A case of pancreatic ductal adenocarcinoma with enteroblastic, neuroendocrine, and squamous differentiation with p53 overexpression and loss of Rb expression.

INTRODUCTION: Herein we report a case of an extremely rare pancreatic adenocarcinoma with enteroblastic differentiation (AED), an underrecognized histological subtype. Moreover, the tumor was mixed with a neuroendocrine carcinoma (NEC), which is also a rare malignancy in the pancreas. CASE PRESENTATION: The patient was an elderly male who was incidentally diagnosed with a 35 mm-sized pancreatic head tumor and underwent pancreatoduodenectomy. Histopathologically, the tumor was composed of four different types: conventional ductal adenocarcinoma, AED, NEC, and squamous cell carcinoma. Interestingly, p53 overexpression and loss of Rb expression, which are characteristic findings of NEC, were observed in all components. He had been received adjuvant chemotherapy after the surgery, however, he died of bath-related cardiac arrest 14 months after surgery. DISCUSSION: In the stomach, AED, a carcinoma resembling fetal gut epithelium, is a rare but established subtype and is considered a related entity of hepatoid carcinoma (HAC). However, gastric AED and HAC differ to some extent. In contrast to the stomach, extragastric AED, including pancreatic AED, is extremely rare, and its biological features are unclear. A mixed tumor with NEC is a complex phenomenon, but it is occasionally reported in extragastric AED. The histogenesis of mixed AED-NEC can be resolved by determining p53 and Rb status. CONCLUSION: Owing to their rare and novel nature, extragastric AED is under-recognized or confused with HAC. Further studies and the establishment of an extragastric AED classification are required.

Rim Enhancement on Contrast-Enhanced CT as a Predictor of Prognosis in Patients with Pancreatic Ductal Adenocarcinoma.

This study investigated the utility of imaging features, such as rim enhancement on contrast-enhanced CT (CECT), in predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). This retrospective study included 158 patients (84 men; mean age, 68 years) with pathologically confirmed PDAC. The following imaging features were evaluated on CECT by two radiologists: tumor size, tumor attenuation, and the presence of rim enhancement. Cox proportional hazards analysis was performed to identify the imaging and clinicopathological features for predicting disease-free survival (DFS) and overall survival (OS). Pathological features were compared with the presence of rim enhancement. Among the 158 patients, 106 (67%) underwent curative surgery (surgery group) and 52 (33%) received conservative treatment (non-surgery group). Rim enhancement was observed more frequently in the non-surgery group than in the surgery group (44% vs. 20%; p < 0.001). Rim enhancement showed significant associations with shorter DFS and OS in the surgery group (hazard ratios (HRs), 3.03 and 2.99; p < 0.001 and p = 0.003, respectively), whereas tumor size showed significant associations with shorter OS (HR per 1 mm increase, 1.08; p < 0.001). PDACs with rim enhancement showed significant associations with higher histological tumor grades (p < 0.001). PDAC with rim enhancement on CECT could predict poorer prognosis and more aggressive tumor grades.

Periostin in Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression by Enhancing Cancer and Stromal Cell Migration.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). CAF-like cells were generated through direct co-culture of human bone marrow-derived mesenchymal stem cells, one of CAF origins, with ESCC cells. Periostin (POSTN) was found to be highly expressed in CAF-like cells. After direct co-culture, ESCC cells showed increased malignant phenotypes, such as survival, growth, and migration, as well as increased phosphorylation of Akt and extracellular signal-regulated kinase (Erk). Recombinant human POSTN activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of POSTN in CAF-like cells by siRNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of POSTN receptor integrin ß4 inhibited Akt and Erk phosphorylation, and survival and migration increased by POSTN. POSTN also enhanced mesenchymal stem cell and macrophage migration and endowed macrophages with tumor-associated macrophage-like properties. Immunohistochemistry showed that high POSTN expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathologic stage, CAF marker expression, and infiltrating tumor-associated macrophage numbers. Moreover, patients with ESCC with high POSTN expression exhibited poor postoperative outcomes. Thus, CAF-secreted POSTN contributed to tumor microenvironment development. These results indicate that POSTN may be a novel therapeutic target for ESCC.

Pseudoimmunofluorescent immunohistochemistry image analysis of phosphorylated signaling proteins in human esophageal squamous cell carcinoma tissue.

Immunohistochemistry is primarily employed to visualize the localization of specific molecules in tissue samples. However, there is an increasing need for software-assisted quantitative assessment. In the present study, we performed inverted blue channel-based pseudoimmunofluorescence image analysis using original immunohistochemistry images. In human esophageal squamous cell carcinoma tissues, various humoral factors promote the phosphorylation of signaling proteins, including protein kinase B (Akt) and/or extracellular signal-regulated kinase 1/2 (ERK1/2), leading to tumor progression. Our method demonstrated applicability in the analysis of localized signaling proteins in histological sections. Relatively high phosphorylated Akt (p-Akt) intensity was observed in the cancer-stroma adjacent (Adj) and noncancerous regions of the superficial layer (SL). Furthermore, localized phosphorylated ERK1/2 (Thr202/Tyr204) was observed in the Adj of the SL and invasive front, distinct from the pattern of p-Akt (Ser473) and p-Akt (Thr308). In conclusion, pseudoimmunofluorescent immunohistochemistry image analysis is useful for the quantitative assessment and objective interpretation of localized signaling proteins in esophageal squamous cell carcinoma. The method can also be applied to analyze various immunohistochemistry images from diverse tissues.

Cine magnetic resonance imaging predicts thrombus adhesion in metastatic renal cell carcinoma with an inferior vena cava tumor thrombus: A case of pathological complete response with pembrolizumab plus lenvatinib.

Introduction: Renal cell carcinoma with an inferior vena cava tumor thrombus is a challenging disease that requires a multimodal treatment approach. Pembrolizumab plus lenvatinib has displayed promising efficacy in metastatic renal cell carcinoma. Case presentation: A 61-year-old man was diagnosed with metastatic renal cell carcinoma and a tumor thrombus adhering to the inferior vena cava wall by cine magnetic resonance imaging. After 6 months of pembrolizumab and lenvatinib therapy, tumor shrinkage was detected, excluding the advanced portion of the inferior vena cava thrombus, and nephrectomy and thrombectomy were performed. Adhesion of the tumor thrombus to the inferior vena cava wall was observed during surgery. Resection produced a remarkable pathological complete response with no viable cells in the resected specimens, including the thrombus site. Conclusion: This case highlights the potential of pembrolizumab plus lenvatinib for treating advanced renal cell carcinoma with an inferior vena cava thrombus and the utility of cine magnetic resonance imaging for evaluating thrombus adhesion to the inferior vena cava.

Colostomy-site carcinoma with primitive phenotype in a rectal cancer patient after achieving pathological complete response with neoadjuvant chemoradiotherapy.

Herein, we report a rare case of a carcinoma with primitive phenotype (enteroblastic and/or hepatoid differentiation) occurring at a colostomy site. The patient was an elderly male who underwent neoadjuvant chemoradiotherapy for rectal cancer, followed by abdominoperineal resection. A biopsy specimen for the rectal carcinoma before neoadjuvant chemoradiotherapy was conventional tubular adenocarcinoma. Moreover, a pathological complete response was confirmed in the proctectomy specimen. However, a colostomy-site tumor appeared 6 months after the proctectomy, and it was resected 1 year after the initial proctectomy. The colostomy-site tumor comprised solid to focal glandular growth of atypical polygonal cells with clear to pale eosinophilic cytoplasm and was immunohistochemically positive for cytokeratin, spalt-like transcription factor 4, glypican-3, caudal type homeobox 2, and special AT-rich sequence-binding protein 2. Thus, the tumor was diagnosed as poorly differentiated adenocarcinoma with primitive phenotype, with suggested origin from the colorectal epithelium. Additionally, a multilocular cystic lesion comprising various types of epithelia was found adjacent to the tumor, suggestive of metaplasia or heterotopia. Changes in the histology and immunophenotype, and the findings of an adjacent cystic lesion suggest a metachronous tumor rather than a recurrence of the primary tumor.

Neurophysiological markers in community-dwelling older adults with mild cognitive impairment: an EEG study.

BACKGROUND: Neurodegeneration and structural changes in the brain due to amyloid deposition have been observed even in individuals with mild cognitive impairment (MCI). EEG measurement is considered an effective tool because it is noninvasive, has few restrictions on the measurement environment, and is simple and easy to use. In this study, we investigated the neurophysiological characteristics of community-dwelling older adults with MCI using EEG. METHODS: Demographic characteristics, cognitive function, physical function, resting-state MRI and electroencephalogram (rs-EEG), event-related potentials (ERPs) during Simon tasks, and task proportion of correct responses and reaction times (RTs) were obtained from 402 healthy controls (HC) and 47 MCI participants. We introduced exact low-resolution brain electromagnetic tomography-independent component analysis (eLORETA-ICA) to assess the rs-EEG network in community-dwelling older adults with MCI. RESULTS: A lower proportion of correct responses to the Simon task and slower RTs were observed in the MCI group (p < 0.01). Despite no difference in brain volume between the HC and MCI groups, significant decreases in dorsal attention network (DAN) activity (p < 0.05) and N2 amplitude of ERP (p < 0.001) were observed in the MCI group. Moreover, DAN activity demonstrated a correlation with education (Rs = 0.32, p = 0.027), global cognitive function (Rs = 0.32, p = 0.030), and processing speed (Rs = 0.37, p = 0.010) in the MCI group. The discrimination accuracy for MCI with the addition of the eLORETA-ICA network ranged from 0.7817 to 0.7929, and the area under the curve ranged from 0.8492 to 0.8495. CONCLUSIONS: The eLORETA-ICA approach of rs-EEG using noninvasive and relatively inexpensive EEG demonstrates specific changes in elders with MCI. It may provide a simple and valid assessment method with few restrictions on the measurement environment and may be useful for early detection of MCI in community-dwelling older adults.

IFI16 Induced by Direct Interaction between Esophageal Squamous Cell Carcinomas and Macrophages Promotes Tumor Progression via Secretion of IL-1α.

Tumor-associated macrophages (TAMs), one of the major components of the tumor microenvironment, contribute to the progression of esophageal squamous cell carcinoma (ESCC). We previously established a direct co-culture system of human ESCC cells and macrophages and reported the promotion of malignant phenotypes, such as survival, growth, and migration, in ESCC cells. These findings suggested that direct interactions between cancer cells and macrophages contribute to the malignancy of ESCC, but its underlying mechanisms remain unclear. In this study, we compared the expression levels of the interferon-induced genes between mono- and co-cultured ESCC cells using a cDNA microarray and found that interferon-inducible protein 16 (IFI16) was most significantly upregulated in co-cultured ESCC cells. IFI16 knockdown suppressed malignant phenotypes and also decreased the secretion of interleukin-1α (IL-1α) from ESCC cells. Additionally, recombinant IL-1α enhanced malignant phenotypes of ESCC cells through the Erk and NF-κB signaling. Immunohistochemistry revealed that high IFI16 expression in human ESCC tissues tended to be associated with disease-free survival and was significantly associated with tumor depth, lymph node metastasis, and macrophage infiltration. The results of this study reveal that IFI16 is involved in ESCC progression via IL-1α and imply the potential of IFI16 as a novel prognostic factor for ESCC.

Cluster Analysis of Subjective Shoulder Stiffness and Muscle Hardness: Associations with Central Sensitization-Related Symptoms.

Background and Objectives: Understanding the relationships between subjective shoulder stiffness, muscle hardness, and various factors is crucial. Our cross-sectional study identified subgroups of shoulder stiffness based on symptoms and muscle hardness and investigated associated factors. Materials and Methods: measures included subjective stiffness, pain, muscle hardness, and factors like physical and psychological conditions, pressure pain threshold, postural alignment, heart rate variability, and electroencephalography in 40 healthy young individuals. Results: Three clusters were identified: Cluster 1 with high stiffness, pain, and muscle hardness; Cluster 2 with low stiffness and pain but high muscle hardness; and Cluster 3 with low levels of all factors. Cluster 1 had significantly higher central sensitization-related symptoms (CSS) scores than Cluster 2. Subjective stiffness is positively correlated with psychological factors. Conclusions: our results suggest that CSS impacts subjective symptom severity among individuals with similar shoulder muscle hardness.

Development and Validation of the Body Cognition Assessment System.

Body awareness, which comprises the sense of body possession and action ownership, is essential for the adaptive movement of humans in response to external environments. However, existing body cognition assessments include many overt elements of cognitive functional activity, but no assessment captures the latent body cognition necessary for exercise and daily life activities. Therefore, this study aimed to devise a body cognition assessment system (BCAS) to examine the functional basis of body cognition in healthy participants and investigate its usefulness. The BCAS was used to assess body cognition on three occasions, and BCAS values were calculated from the results of the assessment. The intraclass correlation coefficient (ICC) was used to determine reproducibility. Neural activity in the brain during somatocognition assessment while conducting the BCAS was measured by electroencephalogram. Moreover, the functional basis for somatocognition with the BCAS was also investigated. The results demonstrated that the BCAS values varied across the three administrations (ICC (1.3) = 0.372), and changes in the state of neural activity in the brain were observed. The results suggest that assessment using the BCAS may be a new indicator of ever-changing body cognition.

The Impact of Stretching Intensities on Neural and Autonomic Responses: Implications for Relaxation.

Stretching is an effective exercise for increasing body flexibility and pain relief. This study investigates the relationship between stretching intensity and relaxation effects, focusing on brainwaves and autonomic nervous system (ANS) activity. We used a crossover design with low- and high-intensity conditions to elucidate the impact of varying stretching intensities on neural activity associated with relaxation in 19 healthy young adults. Participants completed mood questionnaires. Electroencephalography (EEG) and plethysmography measurements were also obtained before, during, and after stretching sessions. The hamstring muscle was targeted for stretching, with intensity conditions based on the Point of Discomfort. Data analysis included wavelet analysis for EEG, plethysmography data, and repeated-measures ANOVA to differentiate mood, ANS activity, and brain activity related to stretching intensity. Results demonstrated no significant differences between ANS and brain activity based on stretching intensity. However, sympathetic nervous activity showed higher activity during the rest phases than in the stretch phases. Regarding brain activity, alpha and beta waves showed higher activity during the rest phases than in the stretch phases. A negative correlation between alpha waves and sympathetic nervous activities was observed in high-intensity conditions. However, a positive correlation between beta waves and parasympathetic nervous activities was found in low-intensity conditions. Our findings suggest that stretching can induce interactions between the ANS and brain activity.

Effects of Robot-Assisted Activity Using a Communication Robot on Neurological Activity in Older Adults with and without Cognitive Decline.

Robot-assisted activity (RAA) using a communication robot (RAA-CR) has been proposed as a tool for alleviating behavioral and psychological symptoms accompanying dementia (BPSD) in patients with cognitive decline. This study aimed to clarify the effects of differences in cognitive function among older adults on changes in active brain areas induced by RAA-CR. Twenty-nine older adults were divided into a cognitive decline group (n = 11) and a control group (n = 18). The participants individually received a 5-minute RAA session, and their resting EEG activity was measured before and after the session. Brain spatial analysis was performed on recorded EEG data using standardized low-resolution brain electromagnetic tomography. In addition, statistical comparisons of neural activity in the brain were made before and after RAA-CR and between the cognitively impaired and control groups. These results suggest that RAA-CR stimulates neural activity in the region centered on the posterior cingulate gyrus and precuneus in cognitively healthy older adults but does not significantly alter brain neural activity in cognitively impaired older adults. Therefore, modifications to the implementation methods may be necessary to effectively implement RAA-CR in cognitively impaired individuals.

Biological and clinical significance of the YKL-40/osteopontin-integrin ß4-p70S6K axis induced by macrophages in early oesophageal squamous cell carcinoma.

M2 macrophages contribute to the progression of oesophageal squamous cell carcinoma (ESCC); however, the roles of M2 macrophages in early ESCC remain unclear. To clarify the biological mechanisms underlying the interaction between M2 macrophages and oesophageal epithelial cells in early-stage ESCC, in vitro co-culture assays between the immortalised oesophageal epithelial cell line Het-1A and cytokine-defined M2 macrophages were established. Co-culture with M2 macrophages promoted the proliferation and migration of Het-1A cells via the mTOR-p70S6K signalling pathway activated by YKL-40, also known as chitinase 3-like 1, and osteopontin (OPN) that were hypersecreted in the co-culture supernatants. YKL-40 and OPN promoted the above phenotypes of Het-1A by making a complex with integrin ß4 (ß4). Furthermore, YKL-40 and OPN promoted M2 polarisation, proliferation, and migration of macrophages. To validate the pathological and clinical significances of in vitro experimental results, immunohistochemistry of human early ESCC tissues obtained by endoscopic submucosal dissection (ESD) was performed, confirming the activation of the YKL-40/OPN-ß4-p70S6K axis in the tumour area. Moreover, epithelial expression of ß4 and the number of epithelial and stromal infiltrating YKL-40- and OPN-positive cells correlated with the Lugol-voiding lesions (LVLs), a well-known predictor of the incidence of metachronous ESCC. Furthermore, the combination of high expression of ß4 and LVLs or high numbers of epithelial and stromal infiltrating YKL-40- and OPN-positive immune cells could more clearly detect the incidence of metachronous ESCC than each of the parameters alone. Our results demonstrated that the YKL-40/OPN-ß4-p70S6K axis played important roles in early-stage ESCC, and the high expression levels of ß4 and high numbers of infiltrating YKL-40- and OPN-positive immune cells could be useful predictive parameters for the incidence of metachronous ESCC after ESD. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Matrix Metalloproteinase 9 Induced in Esophageal Squamous Cell Carcinoma Cells via Close Contact with Tumor-Associated Macrophages Contributes to Cancer Progression and Poor Prognosis.

Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely simulate actual ESCC cell-TAM contact. We found that matrix metalloproteinase 9 (MMP9) was induced in ESCC cells by direct co-culture with TAMs, not by indirect co-culture. MMP9 was associated with ESCC cell migration and invasion, and its expression was controlled by the Stat3 signaling pathway in vitro. Immunohistochemical analyses revealed that MMP9 expression in cancer cells at the invasive front ("cancer cell MMP9") was related to high infiltration of CD204 positive M2-like TAMs (p < 0.001) and was associated with worse overall and disease-free survival of patients (p = 0.036 and p = 0.038, respectively). Furthermore, cancer cell MMP9 was an independent prognostic factor for disease-free survival. Notably, MMP9 expression in cancer stroma was not associated with any clinicopathological factors or patient prognoses. Our results suggest that close interaction with TAMs infiltrating in cancer stroma or cancer nests induces MMP9 expression in ESCC cells, equipping them with more malignant features.

Roles of IL-7R Induced by Interactions between Cancer Cells and Macrophages in the Progression of Esophageal Squamous Cell Carcinoma.

High infiltration of tumor-associated macrophages (TAMs), which contribute to the progression of several cancer types, is correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). In addition to the previously reported increase in migration and invasion, ESCC cells co-cultured directly with macrophages exhibited enhanced survival and growth. Furthermore, interleukin-related molecules are associated with ESCC; however, the precise mechanism underlying this association is unclear. Therefore, we explored the role of interleukin-related molecules in ESCC progression. A cDNA microarray analysis of monocultured and co-cultured ESCC cells revealed that the interleukin 7 receptor (IL-7R) was upregulated in ESCC cells co-cultured with macrophages. Overexpression of IL-7R promoted the survival and growth of ESCC cells by activating the Akt and Erk1/2 signaling pathways. The IL-7/IL-7R axis also contributed to the promotion of ESCC cell migration via the Akt and Erk1/2 signaling pathways. Furthermore, immunohistochemistry showed that ESCC patients with high IL-7R expression in cancer nests exhibited a trend toward poor prognosis in terms of disease-free survival, and showed significant correlation with increased numbers of infiltrating macrophages and cancer-associated fibroblasts. Therefore, IL-7R, which is upregulated when directly co-cultured with macrophages, may contribute to ESCC progression by promoting the development of various malignant phenotypes in cancer cells.

S100A8/A9 Induced by Interaction with Macrophages in Esophageal Squamous Cell Carcinoma Promotes the Migration and Invasion of Cancer Cells via Akt and p38 MAPK Pathways.

Tumor-associated macrophages are associated with more malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. Previously, an indirect co-culture assay of ESCC cells and macrophages was used to identify several factors associated with ESCC progression. Herein, a direct co-culture assay of ESCC cells and macrophages was established, which more closely simulated the actual cancer microenvironment. Direct co-cultured ESCC cells had significantly increased migration and invasion abilities, and phosphorylation levels of Akt and p38 mitogen-activated protein kinase (MAPK) compared with monocultured ESCC cells. According to a cDNA microarray analysis between monocultured and co-cultured ESCC cells, both the expression and release of S100 calcium binding protein A8 and A9 (S100A8 and S100A9), which commonly exist and function as a heterodimer (herein, S100A8/A9), were significantly enhanced in co-cultured ESCC cells. The addition of recombinant human S100A8/A9 protein induced migration and invasion of ESCC cells via Akt and p38 MAPK signaling. Both S100A8 and S100A9 silencing suppressed migration, invasion, and phosphorylation of Akt and p38 MAPK in co-cultured ESCC cells. Moreover, ESCC patients with high S100A8/A9 expression exhibited significantly shorter disease-free survival (P = 0.005) and cause-specific survival (P = 0.038). These results suggest that S100A8/A9 expression and release in ESCC cells are enhanced by direct co-culture with macrophages and that S100A8/A9 promotes ESCC progression via Akt and p38 MAPK signaling pathways.

Evaluation of Intervention Effectiveness of Sensory Compensatory Training with Tactile Discrimination Feedback on Sensorimotor Dysfunction of the Hand after Stroke.

We investigated the intervention effect of training using a feedback-type tactile discrimination system on sensorimotor dysfunction of the hand after a stroke. A human male subject with sensorimotor dysfunction in his left hand after a stroke was asked to perform peg manipulation practice, a building block stacking task, and a material identification task for 10 min each for six weeks. During the activities, a tactile discrimination feedback system was used. The system is a device that detects the vibration information generated when touching an object with a hand and that feeds back the captured information in real time as vibration information. After the intervention, in addition to the reorganization of the sensorimotor areas, the deep sensation, sense of agency, numbness, amount of use, and quality of the left-hand movement improved. Our results suggest that training with the use of a feedback system could be a new form of rehabilitation for sensorimotor dysfunction of the hand.

Pineal gland differentiation in mature teratoma: An under-recognized condition and potential pitfalls for overdiagnosis.

We herein report three cases of mature teratomas with pineal gland differentiation, which is a less recognized phenomenon. Case 1 was a 6-year-old male with a neck mass, Case 2 was a 23-year-old female with a retroperitoneal mass, and Case 3 was a 45-year-old female with a retroperitoneal mass. Each case showed the typical macroscopic and histological findings of mature teratoma, such as solid and cystic lesions mainly lined with a mature squamous epithelium. All cases also showed glial differentiation. Small foci of lobulated cell nests were detected in the center of or adjacent to mature glial tissue. Cells had a clear to pale eosinophilic cytoplasm with small round nuclei. Immunohistochemically, cells were positive for synaptophysin, neurofilament protein with a perivascular "club-shaped swelling" pattern, and cone-rod homeobox protein. To the best of our knowledge, this is the first report of pineal gland differentiation arising in mature teratoma, which may be easily overlooked or misdiagnosed as somatic-type tumors, particularly neuroendocrine tumors. To avoid overtreatment, pathologists need to be aware that pineal gland differentiation may occur in mature teratomas.

Metallothionein 2A Expression in Cancer-Associated Fibroblasts and Cancer Cells Promotes Esophageal Squamous Cell Carcinoma Progression.

Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also established CAF-like cells by indirect co-culture of bone marrow-derived mesenchymal stem cells with ESCC cell lines and found metallothionein 2A (MT2A) to be highly expressed in them. Here, to explore the function of MT2A in CAFs, we silenced MT2A in the CAF-like cells and ESCC cell lines using small interfering RNA. MT2A knockdown in the CAF-like cells suppressed expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2); recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A knockdown in the ESCC cell lines inhibited their growth, migration, and invasiveness. Immunohistochemistry demonstrated that high MT2A expression in the cancer stroma and cancer nest of ESCC tissues correlated with poor prognosis of ESCC patients. Hence, we report that MT2A in CAFs and cancer cells contributes to ESCC progression. MT2A and IGFBP2 are potential novel therapeutic targets in ESCC.