Corrigendum to "MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma" [Cancer Lett. 645, (2026), 218348].
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Published Erratum↗
Biomedical subjects
Shohei Koyama
Publications and source records attributed to Shohei Koyama.
MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.
Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.
Humans↗
Intracellular localization of matrix metalloproteinases and their inhibitors in cultured tumor cell lines: flow cytometric analysis.
Coordinate cell-surface expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) on cancer cells, tumor-infiltrating lymphocytes (TIL) and cancer-associated myofibroblasts has been shown to play an important role in tumor invasion and metastasis in organ tissues. However, precise localization of tumor cell lines in vitro has remained obscure. The aim of this study was to investigate the spatial localization of these proteolytic enzymes in 21 tumor cell lines consisting of 8 gastric, 4 pancreatic, 2 gallbladder, 1 extrahepatic bile duct cancer and 6 T- or B-cell tumors. The cell-surface and/or intracellular localization of MMP-2, -7, and -9, membrane type-1 (MT1)-MMP and TIMP-2 and -4 was quantitatively determined by flow cytometry in living (non-permeabilized) and permeabilized tumor cell lines. As a result, all of the tumor cell lines showed a high level of intracellular expression, but a low or undetectable level of cell-surface expression of MMPs and TIMPs. The findings revealed that intracellular MMPs and TIMPs in tumor cell lines were preserved as latent pro-enzymes.
Cell Line, Tumor↗
Coordinate cell-surface expression of matrix metalloproteinases and their inhibitors on cancer-associated myofibroblasts from malignant ascites in patients with gastric carcinoma.
PURPOSE: The crucial role of tumor stroma in cancer cell invasion has been described in human carcinoma tissues. However, myofibroblastic invasion remains largely unexplored in malignant ascites. Purpose of this study is to investigate the spatial localization or regulation of matrix metalloproteinases (MMP-2, -7 -9, MT1-MMP) and their inhibitors (TIMP-2 and -4) on myofibroblasts from malignant ascites in 20 patients with gastric carcinoma. METHODS: The quantitative flow cytometric analysis of MMPs or TIMPs on myofibroblasts was based on the percentage of double positive cells defined by anti MMPs or anti TIMPs, and anti alpha-smooth muscle actin (alpha-SMA) antibodies. RESULT: The results clearly showed that the coordination of the high level of cell-surface expression of secreted MMPs and TIMPs was noted on the alpha-SMA+ myofibroblasts. The finding suggests the possible formation of ternary complex, MT1-MMP/TIMPs/MMPs on the cells. The events might be a cause and result of activation processing of MMPs on the cells. CONCLUSION: This study provides the presence of invasive myofibroblasts with activated MMPs in close association with MMPs+ and TIMPs+ cancer cells and tumor-infiltrating lymphocytes from malignant ascites, emphasizing the importance of molecular cross-talk in tumor-host microenvironment for cancer invasion, metastasis and progression.
Aged↗
Enhanced cell surface expression of matrix metalloproteinases and their inhibitors, and tumor-induced host response in progression of human gastric carcinoma.
The cell surface and/or intracellular expression of the matrix metalloproteinases (MMP -2, 7, and -9 and MT1-MMP) and their inhibitors (TIMP-2 and -4) were investigated in tumor and tumor-infiltrating lymphocytes (TIL) in gastric carcinoma (n = 15) from the primary locus, metastatic gastric carcinoma (n = 20) from malignant ascites, and benign gastric mucosa (n = 20) for the control. The quantitative analysis was based on the percentage of positive cells by flow cytometry. The results clearly showed increased cell surface expression of MMP-2, -7, and -9, MT1-MMP, and TIMP-2 and -4 in both tumor cells and TIL during the development of invasion and/or metastasis of gastric carcinoma. There were equilateral correlations with cancer progression and frequency of cell surface expression of MMPs and their inhibitors, TIMPs, suggesting not only the aggressive nature of particularly metastatic gastric carcinoma, but also the presence of MMPs complexed with TIMPs on tumor cells and TIL. The enhanced cell surface expression of MMPs and TIMPs on TIL within metastatic carcinoma nests showed the result of a host response induced by tumors. These suggest that the increased cell surface expression of MMPs and TIMPs, and tumor-induced host response play a key role in gastric cancer invasion and/or metastasis.
Adenocarcinoma↗
Proton beam therapy with high-dose irradiation for superficial and advanced esophageal carcinomas.
PURPOSE: With the aim of improving the results of treatment for esophageal carcinoma, we have investigated the efficacy and toxicity associated with the use of a 250-MeV proton beam for radical radiation therapy in esophageal carcinoma. EXPERIMENTAL DESIGN: Thirty patients with esophageal carcinoma (superficial, n = 13; advanced, n = 17) had been treated with proton beam therapy alone or with photon therapy followed by proton beam therapy. In combination therapy with photon and proton beams, one fraction dose was 1.8-2.0 Gy for photon and 2.5-3.7 Gy (mean, 3.1 Gy) for proton beam. In proton beam therapy alone, one fraction dose was 3.1-3.6 Gy (mean, 3.2 Gy). Overall mean total doses of the irradiation were 77.7 Gy in superficial carcinoma and 80.7 Gy in advanced carcinoma, respectively. RESULTS: Mean overall actuarial survival in patients with superficial and advanced carcinomas was 60.1 and 38.6 months, respectively. The local recurrence and disease- specific survival rates for patients with superficial carcinoma were 0 and 100% at 5 years, and 0 and 87.5% at 10 years, respectively; the same rates for the patients with advanced carcinoma were 56.6 and 49.0% at 5 years, 78.3 and 38.1% at 10 years, respectively. Radiation-induced esophageal ulcer without injury of adjacent organs occurred in 20 (66.7%) of 30 treated patients. CONCLUSIONS: Better local control and 5- and 10-year disease-specific survival rates were achieved by a higher dose of irradiation with well-defined proton fields in superficial and advanced esophageal carcinomas.
Aged↗
N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers.
Therapeutic modalities that overcome the antiapoptotic function of Bcl-2 that is often overexpressed in cancer cells are expected to be a novel strategy for cancer treatment. We previously reported that the leukemic cell death induced by an N-terminally truncated Bax (deltaN Bax: corresponding to amino acid 112-192 of full-length Bax) was not blocked by Bcl-2 or Bcl-x(L) owing to the lack of the BH3 domain needed to interact with the antiapoptotic Bcl-2 family molecules. In this study, we used the Cre-loxP system that allowed us to propagate adenoviruses expressing deltaN Bax, and investigated the effects of the deltaN Bax gene transfer into A549 and NCI-H1299 nonsmall cell lung cancer cell lines. deltaN Bax showed more cell-death-inducing activity in both cells than did the full-length Bax in vitro. It was found that the deltaN Bax-induced cell death was not inhibited by the pan-caspase inhibitor z-VAD-fmk, suggesting that deltaN Bax induces cell death through a caspase-independent mechanism. Intratumoral injection of adenoviruses expressing deltaN Bax into A549 tumors in Balb/c nude mice showed a significantly stronger suppression of tumor growth (74%) than full-length Bax (25%) compared to the control. Our results suggest that deltaN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.
Adenoviridae↗
Differential expression of intracellular apoptotic signaling molecules in tumor and tumor-infiltrating lymphocytes during development of invasion and/or metastasis of gastric carcinoma.
The presence and functional status of intracellular expression of caspase 8, caspase 10, cFLIP, caspase 3, survivin, and NF-kappaB was investigated in permeabilized tumor and tumor-infiltrating lymphocytes (TIL) in gastric carcinoma (N = 20) from primary locus, metastatic gastric carcinoma (N = 22) from malignant ascites, and benign gastric mucosa (N = 20) for the control. The quantitative analysis was based on the percentage of positive cells by a flow cytometry. The results showed that the six intracellular molecules were constitutively expressed in primary and metastatic carcinomas as well as normal epithelium in nearly all the patients. In particular, metastatic carcinoma revealed to significantly overexpress these molecules. In the analysis of TIL, the expression of these six molecules could usually be observed in carcinoma and normal epithelium. There was aberrant expression of these molecules in immune TIL within metastatic carcinoma nests. Taken together, the results showed the significantly different expression of the signaling molecules in both tumor and TIL between primary and metastatic carcinoma nests. Increased expression of cFLIP, survivin, and NF-kappaB in carcinoma might play an important role in hindering an intracellular apoptotic process, followed by accelerating the cancer invasion and/or metastasis.
Adult↗
Flow cytometric measurement of tumor necrosis factor-related apoptosis-inducing ligand and its receptors in gastric epithelium and infiltrating mucosal lymphocytes in Helicobacter pylori-associated gastritis.
BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors have recently been reported to be responsible for apoptotic signaling molecules. However, little is known about TRAIL-mediated apoptosis in the human glandular stomach. METHODS: Biopsies from 66 patients (28 Helicobacter pylori-negative, 38 H. pylori-positive) were investigated for phenotypic distribution of TRAIL and its receptors DR4/DR5 and DcR2 on mucosal epithelium, and infiltrating mucosal lymphocytes using flow cytometry. Apoptosis of the cells was examined by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL). In addition, the phenotypic distribution of CD antigens on infiltrating major T- and B-lymphocytes were determined. RESULTS: Membrane-bound TRAIL and its receptors were constitutively expressed in all patients with high levels in the gastric mucosal epithelium. In particular, these protein molecules were overexpressed in mucosal lymphocytes coupled with increased proportions of CD19+ B cells, and CD3+ T cells bearing CD8+CD11b- and CD4+CD62L- surface phenotypes in H. pylori-positive gastric mucosa. The frequencies of apoptotic epithelium and infiltrating lymphocytes in H. pylori-associated gastritis were significantly greater than those of H. pylori-negative normal mucosa (P < 0.01). CONCLUSION: The present findings show that flow cytometric analysis is useful for detection of membrane-bound TRAIL and its receptors in gastric epithelium and infiltrating mucosal lymphocytes.
Adult↗
Idiopathic granulomatous gastritis with multiple aphthoid ulcers.
A 47-year-old woman had idiopathic granulomatous gastritis characterized by serpiginous aphthoid ulcer with satellite aphthous ulcers at the antrum to angulus with noncaseating epithelioid granulomas including giant cells in the gastric mucosa. No definite etiologic factors could be detected; systemic sarcoidosis, Crohn's disease, infections (tuberculosis, syphilis and fungus), neoplasm, and foreign body reaction were excluded by additional investigations. However, the patient was found to be infected with H. pylori. Despite the success of H. pylori-eradication, the granulomatous lesion took a long time to heal for at least 17 months or more. The relation between granulomatous gastritis and H. pylori was discussed. There was no apparent evidence of granuloma in the other organs during clinical and follow-up studies for over three years.
Anemia, Iron-Deficiency↗
Esophageal intramural pseudodiverticulosis (diffuse type).
A rare case of esophageal intramural pseudodiverticulosis (EIPD) in a 65-year-old woman with intermittent dysphagia is reported. An upper gastrointestinal series revealed multiple pseudodiverticula, which had tiny flask-shaped outpouchings with a narrow neck extending outward from the upper to the lower thoracic esophageal wall. In particular, the occurrence of the pseudodiverticula was coincident with a narrowed segment of inflamed esophagus. The length of the esophagus involved was approximately 15 cm. Endoscopic findings included mild stricture and chronic inflammation of the mucosa. Biopsy specimens showed active chronic esophagitis with bacterial and Candida superinfection, but no evidence of neoplasm. Cellular local immune reactions, as a consequence of chronic inflammation, and possibly abnormal motor activity in the narrowed esophagus, may explain the etiological agent or may be possible secondary factors that caused the EIPD.
Aged↗
Expression of TNF-related apoptosis-inducing ligand (TRAIL) and its receptors in gastric carcinoma and tumor-infiltrating lymphocytes: a possible mechanism of immune evasion of the tumor.
PURPOSE: TNF-related apoptosis-inducing ligand (TRAIL) and its receptors have recently been known to be responsible for apoptotic signaling molecules in tumor cell lines and tissues. These molecules have been reported to be expressed on merely a transcription level, but not on a protein level. Moreover, little is known about TRAIL-mediated apoptosis in human carcinoma in vivo. METHODS: We investigated the presence and functional status of TRAIL and its receptors, DR4, DR5, and DcR2 on tumor as well as tumor-infiltrating lymphocytes (TIL) in primary ( n=37), and metastatic gastric carcinoma from malignant ascites ( n=37) by a flow cytometry. In addition, phenotypic proportions of major T-cell subsets or B-cells in TIL were also determined. RESULTS: Membrane-bound TRAIL/its receptors are constitutively expressed at high levels in primary and metastatic carcinomas in nearly all the patients. Apoptotic tumor cells detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) were barely identified in primary and metastatic carcinomas. TIL in primary carcinoma showed a very low level of expression of TRAIL/its receptors and TUNEL-positive cells. In metastatic carcinoma, however, there was significant overexpression of TRAIL/its receptors in TIL associated with a higher frequency of apoptotic cell death detected by TUNEL. The TIL within metastatic carcinoma, but not within primary carcinoma, revealed the increased proportions of CD3(+) T cells bearing CD8(+)CD11b(-), CD8(+)CD11b(+), and CD4(+)CD62L(-), CD4(+)CD62L(+) surface phenotype in patients. CONCLUSIONS: These results suggest that TRAIL(+) and DcR2(+) metastatic carcinoma from malignant ascites could not only have resistance to DR4/DR5-induced apoptosis, but also might take the TRAIL-mediated counterattack against activated CD3(+) T cells. These functions of the cancer cells would neutralize host immune responses at the effector phase, and accelerate further invasion and/or metastasis of carcinoma through the escape from immune attack.
Adult↗