (Bd1-Bd3) were significantly associated with higher histological grade, larger tumor size, and increased T and N stages. Each of these features was significantly associated with poorer TTR and OS at 5 years. In Cox multivariable analysis, N stage and TSR were the only variables that were significantly associated with TTR and OS (Table). The relative contribution (%) of TSR to TTR ranked second (17.5%) behind N stage (49.2%) and ahead of TILs (7.2%) and TB (0.1%). Conclusions: Among TME features, TSR was the most robust and was significantly and independently associated with TTR and OS. The relative contribution of TSR to TTR was second only to nodal status. [Table: see text]

Epigenetic modification facilitates proline synthase PYCR1 aberrant expression in gastric cancer

Background & aimsPyrroline-5-carboxylate reductase 1 (PYCR1) upregulation contributes to the progression of gastric cancer (GC) and indicates poor survival. However, PYCR1 expression profile in GC subtypes and the mechanism behind its upregulation are not well-studied. MethodsPYCR1 expression profiles in GC subtypes and different stages of gastric carcinogenesis were assessed in different GC cohorts. Genetic alterations and epigenetic modulation in PYCR1 regulation were further investigated using bioinformatics analysis and in vitro experiments. ResultsPYCR1 expression was significantly higher in intestinal-type GC and associated molecular subtypes in TCGA and ACRG GC cohorts. During the cascade of intestinal-type GC, PYCR1 was continuously increased from normal gastric tissues through to atrophic gastritis, to intraepithelial neoplasia, and to GC. Copy number alterations in PYCR1 were associated with PYCR1 transcript expression. One CpG island was observed in PYCR1 promoter region, and the hypomethylation occurred at this region could contribute to PYCR1 transcriptional activation in GC. Besides, H3K27ac combination was found in PYCR1 promoter, and acetyltransferase p300 induced H3K27ac could promote PYCR1 expression in GC. ConclusionsPYCR1 expression varies across GC subtypes, with intestinal-type GC and associated molecular subtypes having the highest expression. Hypomethylation at CpG sites and p300-induced H3K27ac modification within PYCR1 promoter could contribute to maintaining PYCR1 overexpression in GC. These results provide us with a new insight into epigenetic modulation in mitochondrial proline metabolism.

SERUM PEPSINOGEN I AND PEPSINOGEN II AS NON-INVASIVE BIOMARKERS FOR THE DIAGNOSIS OF CHRONIC ATROPHIC GASTRITIS

Atrophic gastritis, intestinal metaplasia and dysplasia of the gastric mucosa are major risk factors for the development of an intestinal type of gastric cancer. The selection of patients with such lesions could help with early detection and improve better the prognosis. Esophagogastroscopy is the "gold standard" in detecting gastric cancer and precancerous lesions of the stomach. However, this examination is invasive, expensive, and cannot serve as a screening method. Measurement of serum levels of pessinogen I and pessinogen II is used in high-risk populations in Europe and Asia as a non-invasive marker for the diagnosis of chronic atrophic gastritis. A serum pepsinogen I level ≤ 70ng/ml and pepsinogen I/pepsinogen II ratio ≤ 3 are accepted in many countries as values that most accurately identify patients with advanced atrophic gastritis. On the other hand, the differences in the analytical methods used to determine the level of pepsinogens make the interpretation of results and diagnostic validation difficult.

Quantification of the Landscape for Revealing the Underlying Mechanism of Intestinal-Type Gastric Cancer.

Gastric cancer is a daunting disease with a tragic impact on global health. It is the fourth most common cancer and has become the second most frequent cause of cancer death in recent times. According to the Lauren classification, gastric cancer can be classified into two types: intestinal and diffuse. Intestinal-type gastric cancer (IGC) is more common in elderly people, and atrophic gastritis (AG) and intestinal metaplasia (IM) have been proven to be the main premalignant causes of intestinal-type gastric cancer. In turn, Helicobacter pylori infection has been identified as the most significant cause of AG and IM. In this study, we determine the mechanism of IGC progression and how H. pylori infection induces IGC. Through researching the relevant literature, we identified the key genes associated with gastric cancer and the specific genes associated with IGC. We then use hese genes to build up a gene regulatory network for IGC. Based on this gene regulatory network, we quantify the IGC landscape. Within this landscape, there are three stable states, which are classified as the normal, AG, and gastric cancer states. Through landscape topography, we can determine the biological features and progression process of IGC. To investigate the influence of H. pylori infection on IGC, we simulated different degrees of H. pylori infection. As the H. pylori infection becomes more serious, the landscape topography changes accordingly. A fourth state, named the intestinal metaplasia (IM) state, emerges on the landscape and is associated with a very high risk of developing gastric cancer. The emergence of this state is due to the interactions/regulations among genes. Through variations in the landscape topography, we can determine the influence of H. pylori infection on IGC. Finally, we use global sensitivity analysis to research the regulations most sensitive to IGC prevention or therapies. This study presents a new approach and a novel model with which to explore the mechanism of IGC. The simulations of different degrees of H. pylori infection can provide us with a systematic view of IGC progression. The key regulations found can give us some insight and guidance for clinical trials and experimental studies.

Photodynamic Diagnosis for the Identification of Intestinal-Type Gastric Cancers and High-Grade Adenomas.

Gastric cancer is the second most common cancer in Japan. The incidence of gastric cancer remains high owing to the increase in the elderly population. Endoscopy outperforms radiography in identifying early gastric cancer (EGC). Furthermore, image-enhanced endoscopy (IEE) has been developed and implemented worldwide in clinical practice. Magnifying IEE images can help to visualize the microvascular pattern and microstructure architecture, which is used for the characterization of EGC. However, accurate endoscopic diagnosis requires the experience and skill of endoscopists, making an objective and simple diagnostic method desirable. In this retrospective study, we investigated the diagnostic yield of 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) for identifying gastric cancers and high-grade adenomas. In total, 52 lesions from 43 patients were ultimately included in the study. We detected 5-ALA-mediated protoporphyrin IX fluorescence in 45 of the 52 lesions that were initially intended for PDD, resulting in a detection rate of 86.5%, whereas each signet ring cell carcinoma was negative using 5-ALA PDD. In eight of the patients with multiple lesions, 17 lesions were identified using 5-ALA PDD. Again, we took biopsies from six areas that we suspected as new lesions. While 4 lesions were gastric neoplasms resected by endoscopic submucosal dissection, two other lesions were normal. Preoperative 5-ALA-PDD could provide additional diagnostic yields to detect such multiple lesions simultaneously. No severe adverse events were observed. Prospective multicenter studies are warranted to confirm the usefulness of 5-ALA PDD for EGC identification.

Differential expression of metallothionein and p21 in gastric cancer and some precursor lesions.

Gastric cancer (GC) is a heterogeneous disease with molecular diversity between and within tumors; therefore, searching for altered genes within this cancer is mandatory to reach the proper individualized targeted therapy. Expressions of Metallothionein (MT) and p21 are not uniform in various types of cancers and their predictive value in GC is controversial. This study aimed to assess the role of MT and p21 in intestinal-type GC and some of its precursor lesions. Immunohistochemical staining for MT and p21 was applied on paraffin blocks belonging to 30 GCs and 51 benign gastric lesions/precancerous lesions [33 chronic gastritis and 18 chronic gastritis with gastric intestinal metaplasia (GIM)]; 27 of them were associated with H. pylori infection. MT expression was dramatically increased while p21 expression was dramatically decreased from chronic gastritis to GIM to GC. In precancerous lesions, H. pylori-positive cases had significantly higher MT expression and lower p21 expression compared to H. pylori-negative cases. In GCs, decreased expression of both MT and p21 was associated with high-grade and advanced-stage cancers. Both MT and p21 may have a role in the development and progression of GC, and both proteins may be useful for selecting targeted therapy for GC patients.

EXOC4 Promotes Diffuse-Type Gastric Cancer Metastasis via Activating FAK Signal.

The EXOC4-FAK axis promoted DGC metastasis and could be a potential therapeutic target for patients with DGC.

Differential Expression of Long Noncoding RNA HOTAIR in Intestinal Metaplasia and Gastric Cancer.

INTRODUCTION:High expression of HOTAIR promotes tumor growth and carries a dismal prognosis for the patient. We investigated the prognostic value of HOTAIR expression in gastric cancer (GC) and systematically delineate the expression in relation to Helicobacter pylori infection and preneoplastic changes.METHODS:HOTAIR expression was analyzed in surgical paired tissue samples of patients with GC and biopsy samples from patients with atrophic gastritis and/or intestinal metaplasia (AG ± -IM), chronic nonatrophic gastritis, and controls. The cancer genome atlas (TCGA) data were used for validation. HOTAIR expression was evaluated in sera and ascites of patients with GC. Quantitative HOTAIR expression analysis was performed using quantitative polymerase chain reaction, and LINE-1 methylation was assessed by bisulfite pyrosequencing.RESULTS:HOTAIR was more frequently detected in tumor tissues compared with adjacent gastric mucosa (65.4% vs 8.6%). HOTAIR expression was associated with depth of tumor invasion and tumor location and with shorter overall survival in patients with diffuse-type GC as confirmed in the TCGA cohort. HOTAIR was not detectable in controls but was found in 2.2% of patients with chronic nonatrophic gastritis and 18.3% of patients with AG ± IM, which was further associated with IM, grade of IM, and H. pylori positivity.DISCUSSION:HOTAIR expression was associated with GC and preneoplastic changes of stomach mucosa. Although HOTAIR expression was strongly linked to IM, HOTAIR expression was only associated with worse prognosis in Lauren diffuse and not intestinal type of GC. Further studies are needed to evaluate the value of HOTAIR as diagnostic and predictive biomarker in IM and translational therapeutic relevance of HOTAIR in diffuse-type GC.

AGA Institute Quality Measure Development for the Management of Gastric Intestinal Metaplasia With Helicobacter pylori

AGA Institute Quality Measure Development for the Management of Gastric Intestinal Metaplasia With Helicobacter pylori

Gastric Cancer in Older Patients: A Retrospective Study and Literature Review.

BackgroundWith increasing life expectancy, the incidence of gastric cancer (GC) in older adults is increasing. This study analyzed differences in GC characteristics according to age and sex among patients who underwent surgical treatment for GC.MethodsA total of 2,983 patients diagnosed with gastric adenocarcinoma who underwent surgical treatment at Seoul National University Bundang Hospital between 2003 and 2017 were classified into three groups: I (<65 years, n=1,680), II (60–74 years, n=919), and III (≥75 years, n=384). We compared the baseline clinical characteristics, pathological characteristics of the tumor, overall and GC-specific survival rates, and associated risk factors between the groups.ResultsCancer of the distal third of the stomach (p<0.001), with intestinal-type histology (p<0.001), and with p53 overexpression (p=0.004) were more common in groups II and III than in group I, and the proportion of intestinal-type GC increased with age. The cancer type, lymph node metastasis, and cancer stage did not differ significantly. In terms of overall survival, survival decreased with increasing age (p<0.001), but this difference decreased significantly for GC-specific survival. Cox multivariate analyses revealed age, histologic type (diffuse or mixed type), and advanced cancer stage (p=0.002, 0.001, and <0.001, respectively) as risk factors for GC-related mortality.ConclusionAge itself was found to be one of the most important prognostic factors for overall and disease-specific survival in elderly GC patients, along with cancer stage.

The Prognostic Significance and Gene Expression Characteristics of Gastric Signet-Ring Cell Carcinoma: A Study Based on the SEER and TCGA Databases.

PurposeThis study is based on the Surveillance, Epidemiology, and End Results (SEER) program to explore the prognostic differences between signet-ring cell carcinoma (SRC) and intestinal-type gastric carcinoma (ITGC). This study is also based on gene sequencing data from The Cancer Genome Atlas (TCGA) to identify unique genetic contributions to the prognostic differences between the two subtypes of gastric cancer.Patients and MethodsThe clinical data were based on the SEER database from 2004 to 2015. Kaplan–Meier (KM) curves were used to compare 5-year overall survival (OS), and Cox regression was used for univariate and multivariate analyses. Gene expression profiles were obtained from TCGA database, and differentially expressed genes (DEGs) were screened. Functional enrichment analysis, protein interaction and survival analysis will be further carried out. Genes of interest were verified by the Human Protein Atlas, immunohistochemistry, and encyclopedia of Cancer Cell Lines (CCLE). The relationship between genes of interest and immune cell infiltration was also analyzed by Tumor Immune Estimation Resource (TIMER).ResultsCompared with ITGC patients, SRC patients were more likely to be female, tended to be younger, and have a greater tumor distribution in the middle and lower stomach (p < 0.01). SRCs showed a significantly better prognosis than ITGCs (p < 0.01) in early gastric cancer (EGC), while the prognosis of SRCs was significantly worse than ITGCs (p < 0.05) in advanced gastric cancer (AGC). A total of 256 DEGs were screened in SRCs compared to ITGCs, and the enrichment analysis and protein interactions revealed that differential genes were mainly related to extracellular matrix organization. Thrombospondin1 (THBS1) and serpin peptidase inhibitor, clade E, member 1 (SERPINE1) are significantly differentially expressed between SRC and ITGC, which has been preliminarily verified by immunohistochemistry and open-source databases. THBS1 and SERPINE1 are also associated with multiple immune cell infiltrates in gastric cancer.ConclusionsThere were significant differences in the clinicopathological features and prognosis between SRC and ITGC. These results suggest that SRC and ITGC may be two distinct types of tumors with different pathogeneses. We found many codifferentially expressed genes and important pathways between SRC and ITGC. THBS1 and SERPINE1 were significantly differentially expressed in the two types of gastric cancer, and may have potentially important functions.

Diffuse-type Gastric Cancer

Gastric cancer is the most prevalent malignant tumor in Korea. Histologically, it is often classified into intestinal-type and diffuse-type. Intestinal-type gastric cancer is known to occur mainly from chronic gastritis caused by Helicobacter pylori (H. pylori) through atrophic gastritis and intestinal metaplasia, a precancerous change of the mucosa, whereas diffuse-type gastric cancer is caused by H. pylori infection, wherein active inflammation of the gastric mucosa occurs without precancerous changes in the mucosa. Compared with intestinal-type gastric cancer, it occurs at a young age, there is no difference in male to female ratio, or tends to occur more in women, and is more aggressive than intestinal-type gastric cancer. Intestinal-type gastric cancer is predominant in East Asian populations such as Koreans and Japanese, whereas diffuse-type gastric cancer has more uniform geographic distribution. In the present manuscript, I have reviewed diffuse-type gastric cancer, distinct from intestinal-type gastric cancer.

Sex-based differences in histology, staging, and prognosis among 2983 gastric cancer surgery patients.

BACKGROUNDFew studies have been conducted on sex differences in the incidence, pathophysiology, and prognosis of gastric cancer (GC).AIMTo analyze the differences in GC characteristics according to sex in patients who underwent surgical treatment for GC.METHODSA total of 2983 patients diagnosed with gastric adenocarcinoma who received surgical treatment at the Seoul National University Bundang Hospital between 2003 and 2017 were included. Baseline clinicopathological characteristics, histologic type of GC, overall and GC-specific survival rates, and associated risk factors were analyzed.RESULTSAmong the 2983 patients, 2005 (67.2%) and 978 (32.8%) were males and females, respectively. The average age of the female group (59.36 years) was significantly younger than that of the male group (61.66 years; P < 0.001). Cancer of the gastric body (P < 0.001) and diffuse-type histology (P < 0.001) were more common in females than in males. This trend was more prominent in females younger than 60 years of age, with a significantly higher proportion of diffuse-type cancer than in the male group. Regardless of sex, diffuse-type GC was more common in younger patients, and the proportion of intestinal-type GC increased with age. The overall survival rate was significantly higher in females (P < 0.001). However, this difference disappeared for GC-specific survival (P = 0.168), except for the poor GC-specific survival rate in advanced-stage cancer (stage III or above) in females (P = 0.045). The risk factors for GC-related mortality were older age, upper location of GC, and diffuse- or mixed-type histology. In terms of comorbidities, more males died from diseases other than GC, including other malignancies such as lung cancer, hepatocellular carcinoma, and pancreatic cancer, and respiratory diseases such as interstitial lung disease and chronic obstructive pulmonary disease, while there were relatively more cardiovascular or cerebrovascular deaths in females.CONCLUSIONSex-based differences in GC were observed in clinicopathological features, including age at diagnosis, tumor location, histologic type, survival rate, and comorbidities.

Intestinal Type Gastric Cancer and Gastric Adenoma

Gastric adenoma (dysplasia) is a precursor for gastric cancer and is closely associated with intestinal type gastric cancer. Thus, accurate diagnosis and proper management of gastric adenoma are extremely critical for preventing gastric cancer. The revised Vienna and World Health Organization classifications have categorized gastric adenomas into two types: high-grade and low-grade dysplasia. High-grade dysplasia requires endoscopic resection due to synchronous carcinoma or the high risk of progression to carcinoma. Although the treatment for low-grade dysplasia remains controversial, endoscopic resection is also recommended due to the potential of progression to carcinomas and the unrevealed histologic discrepancies between forceps biopsy and endoscopic specimens. According to the Lauren classification, gastric cancer is categorized into three histologic types: intestinal, diffuse, and mixed types. Intestinal and diffuse types show a distinct difference in their clinical and epidemiological features. The intestinal type, in its pathogenesis, follows the cascade of non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, adenoma, and intramucosal neoplasia (correa cascade). It tends to appear in older ages than diffuse type and show some predominance in the distal portion of the stomach. It is more common in males and is often associated with environmental factors. In this review, the current knowledge of gastric adenoma and intestinal type gastric cancer, together with relevant diagnostic and therapeutic strategies, is discussed.

E-Cadherin Modulation and Inter-Cellular Trafficking in Tubular Gastric Adenocarcinoma: A High-Resolution Microscopy Pilot Study.

Despite the numerous advances in tumor molecular biology and chemotherapy options, gastric adenocarcinoma is still the most frequent form of gastric cancer. One of the core proteins that regulates inter-cellular adhesion, E-cadherin plays important roles in tumorigenesis as well as in tumor progression; however, the exact expression changes and modulation that occur in gastric cancer are not yet fully understood. In an attempt to estimate if the synthesis/degradation balance matches the final membrane expression of this adhesion molecule in cancer tissue, we assessed the proportion of E-cadherin that is found in the Golgi vesicles as well as in the lysosomal pathway We utilized archived tissue fragments from 18 patients with well and poorly differentiated intestinal types of gastric cancer and 5 samples of normal gastric mucosa, by using high-magnification multispectral microscopy and high-resolution fluorescence deconvolution microscopy. Our data showed that E-cadherin is not only expressed in the membrane, but also in the cytoplasm of normal and tumor gastric epithelia. E-cadherin colocalization with the Golgian vesicles seemed to be increasing with less differentiated tumors, while co-localization with the lysosomal system decreased in tumor tissue; however, the membrane expression of the adhesion molecule clearly dropped from well to poorly differentiated tumors. Thus E-cadherin seems to be more abundantly synthetized than eliminated via lysosomes/exosomes in less differentiated tumors, suggesting that post-translational modifications, such as cleavage, conformational inactivation, or exocytosis, are responsible for the net drop of E-cadherin at the level of the membrane in more anaplastic tumors. This behavior is in perfect accordance with the concept of partial epithelial-to-mesenchymal transition (P-EMT), when the E-cadherin expression of tumor cells is in fact not downregulated but redistributed away from the membrane in recycling vesicles. Moreover, our high-resolution deconvolution microscopy study showed for the first time, at the tissue level, the presence of Lysosome-associated membrane glycoprotein 1 (LAMP1)-positive exosomes/multivesicular bodies being trafficked across the membranes of tumor epithelial cells. Altogether, a myriad of putative modulatory pathways is available as a treatment turning point, even if we are to only consider the metabolism of membrane E-cadherin regulation. Future super-resolution microscopy studies are needed to clarify the extent of lysosome/exosome exchange between tumor cells and with the surrounding stroma, in histopathology samples or even in vivo.

Effects of Reproductive Factors on Lauren Intestinal-Type Gastric Cancers in Females: A Multicenter Retrospective Study in South Korea.

Background/AimsGastric cancers (GCs), particularly the Lauren intestinal type, show a male predominance. The aim of this study was to investigate the effects of reproductive factors on GCs in females, according to Lauren classification.MethodsMedical records of 1,849 males and 424 females who underwent radical gastrectomy or endoscopic resection for GCs between 2010 and 2018 were reviewed. The incidences of intestinal-type GCs were compared between males and groups of females stratified according to postmenopausal period. Associations between reproductive factors in females and intestinal-type GCs were analyzed using multivariate models.ResultsThe proportions of intestinal-type GCs were significantly lower in premenopausal (19%), less than 10 years postmenopausal (30.4%), and 10 to 19 years postmenopausal females (44.1%) than in males (61.0%) (p<0.05 for all). Females ≥20 years postmenopause had a proportion of intestinal-type GCs similar to that in males (60.6% vs 61.0%; p=0.948). Multivariate analysis revealed that age (odds ratio [OR], 1.075; 95% confidence interval [CI], 1.039 to 1.113; p<0.001) and parity ≥3 (OR, 1.775; 95% CI, 1.012 to 3.114; p=0.045) were positively associated with an increased risk of intestinal-type GCs in postmenopausal females, while long fertility duration (OR, 1.147; 95% CI, 1.043 to 1.261; p=0.005) was positively associated with an increased risk of intestinal-type GCs in premenopausal females.ConclusionsThere were no significant differences in the proportions of intestinal-type GCs between males and females ≥20 years postmenopause, suggesting that female reproductive factors play a role in the prevention of intestinal-type GC.

Expression of Alpha-Methyl Acyl-Co-enzyme Racemase in Gastric Carcinomas

Introduction: Alpha-Methyl Acyl-Co-enzyme Racemase (AMACR, EC 5.1.99.4, also known as P504S) is a mitochondrial and peroxisomal enzyme involved in branched fatty acids oxidation. High dietary intake of branched fatty acids may result in overproduction of AMACR, which is associated with the development of many cancers including prostate, kidney, breast, ovary, liver and gastrointestinal cancers. Several reports have also shown an association between consumption of fat and increased risk of gastric cancer, especially intestinal type gastric carcinomas. Aim: To determine and compare the expression of AMACR in clinical types and various histological grades of gastric carcinomas. Materials and Methods: This was a cross-sectional study conducted from November 2016 to May 2018 at Osmania Medical College/General Hospital, Hyderabad, Telangana, India. The tissue cores of the included biopsied samples of 50 gastric carcinomas, with regions of interest were removed to prepare a tissue microarray and Immunohistochemical (IHC) staining for AMACR was performed. The stained slides were graded based on the intensity of staining and results were evaluated using Chi-square test. Results: Of the 50 gastric carcinomas (32 males and 18 females; age range: 22-80 years) cases studied, 26 were intestinal type and 24 were diffuse type. According to cancer grade, 17 were well differentiated, nine were moderately differentiated and 24 were poorly differentiated. Abnormal AMACR staining was seen in 73.07% (19) cases of well and moderately differentiated adenocarcinoma and 33.33% (8) cases of poorly differentiated adenocarcinoma. The AMACR staining was found to be statistically significantly associated with the differentiation grading of the tumour (p-value 0.016). Abnormal staining for AMACR was seen more in well differentiated compared to moderately and poorly differentiated carcinomas. IHC expression of AMACR showed a statistically significant correlation with Lauren’s type of gastric cancer (p-value 0.005). Conclusion: The AMACR is a racemase present in the cytoplasm; cytoplasmic staining is observed in gastric carcinoma and also with histological grade. Abnormal staining for AMACR was seen more in well differentiated compared to moderately and poorly differentiated carcinomas. The expression of AMACR was significantly higher in intestinal type gastric carcinoma. Hence, the role of AMACR as a target for treating gastric cancer seems to be promising. Further studies are required to establish the role of AMACR as a diagnostic, therapeutic and prognostic tool in gastric malignancies.