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
Atsushi Ochiai
Publications and source records attributed to Atsushi Ochiai.
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↗
Serum c-erbB-2 protein is a useful marker for monitoring tumor recurrence of the breast.
C-erbB-2 oncogene protein (ErbB-2/HER-2) overexpression is a prognostic marker of breast carcinoma. The purpose of this study was to evaluate serum ErbB-2 for monitoring tumor recurrence of operable breast carcinoma patients. The subjects were 86 breast carcinoma patients with stage I-IIIB. Sera were collected at preoperative and postoperative periods from 1996 to 2000. The cutoff value was set at 5.4 ng/ml for preoperative patients and at 6.5 ng/ml for postoperative patients. Twenty-nine patients (34%) had higher preoperative serum ErbB-2 levels (>or=5.4 ng/ml). A higher preoperative serum ErbB-2 was associated with higher clinical stage, larger tumor size, nodal metastasis, higher histologic grade and lymphatic invasion, but not with vascular invasion, hormonal receptor status or other tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3). As of April 2005, 27 patients (31%) had recurrence and 18 (62%) of them had a higher preoperative serum ErbB-2. Seventeen patients died of tumor progression. The recurrence-free survival rates at 7 years after breast surgery were 84% in 57 patients with a normal preoperative serum ErbB-2 and 41% in 29 patients with a higher preoperative serum ErbB-2 (p < 0.0001). The overall survival rates at 7 years were 93% and 55% (p < 0.0001), respectively. A multivariate analysis revealed that preoperative serum ErbB-2 was an independent prognostic factor for recurrence-free survival and overall survival in breast carcinoma patients. The specificities and sensitivities of postoperative tumor markers (CEA, CA15-3 and ErbB-2) were 91%, 100% and 85%, and 40%, 30% and 70%, respectively. Serum ErbB-2 is a preoperative prognostic marker and may be useful for monitoring tumor recurrence of the breast.
Biomarkers, Tumor↗
Microfabricated airflow nozzle for microencapsulation of living cells into 150 micrometer microcapsules.
Microencapsulation of genetically engineered cells has attracted much attention as an alternative nonviral strategy to gene therapy. Though smaller microcapsules (i.e. less than 300 microm) theoretically have various advantages, technical limitations made it difficult to prove this notion. We have developed a novel microfabricated device, namely a micro-airflow-nozzle (MAN), to produce 100 to 300 microm alginate microcapsules with a narrow size distribution. The MAN is composed of a nozzle with a 60 microm internal diameter for an alginate solution channel and airflow channels next to the nozzle. An alginate solution extruded through the nozzle was sheared by the airflow. The resulting alginate droplets fell directly into a CaCl2 solution, and calcium alginate beads were formed. The device enabled us to successfully encapsulate living cells into 150 microm microcapsules, as well as control microcapsule size by simply changing the airflow rate. The encapsulated cells had a higher growth rate and greater secretion activity of marker protein in 150 microm microcapsules compared to larger microcapsules prepared by conventional methods because of their high diffusion efficiency and effective scaffold surface area. The advantages of smaller microcapsules offer new prospects for the advancement of microencapsulation technology.
Air↗
Evaluation of extratumoral lymphatic permeation in non-small cell lung cancer as a means of predicting outcome.
BACKGROUND: Lymphatic permeation (ly) has been described as a potential prognostic factor for non-small cell lung cancer (NSCLC). METHODS: The purpose of this study was to analyze whether evaluation of the presence or absence of ly and its location (ly 0: absent, N=464; ly 1: intratumoral, N=42; ly 2: extratumoral, N=52) provides an appropriate means of predicting the outcome of NSCLC. We investigated the clinical implications of ly in 558 consecutive patients with surgically resected NSCLC. RESULTS: Evaluation according to ly status showed that the recurrence-free survival (RFS) time of the ly 2 patients was significantly shorter than that of the ly 0 patients (P<0.0001), the ly 1 patients (P=0.0028). A significant difference in RFS time was also observed between the ly 0 patients and the ly 1 patients (P=0.0025). RFS time of the ly 0 patients was significantly longer than that of the ly 1 plus ly 2 patients (P<0.0001). We also evaluated the patients with pathological stage I disease (N=378) separately. The RFS time of the ly 2 patients (N=9) was significantly shorter than that of the ly 0 plus ly 1 patients (P<0.0001). In the nine ly 2 patients, six developed a distant metastasis within 1 year. A multivariate analysis revealed that ly status (ly 0 plus ly 1 versus ly 2) was an independent prognostic factor (P=0.0116), demonstrating the significant prognostic value of extratumoral lymphatic permeation in NSCLC. CONCLUSIONS: These results indicate that ly status is a good prognostic marker of poorer outcome in patients with resected NSCLC.
Adenocarcinoma↗
Prostate-specific antigen induces apoptosis of osteoclast precursors: potential role in osteoblastic bone metastases of prostate cancer.
BACKGROUND: Prostate cancer is frequently associated with bone metastases with marked osteoblastic changes and low osteoclastic activity but its mechanism is not well understood. We previously reported that prostate-specific antigen (PSA) stimulated the proliferation and the activation of osteoblasts. In this study, we investigated the effect of PSA on osteoclastogenesis. METHODS: Two human prostate cancer cell lines and PSA were directly injected into human adult bone (HAB) implanted into NOD/SCID mice, followed by morphological analysis. RAW 264.7 cells, murine osteoclast precursor, were treated with PSA. RESULTS: PSA-producing LNCaP and PSA caused a significant decrease of osteoclast precursors and osteoclasts in HAB accompanied by osteoblast proliferation and new bone formation, while PSA-nonproducing PC3 showed increasing osteoclasts with osteolysis. PSA induced apoptosis of RAW 264.7 cells in vitro. PSA-induced apoptosis was dependent of enzymatic activity of PSA and was specific to immature tartrate-resistant acid phosphatase-negative mononuclear RAW 264.7 cells. CONCLUSIONS: PSA plays a crucial role for osteoblastic bone metastasis by promoting both osteoblasts proliferation and apoptosis of osteoclast precursors.
Adenocarcinoma↗
Accurate assessment of lymph vessel tumor emboli in invasive ductal carcinoma of the breast according to tumor areas, and their prognostic significance.
Lymph vessel tumor emboli (LVTEs) within tumors are difficult to distinguish from stroma-invasive tumor foci. The purpose of this study was to evaluate staining of LVTEs with hematoxylin-eosin (HE) and with D2-40 to determine whether LVTEs identified by HE staining alone are D2-40-positive LVTE and whether the presence of LVTE identified by HE or D2-40 staining is an accurate predictor of outcome in 151 patients with invasive ductal carcinoma (IDC) of the breast. We first attempted to identify LVTE in the stroma-invasive tumor area (intratumor area), the advance area, and the nontumor area by HE staining alone, and then LVTE identified by HE staining was confirmed by D2-40 staining. The number of LVTE identified by HE staining and D2-40 staining successively increased from the intratumor area to the nontumor area. Although D2-40 staining detected larger numbers of LVTE than HE staining in all tumor areas, the highest positive predictive value of LVTE was observed in the intratumor area, and the next was in the advance area, and then the nontumor area, and significant correlations were found between the numbers of LVTE stained by HE and D2-40 in the same tumor areas. LVTE identified by HE staining or D2-40 staining in the intratumor area or nontumor area significantly increased the risk for tumor recurrence or death of patients with IDC, independent of hormone receptor status or nodal status. The results of this study demonstrate that the existence of intratumoral LVTE and that the presence of intratumoral LVTE identified by HE staining or D2-40 staining are accurate predictors of the outcome of patients with IDC of the breast.
Adult↗
Carbonic anhydrase IX expression is associated with tumor progression and a poor prognosis of lung adenocarcinoma.
Carbonic anhydrase (CA) IX catalyzes the hydration of carbon dioxide into carbonic acid and participates in a variety of physiological and biological processes. The aim of this study was to evaluate the prognostic significance of CA IX expression in patients with lung adenocarcinoma. Standard immunohistochemical techniques were used to study CA IX expression in 134 patients who underwent curative resection for adenocarcinoma of the lung at our hospital between January 1995 and December 1996. We evaluated the correlations between CA IX expression levels on cancer cells and clinicopathological factors. CA IX expression was not observed in normal lung tissue or specimens from non-invasive adenocarcinomas. CA IX immunostaining was detected in 33 (24.6%) invasive adenocarcinoma cases. Poor differentiated histological phenotype (p=0.0015), pathological stage (p=0.0400), vascular invasion (p=0.0009) and lymphatic permeation (p=0.0050) were significantly related to CA IX expression. On univariate analysis, CA IX positive cases showed significantly shorter overall survival (p=0.0083) and disease-free survival (p=0.0122). In particular, the overall and disease-free survivals in stages I+II were significantly shorter in the CA IX positive than in the CA IX negative cases (p=0.0269 and 0.0011, respectively). Our results suggest that CA IX expression is strongly associated with tumor progression and indicates a poor prognosis for patients with stages I+II lung adenocarcinoma.
Adenocarcinoma↗
Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy.
BACKGROUND: Eg5 is a microtubule motor protein that functions in bipolar spindle assembly. We investigated the relationship between Eg5 expression and the response to chemotherapy of patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eg5 expression was investigated immunohistochemically in 122 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients. We also investigated cyclin B1 expression, which is involved in the G2/M transition. All patients received antimitotic agents combined with platinum chemotherapy. The response to chemotherapy was compared in relation to Eg5 and cyclin B1 expression and in relation to clinicopathological factors. RESULTS: The response rate to chemotherapy of patients with Eg5-positive tumors was 37%, as opposed to 10% for patients with Eg5-negative tumors, and Eg5 expression was significantly associated with the response to chemotherapy (P=0.002). The response rate of patients with cyclin B1-positive tumors (53%) was higher than that of patients with cyclin B1-negative tumors (23%) (P=0.009), and Eg5 expression was significantly correlated with cyclin B1 expression (P=0.005). A multivariate analysis confirmed Eg5 status to be an independent variable related to response to chemotherapy (P=0.008). CONCLUSIONS: Eg5 expression can predict a response to antimitotic agents combined with platinum chemotherapy among patients with advanced NSCLC.
Adult↗
Immunohistochemical and mutational analysis of c-kit in gastrointestinal neuroendocrine cell carcinoma.
BACKGROUND: Gastrointestinal neuroendocrine cell carcinoma (NEC) is a highly aggressive tumor with poor prognosis, for which an effective therapy is highly desirable. Recently, use of a c-kit inhibitor achieved excellent results against gastrointestinal stromal tumor (GIST) that showed c-kit overexpression and mutation in most cases. According to recent studies, 17-44% of pulmonary NEC also expressed c-kit and the antitumor effect of c-kit inhibitor was demonstrated in vitro against small cell carcinoma of the lung. As gastrointestinal NECs are clinicopathologically similar to pulmonary NECs, we investigated c-kit expression and mutation in gastrointestinal NEC. METHODS: Surgically resected gastrointestinal NEC was examined for c-kit expression by immunohistochemistry and RT-PCR. Mutation of the c-kit gene was also investigated by means of single-strand conformation polymorphisms (SSCP). RESULTS: Twenty-six percent (6 out of 23 patients) of gastrointestinal NEC expressed c-kit protein. c-kit protein expression was demonstrated in 1 out of 4 colorectal, 1 out of 2 duodenal, 4 out of 16 gastric and no esophageal (sample size of 1) NECs. The results of immunohistochemistry for c-kit were consistent with the RT-PCR. No c-kit gene mutation was found in gastrointestinal NEC. CONCLUSION: The frequency of c-kit expression in gastrointestinal NEC was similar to that previously reported for pulmonary NEC. These findings suggest that c-kit inhibitor may be effective against some gastrointestinal NECs.
Aged↗
The reduced expression and aberrant methylation of p16(INK4a) in chromate workers with lung cancer.
STUDY OBJECTIVES: It is known that chromium is one of the important inhaled carcinogens that cause lung cancer. Our previous studies revealed a variety of genetic changes in lung cancers from chromate-exposed workers (chromate lung cancer). However, the epigenetic effects of chromium are not understood. MATERIALS AND METHODS: We investigated the methylation of the p16 gene using a methylation-specific PCR method in 30 chromate lung cancers and 38 non-chromate lung cancers, and the expression of the p16 protein using immunohistochemistry in 25 chromate lung cancers. RESULTS: Ten (33%) chromate lung cancers showed methylation of the p16 promoter region. On the other hand, 10 (26%) of the non-chromate lung cancers also showed it. The frequency of p16 methylation in non-chromate lung cancer was 0%, 33% and 30% for low (< or =600), moderate (<600, >1000) and high (> or =1000) Brinkman indexes, respectively. However, the frequency of p16 methylation in chromate lung cancer was constant, irrespective of the Brinkman index. In chromate lung cancer, patients with chromate exposure of less than 15 years never had p16 methylation, while 40% (> or =25 years) or 43% (> or =15, <25 years) of patients with chromate exposure of more than 15 years did. In chromate lung cancer, chromate exposure, not smoking, mainly influenced the p16 methylation. Most of the chromate lung cancers with p16 methylation (85.7%) showed repression of the p16 protein. CONCLUSIONS: We speculate that not only genetic but also epigenetic alterations are involved in the carcinogenesis due to chromium.
Adult↗
Depressed-type early invasive colon cancer in a patient treated with cyclooxygenase-2 inhibitor.
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Adenocarcinoma↗
Hormonal stimulation increases the recruitment of bone marrow-derived myoepithelial cells and periductal fibroblasts into the mammary gland.
Recent reports have revealed that bone marrow (BM)-derived cells can be constituents in a number of organs, especially in remodeling tissue. Using bone marrow transplantation (BMT) technique, we found that BM can serve as a source of both myoepithelial cells and periductal fibroblasts in the mammary gland. The numbers of BM-derived myoepithelial cell were 4.8-fold, and those of periductal fibroblast were 2.4-fold higher in the mice when BMT which was performed at the pubertal stage, as compared with BMT was performed at the postpubertal stage. Treatment with estrogen+progesterone pellet increased numbers of BM-derived myoepithelial cells and periductal fibroblasts, to levels 4.5- and 2.6-fold higher than in placebo mice, respectively. In situ hybridization revealed BM-derived periductal fibroblasts expressed insulin-like growth factor I mRNAs that are known to regulate mammary gland. These results suggest that drastic structural change that is induced by hormonal stimulation increased the recruitment of BM-derived myoepithelial cells and periductal fibroblasts to the mammary gland context.
Animals↗
Primary signet-ring cell carcinoma of the colon at early stage: a case report and a review of the literature.
A 67-year-old man, who had undergone surgery to resect multiple gastric cancers 4 years ago, visited our hospital for surveillance colonoscopy. Colonoscopy revealed a discolored, 7-mm in diameter, flat-elevated lesion with central depression in the transverse colon near the splenic flexure. Although the findings of endoscopy and barium enema were suggestive of submucosal invasion, the patient chose to undergo endoscopic mucosal resection. Pathological examination of the resected specimen revealed signet-ring cell carcinoma and a positive surgical margin. A second operation was performed, and no residual tumor or metastasis to lymph nodes was found in the resected specimens. Primary colorectal cancers composed of signet-ring cell carcinoma detected and treated at an early stage are extremely rare. We present a case and review the literature.
Aged↗
Inhibition of bone-derived insulin-like growth factors by a ligand-specific antibody suppresses the growth of human multiple myeloma in the human adult bone explanted in NOD/SCID mouse.
Multiple myeloma (MM) is a fatal disease that affects plasma cells. Patients with MM have 1 or more osteolytic lesions in their bone tissues, where insulin-like growth factors (IGFs; IGF-I and IGF-II) are mainly stored. The role of bone-derived IGFs in the development of MM has not been extensively studied because reliable animal models are lacking. We established an animal model using a human MM cell line, RPMI8226, in nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice implanted with human adult bone (HAB) fragments. Treatment with an anti-human IGF-neutralizing monoclonal antibody, KM1468, inhibited the IGF-I-stimulated phosphorylation of type-I IGF receptors (IGF-IR) in RPMI8226 cells and the activation of the downstream PI3-K/Akt signaling pathway in vitro. KM1468 inhibited IGF-I-mediated RPMI8226 cell growth in a dose-dependent manner. In the NOD/SCID-HAB model, treatment with KM1468 significantly inhibited the growth of RPMI8226 cells (p<0.02). These results indicated that the growth of MM cells was predominantly stimulated not by serum-derived IGFs, but by bone-derived IGFs. Furthermore, the targeting of bone-derived IGFs, using a neutralizing antibody, may offer a new therapeutic strategy for MM.
Animals↗
Computer-assisted analysis of biopsy specimen microvessels predicts the outcome of esophageal cancers treated with chemoradiotherapy.
PURPOSE: A computer-assisted microvessel analysis system was developed to evaluate correlations between the architecture of biopsy specimen microvessels and the outcome for patients with esophageal cancer treated with chemoradiotherapy. EXPERIMENTAL DESIGN: Biopsy specimens from 51 patients with esophageal cancer (T(2-3), any N, M0) treated with chemoradiotherapy were immunostained with an anti-CD31 antibody and quantified using computerized image analysis. We evaluated the association of several microvessel factors with overall survival, including the ratio of total microvessel perimeter to total tumor area (TP/TA), the tumor hypoxic ratio, and the ratio of total microvessel number to total tumor area (TN/TA). Results from traditional manual microvessel density (MVD) hotspot count and computerized hotspot count were compared and the relation between hotspot MVD count and survival rate was evaluated. RESULTS: The median follow-up time was 32 months. Both univariate and multivariate analyses revealed that computer-counted hotspot MVD and TN/TA and TP/TA ratios correlated significantly with the outcome of chemoradiotherapy. Kaplan-Meier survival curves showed that patients with high computer-counted hotspot MVDs and high TN/TA and TP/TA ratios had better overall survival rate than patients with low MVDs or ratios (P = 0.025, 0.008, and 0.031, respectively). Combining computer-counted MVD or TN/TA ratio with TP/TA ratio proved more predictive than any single factor. Two researcher-counted hotspot MVDs had no significant relation with outcome. CONCLUSION: Computer-assisted tumor microvessel analysis is a powerful tool in predicting the outcome for patients with esophageal cancer treated with chemoradiotherapy because intraobserver and interobserver variability is minimized.
Adult↗
Differences in clinicopathological and biological features between central-type and peripheral-type squamous cell carcinoma of the lung.
The central type and peripheral type squamous cell carcinoma (SCC) of the lung have different clinicopathological characteristics, but, little is known about their biological characteristics. We investigated differences between the properties and phenotypes of peripheral-type (P-type) and central-type (C-type) SCC by performing an immunohistochemical analysis of each type by tissue microarray analysis with a large panel of antibodies. To examine strictly, we selected 20 P-type SCCs that were pathological stage T1 and limited to more peripherally than the fifth bronchial bifurcation, and 21 C-type SCCs that were pathological stage T1 and limited to a lobar bronchus. The results of the clinicopathological study showed that the patients with P-type SCC were significantly older than the patients with C-type SCC and that squamous metaplasia was predominant in C-type SCC than in P-type SCC. The 36 antibodies revealed different expression patterns of cytokeratin 7 (CK 7) and cytokeratin 19 (CK 19) between C-type and P-type SCC. CK 7 expression was more predominant in P-type SCC than in C-type SCC, and CK 19 expression was more predominant in C-type SCC than in P-type SCC. These results suggest that C-type and P-type SCC have different clinicopathological and biological features.
Adult↗
Epstein-Barr virus involvement is a predictive factor for the resistance to chemoradiotherapy of gastric diffuse large B-cell lymphoma.
Primary gastric diffuse large B-cell lymphomas are generally well controlled by non-surgical treatment with combination chemotherapy followed by radiotherapy. We have previously reported that over 90% of patients achieved complete response (CR) with this therapeutic strategy: three cycles of cyclophosphamide, adriamycin, vincristine and prednisone followed by radiotherapy (40.5 Gy). Although the CR rate was very high, some patients still showed resistance to this combination therapy. In order to clarify the factors related to therapy resistance, we examined the relationship between Epstein-Barr virus (EBV), which was examined using an in situ hybridization technique, and the patients' clinical courses. Out of the 50 patients, four were EBV positive; over half of lymphoma cells were positive for EBV by in situ hybridization. Of the three EBV-positive patients, two showed progressive disease and one achieved partial response (PR). Two of the patients died of disease progression. The other patient achieved CR, but the lymphoma recurred with distant metastasis in the cerebellum 3 months after remission. In the present study, eight patients did not achieve CR or they relapsed, four patients showed progressive disease, one patient achieved PR, and three patients achieved CR with recurrence. Therefore, half of these unfavorable patients were EBV positive. This finding strongly indicated that EBV-associated gastric diffuse large B-cell lymphomas frequently show resistance to standard chemoradiotherapy, although some other adverse factors remain unclear.
Antineoplastic Combined Chemotherapy Protocols↗