Mesenchymal stem cells induce tumor stroma formation and epithelial­mesenchymal transition through SPARC expression in colorectal cancer.

Tumor­stroma interactions serve a crucial role in the development of colorectal cancer (CRC), in which secreted protein acidic and rich in cysteine (SPARC) has been implicated. Due to interactions between cancer and stromal cells [mesenchymal stem cells (MSCs)], SPARC gene expression is markedly upregulated in CRC cells. The present study investigated the role of SPARC in CRC development and its potential as a biomarker. Specifically, the present study examined the association between SPARC expression and clinicopathological characteristics in 42 cases of CRC. SPARC expression in cancer cells was associated with T grade, N grade (TNM classification), stage and poor prognosis. Furthermore, the area of fibroblast­activating protein­positive staining around the cancer cells was increased in SPARC­positive compared with SPARC­negative cases. Proliferation and wound healing assays in SPARC­silenced KM12SM cells [short hairpin RNA SPARC (shSPARC)], the reduced SPARC expression of which was demonstrated by reverse transcription­quantitative PCR, revealed that the proliferative and migratory capacity of shSPARC cells did not differ from that of wild­type (WT) cells. However, it was markedly reduced when co­cultured with MSCs. Furthermore, in vivo, immunohistological analysis and RNA sequencing were conducted in an orthotopic implanted mouse model. Tumor growth and lymph node metastasis were markedly suppressed in shSPARC­transplanted tumors compared with WT­transplanted tumors, with a more marked suppression observed following shSPARC co­transplantation with MSCs. Immunohistological examination further revealed that the stromal reaction and epithelial­mesenchymal transition (EMT) were markedly suppressed in tumors co­transplanted with shSPARC and MSCs, and these results were consistent with RNA sequencing using RNA extracted from orthotopic tumors. Overall, these results suggested that SPARC expression in CRC cells is dependent on the interaction between cancer cells and stromal cells to induce EMT and promote stromal formation in the tumor microenvironment, suggesting its suitability as a novel target molecule for CRC treatment.

Involvement of non-Helicobacter pylori helicobacter infections in Helicobacter pylori-negative gastric MALT lymphoma pathogenesis and efficacy of eradication therapy.

BACKGROUND: Eradication therapy is known to be effective against Helicobacter pylori-positive gastric MALT lymphoma but predicting the efficacy of eradication therapy against Helicobacter pylori-negative gastric MALT lymphoma is difficult. Recent reports have shown that non-Helicobacter pylori helicobacter infections induce gastric MALT lymphoma, and we aimed to clarify whether non-Helicobacter pylori helicobacter infections are associated with the efficacy of eradication therapy. METHODS: We analyzed eradication therapy as a first-line treatment for 182 cases of gastric MALT lymphoma, classified according to Helicobacter pylori infection and API2-MALT1 mutation status. We also evaluated the non-Helicobacter pylori helicobacter infection status in 29 Helicobacter pylori-negative cases via PCR with DNA extracted from paraffin-embedded biopsy tissues. Finally, we analyzed the relationship between non-Helicobacter pylori helicobacter infection status and eradication therapy outcome. RESULTS: The API2-MALT1 mutation was observed in 13/182 patients (7.1%), none of whom were cured by eradication therapy. Helicobacter pylori-negative cases had a significantly higher non-Helicobacter pylori helicobacter infection rate than Helicobacter pylori-positive cases (16/29, 55% vs. 3/29, 10%; P < 0.05). Among the Helicobacter pylori-negative cases, non-Helicobacter pylori helicobacter-positive cases had a significantly higher complete response rate than non-Helicobacter pylori helicobacter-negative cases (12/16, 75% vs. 3/13, 23%; P < 0.05). CONCLUSION: Helicobacter pylori-negative and API2-MALT1-negative gastric MALT lymphoma cases exhibited a high rate of non-Helicobacter pylori helicobacter infections, which may have contributed to the success of eradication therapy. Therefore, we recommend eradication therapy as a first-line treatment for non-Helicobacter pylori helicobacter-positive gastric MALT lymphoma.

Gastric mucosa-associated lymphoid tissue lymphoma in conjunction with multiple lymphomatous polyposis in the context of Helicobacter pylori and Helicobacter suis superinfection.

A 53-year-old woman visited a doctor and complained of chest discomfort after meals. Esophagogastroduodenoscopy showed multiple granular elevations in the gastric body. After biopsies from the elevations, she was diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma. Polymerase chain reaction also detected Helicobacter pylori and H. suis. Treatment to eradicate H. pylori and H. suis was successful. Endoscopic examination after the bacterial eradication treatment showed that multiple granular elevations remained in the gastric body; however, no lymphoma cells were found during histopathological examination. Thus, we reported a case of H. pylori-positive gastric MALT lymphoma with a unique morphology associated with H. suis superinfection.

Clinical usefulness of linked color imaging for evaluation of endoscopic activity and prediction of relapse in ulcerative colitis.

PURPOSE: In the treatment of ulcerative colitis (UC), accurate evaluation of UC activity is important to achieve mucosal healing. We sought to investigate the clinical utility of linked color imaging (LCI) for the evaluation of endoscopic activity and prediction of relapse in UC patients. METHODS: We enrolled 72 consecutive UC patients in remission who underwent colonoscopy at our institution between September 2016 and October 2018. The relationship between the presence of redness in white light imaging (WLI) and LCI and histopathological inflammation (Geboes score: GS) at 238 biopsy sites was examined. We also assessed the presence or absence of planar redness in the entire rectum as ± and classified the patients into three groups according to the combination of WLI/LCI: A: WLI-/LCI-, B: WLI-/LCI+, and C: WLI+/LCI+. The relationship between WLI/LCI classification and relapse in 64 patients followed up for more than 12 months from initial colonoscopy was assessed and compared to the Mayo endoscopic subscore (MES). RESULTS: A GS of 0 or 1 accounted for 89% of WLI/LCI non-redness sites, while a GS of 2 or 3 accounted for 42% of WLI non-redness/LCI redness sites. LCI findings were significantly correlated with GS. During follow-up, 10 patients in group C and four patients in group B relapsed, but none in group A. Non-relapse rates were significantly correlated with WLI/LCI classification, but not with MES. CONCLUSION: LCI is a useful modality for accurate assessment of endoscopic activity and prediction of relapse in UC by detecting mild inflammation unrecognizable by WLI.

Clinical characteristics of inflammatory bowel disease patients with immunoglobulin A nephropathy.

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract. Some patients with this condition have been reported to present with immunoglobulin A nephropathy (IgAN), a renal complication that can cause end-stage renal failure, but the frequency of this comorbidity has not been described. Thus, the aim of this study was to investigate the frequency of IgAN in patients with IBD. METHODS: This study included 620 patients with IBD (338 with ulcerative colitis [UC] and 282 with Crohn's disease [CD]) from the Hiroshima University Hospital outpatient department. IgAN cases were identified from medical interviews, blood examinations (serum immunoglobulin A), and urinalyses (occult blood, proteinuria). Definitive IgAN cases were diagnosed by renal biopsies, while those detected through the clinical course and test results, but not clinically recommended for renal biopsy, were defined as suspected IgAN. RESULTS: We analyzed 427 cases meeting the inclusion criteria (220 with UC and 207 with CD). The incidence of IgAN across all patients with IBD was 3.0%. The frequency of IgAN was significantly higher in patients with CD (11/207, 5.3%) than in those with UC (2/220, 0.9%) (P< 0.01). Moreover, a significant correlation was found between CD patients with ileostomy or colostomy and a diagnosis of IgAN. CONCLUSIONS: Patients with IBD present a high incidence of IgAN, especially those with CD who have undergone ileostomy or colostomy.

Serum amyloid A is a better predictive biomarker of mucosal healing than C-reactive protein in ulcerative colitis in clinical remission.

BACKGROUND: Many studies have revealed that mucosal healing improves the long-term prognosis of ulcerative colitis. Frequent colonoscopy is difficult because of its invasiveness and cost. Therefore, in diagnosing and treating ulcerative colitis, noninvasive, low-cost methods for predicting mucosal healing using useful biomarkers are required in the clinical setting. This study aimed to evaluate whether serum amyloid A is a better serum biomarker than C-reactive protein in predicting mucosal healing in ulcerative colitis patients in clinical remission. METHODS: Ulcerative colitis patients whose C-reactive protein and serum amyloid A were measured within 1 month before and after colonoscopy were included in this retrospective study, and the relationship between the C-reactive protein and serum amyloid A values and the mucosal condition was analyzed. Mucosal condition was assessed using the Mayo Endoscopic Score, with score 0 or 1 indicating mucosal healing. RESULTS: A total of 199 colonoscopic examinations were conducted in 108 ulcerative colitis patients who underwent C-reactive protein and serum amyloid A blood tests. In clinical remission patients, serum amyloid A showed a strong correlation with mucosal inflammation compared to C-reactive protein and had excellent sensitivity and specificity rates with significant statistical significance. CONCLUSIONS: Serum amyloid A is a more useful marker compared to C-reactive protein in predicting mucosal inflammation in ulcerative colitis patients in clinical remission.

Helicobacter suis infection is associated with nodular gastritis-like appearance of gastric mucosa-associated lymphoid tissue lymphoma.

Most patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma are infected with Helicobacter pylori, and eradication therapy is the first-line treatment for localized disease with H pylori infection. However, there were several reports showing effectiveness of eradication therapy in even H pylori negative cases. Gastric MALT lymphomas are endoscopically classified into three common types: superficial, ulcerative, and elevated types. For the past 20 years, we have encountered 200 cases of localized gastric MALT lymphoma. Among them, only 4 cases (2%) showed similar macroscopic findings to those of nodular gastritis (gastric MALT lymphoma with nodular gastritis-like appearance; M-NGA). Here, we compared clinicopathological characteristics and prevalence of non-H pylori Helicobacter (NHPH) infection between M-NGA and other common types of gastric MALT lymphoma. To examine the prevalence of NHPH infection, DNA was extracted from formalin-fixed paraffin-embedded biopsy tissues from four cases of M-NGA, 20 cases of common endoscopic types of gastric MALT lymphoma, and 10 cases of nodular gastritis. We used a highly sensitive polymerase chain reaction assay to detect the presence of five species of NHPH (Helicobacter suis, H felis, H bizzozeronii, H salomonis, and H heilmannii). H suis infection was detected in 4, 2, and 0 of the 4, 20, and 10 cases of M-NGA, other types of gastric MALT lymphoma, and nodular gastritis, respectively. Other NHPH species were not detected in any cases. Complete response rate by eradication therapy was 4/4 in M-NGA cases. Therefore, nodular gastritis-like MALT lymphoma, which shows a very rare phenotype, is closely associated with NHPH infection, and eradication therapy may be the first-choice treatment.

Silencing of Discoidin Domain Receptor-1 (DDR1) Concurrently Inhibits Multiple Steps of Metastasis Cascade in Gastric Cancer.

Accumulating evidence suggests that a unique set of receptor tyrosine kinases, known as discoidin domain receptors (DDRs), plays a role in cancer progression by interacting with the surrounding collagen matrix. In this study, we investigated the expression and role of DDR1 in human gastric cancer metastasis. Proliferation, migration, invasion, and tube formation assays were conducted in DDR1-expressing MKN74 gastric cancer cells and corresponding DDR1-silenced cells. The effects of DDR1 on tumor growth and metastasis were examined in orthotopically implanted and experimental liver metastasis models in nude mice. The expression of DDR1 in surgical specimens was analyzed by immunohistochemistry. DDR1 was expressed in human gastric cancer cell lines, and its expression in human gastric tumors was associated with poor prognosis. Among seven gastric cancer cell lines, MKN74 expressed the highest levels of DDR1. DDR1-silenced MKN74 cells showed unaltered proliferation activity. In contrast, migration, invasion, and tube formation were significantly reduced. When examined in an orthotopic nude mouse model, DDR1-silenced implanted tumors significantly reduced angiogenesis and lymphangiogenesis, thereby leading to reductions in lymph node metastasis and liver metastasis. In a model of experimental liver metastasis, DDR1-silenced cells almost completely inhibited liver colonization and metastasis. DDR1 deficiency led to reduced expression of the genes encoding vascular endothelial growth factor (VEGF)-A, VEGF-C, and platelet-derived growth factor-B. These results suggest that DDR1 is involved in gastric cancer tumor progression and that silencing of DDR1 inhibits multiple steps of the gastric cancer metastasis process.