ABSTRACT
BACKGROUND AND OBJECTIVES: This study aimed to evaluate the prognostic value of aberrant right hepatic artery (A-RHA) involvement in patients with pancreatic cancer (PC). METHODS: This study enrolled 474 patients who underwent upfront pancreatectomy or neoadjuvant treatment for resectable (R) or borderline resectable (BR) PC from four institutions. The patients were divided into three groups: A-RHA involvement group (n = 12), patients who had sole A-RHA involvement without major arterial involvement; BR-A group (n = 104), patients who had major arterial involvement; R/BR-PV group (n = 358), others. RESULTS: All patients in the A-RHA involvement group underwent margin-negative resection. The median overall survival of the entire cohort in the A-RHA involvement, R/BR-PV, and BR-A groups was 41.2, 33.5, and 25.2 months, respectively. Although survival in the R/BR-PV group was significantly more favorable than that in the BR-A group (p = 0.0003), no significant difference was observed between the A-RHA involvement group and the R/BR-PV (p = 0.7332) and BR-A (p = 0.1485) groups. CONCLUSIONS: The prognosis of patients with PC and sole A-RHA involvement was comparable to that of patients with R/BR-PV.
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BACKGROUND/OBJECTIVES: Although tumor recurrence after surgical resection in pancreatic cancer (PC) is generally considered incurable, it is well-accepted that clinical presentations and outcomes vary according to the recurrent sites (e.g., liver vs. lung recurrence), suggesting a possible biological inhomogeneity of PC recurrence. Understanding the behavior of biological factors, specifically tumor markers (TMs), at different recurrence sites may contribute to individualized treatment strategies. Therefore, this study aimed to compare the dynamics of pre-recurrence TMs at liver and lung recurrence sites. METHODS: Patients with isolated postoperative liver or lung recurrence as their first recurrence were enrolled. Starting from the recurrence date confirmed by imaging examinations, the values of TMs (carbohydrate antigen 19-9: CA19-9; carcinoembryonic antigen: CEA) were retrospectively evaluated 6 and 3 months before recurrence and at the time of recurrence. RESULTS: Patients with liver recurrence displayed a significant increase in CA19-9 and CEA levels from as early as 6 months before recurrence. Contrastingly, patients with lung recurrence demonstrated a significant elevation of CA19-9 levels starting from 3 months before recurrence, with no increase in CEA levels, even at the time of recurrence. The relative change in CA19-9 and CEA levels during each period were significantly lower in patients with lung recurrence. CONCLUSIONS: Both TMs exhibited organ-specific variations in patients with postoperative PC recurrence. This disparity may reflect the biological heterogeneity of PC between recurrence patterns, thereby highlighting the importance of conducting postoperative follow-up with consideration of this fact.
Subject(s)
Biomarkers, Tumor , Liver Neoplasms , Lung Neoplasms , Neoplasm Recurrence, Local , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/pathology , Male , Neoplasm Recurrence, Local/pathology , Lung Neoplasms/surgery , Lung Neoplasms/pathology , Female , Biomarkers, Tumor/metabolism , Retrospective Studies , Liver Neoplasms/surgery , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Aged , Middle Aged , Follow-Up Studies , CA-19-9 Antigen/blood , Prognosis , Carcinoembryonic Antigen/blood , Survival RateABSTRACT
Signal recognition particles (SRPs) are essential for regulating intracellular protein transport and secretion. Patients with tumors with high SRP9 expression tend to have a poorer overall survival. However, to the best of our knowledge, no reports have described the relationship between SRP9 localization and prognosis in pancreatic cancer. Thus, the present study aimed to investigate this relationship. Immunohistochemical staining for SRP9 using excised specimens from pancreatic cancer surgery cases without preoperative chemotherapy or radiotherapy showed that SRP9 was preferentially expressed in the nucleus of the cancerous regions in some cases, which was hardly detected in other cases, indicating that SRP9 was transported to the nucleus in the former cases. To compare the prognosis of patients with SRP9 nuclear translocation, patients were divided into two groups: Those with a nuclear translocation rate of >50% and those with a nuclear translocation rate of ≤50%. The nuclear translocation rate of >50% group had a significantly better recurrencefree survival than the nuclear translocation rate of ≤50% group (P=0.037). Subsequent in vitro experiments were conducted; notably, the nuclear translocation rate of SRP9 was reduced under amino aciddeficient conditions, suggesting that multiple factors are involved in this phenomenon. To further study the function of SRP9 nuclear translocation, in vitro experiments were performed by introducing SRP9 splicing variants (v1 and v2) and their deletion mutants lacking Cterminal regions into MiaPaCa pancreatic cancer cells. The results demonstrated that both splicing variants showed nuclear translocation regardless of the Cterminal deletions, suggesting the role of the Nterminal regions. Given that SRP9 is an RNAbinding protein, the study of RNA immunoprecipitation revealed that signaling pathways involved in cancer progression and protein translation were downregulated in nucleartranslocated v1 and v2. Undoubtedly, further studies of the nuclear translocation of SRP9 will open an avenue to optimize the precise evaluation and therapeutic control of pancreatic cancer.
Subject(s)
Cell Nucleus , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Prognosis , Male , Female , Cell Nucleus/metabolism , Middle Aged , Aged , Cell Line, Tumor , Signal Recognition Particle/metabolism , Signal Recognition Particle/genetics , Active Transport, Cell Nucleus , Serine-Arginine Splicing Factors/metabolism , Serine-Arginine Splicing Factors/genetics , Adult , Gene Expression Regulation, NeoplasticABSTRACT
Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response within nonlymphoid tissues. In this review, we summarize the characteristics and functions of Trm cells and discuss their profound implications for patient outcomes in gastrointestinal cancers. Positioned strategically in peripheral tissues, Trm cells have functions beyond immune surveillance, affecting tumor progression, prognosis, and response to immunotherapy. Studies indicate that Trm cells are prognostic markers and correlate positively with enhanced survival. Their presence in the tumor microenvironment has sparked interest in their therapeutic potential, particularly with respect to immune checkpoint inhibitors, which may improve cancer treatment. Understanding how Trm cells work will not only help to prevent cancer spread through effective treatment but will also contribute to disease prevention at early stages as well as vaccine development. The role of Trm cells goes beyond just cancer, and they have potential applications in infectious and autoimmune diseases. This review provides a thorough analysis of Trm cells in gastrointestinal cancers, which may lead to personalized and effective cancer therapies.
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Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50 = 19.3, 22.6 mg/dl, p = 0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50 = 7.18,7.60 nM, p = 0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bile Duct Neoplasms , Cholangiocarcinoma , Deoxycytidine , Drug Synergism , Gemcitabine , Pyrimidines , Receptor, Fibroblast Growth Factor, Type 2 , Xenograft Model Antitumor Assays , Humans , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/genetics , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/administration & dosage , Animals , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/genetics , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Pyrimidines/pharmacology , Pyrimidines/administration & dosage , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Receptor, Fibroblast Growth Factor, Type 2/genetics , Mice , Cell Proliferation/drug effects , Mice, Nude , Signal Transduction/drug effects , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/pharmacology , Mutation , Apoptosis/drug effects , Morpholines , PyrrolesSubject(s)
Carcinoma, Pancreatic Ductal , Fibronectins , Muscle, Skeletal , Pancreatic Neoplasms , Humans , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Fibronectins/metabolism , Fibronectins/pharmacology , Muscle, Skeletal/metabolismABSTRACT
BACKGROUND: Chronic pancreatitis (CP) is a progressive disease characterized by pancreatic fibrosis for which effective treatment options are lacking. Mesenchymal stem cells (MSCs) have shown potential for fibrosis treatment but face limitations in clinical application. The high-mobility group box 1 (HMGB1) fragment mobilizes MSCs from bone marrow into the blood and has emerged as a promising therapeutic agent for tissue regeneration in various pathological conditions. The aim of this study was to investigate the potential therapeutic effects of systemic administration of the HMGB1 fragment in a mouse model of CP. METHODS: A caerulein-induced CP mouse model was used, and the HMGB1 fragment was administered by tail vein injection. Parameters such as body weight, pancreatic tissue damage, fibrosis, inflammatory cytokine expression, and collagen-related gene expression were evaluated using various assays, including immunohistochemistry, real-time PCR, serum analysis, and single-cell transcriptome analysis. And the migration of MSCs to the pancreas was evaluated using the parabiosis model. RESULTS: Administration of the HMGB1 fragment was associated with significant improvements in pancreatic tissue damage and fibrosis. It suppressed the expression of inflammatory cytokines and activated platelet-derived growth factor receptor-α+ MSCs, leading to their accumulation in the pancreas. The HMGB1 fragment also shifted gene expression patterns associated with pancreatic fibrosis toward those of the normal pancreas. Systemic administration of the HMGB1 fragment demonstrated therapeutic efficacy in attenuating pancreatic tissue damage and fibrosis in a CP mouse model. CONCLUSION: These findings highlight the potential of the HMGB1 fragment as a therapeutic target for the treatment of CP.
Subject(s)
Ceruletide , Disease Models, Animal , Fibrosis , HMGB1 Protein , Pancreas , Pancreatitis, Chronic , Animals , Pancreatitis, Chronic/drug therapy , HMGB1 Protein/metabolism , HMGB1 Protein/genetics , Mice , Male , Pancreas/pathology , Mice, Inbred C57BL , Cytokines/metabolism , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cell Transplantation/methodsABSTRACT
Nocardia is a gram-positive bacillus with the microscopic appearance of branching hyphae and is mainly distributed in the soil. Nocardiosis more frequently occurs in immunosuppressed patients. Since nocardiosis has a high mortality rate, immediate diagnosis and treatment are needed. We report the first case of pulmonary nocardiosis caused by Nocardia pseudobrasiliensis after liver transplantation. A 58-year-old woman underwent living-donor transplantation for primary biliary cholangitis. Seven months after transplantation, she came to our hospital complaining of fever and anorexia. Computed tomography of the lungs showed a 45 mm large nodule affecting the upper lobe of the left lung. We started administering empiric antibiotics and tapering immunosuppression, but the patient's condition gradually worsened, and lung lesions increased. On the fifth day after hospitalization, bacteria developed from sputum cultures were identified as N. pseudobrasiliensis by matrix-assisted laser desorption ionization time of flight mass spectrometry. We started treatment with trimethoprim-sulfamethoxazole. The patient's clinical symptoms and laboratory data improved quickly. After one month of hospitalization, this patient was discharged. Then, the lung lesion almost vanished. Ten years after her transplant, the patient is alive with a well-functioning graft.
Subject(s)
Liver Transplantation , Nocardia Infections , Nocardia , Humans , Nocardia Infections/drug therapy , Nocardia Infections/microbiology , Nocardia Infections/diagnosis , Female , Middle Aged , Liver Transplantation/adverse effects , Nocardia/isolation & purification , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Anti-Bacterial Agents/therapeutic use , Immunocompromised Host , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients lose insulin independence by 3 years after ITx due to early graft loss, such that multiple donors are required to achieve insulin independence. In the present study, we investigated whether skeletal myoblast cells could be beneficial for promoting angiogenesis and maintaining the differentiated phenotypes of islets. In vitro experiments showed that the myoblast cells secreted angiogenesis-related cytokines (vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and stromal-derived factor-1α (SDF-1α)), contributed to maintenance of differentiated islet phenotypes, and enhanced islet cell insulin secretion capacity. To verify these findings in vivo, we transplanted islets alone or with myoblast cells under the kidney capsule of streptozotocin-induced diabetic mice. Compared with islets alone, the group bearing islets with myoblast cells had a significantly lower average blood glucose level. Histological examination revealed that transplants with islets plus myoblast cells were associated with a significantly larger insulin-positive area and significantly higher number of CD31-positive microvessels compared to islets alone. Furthermore, islets cotransplanted with myoblast cells showed JAK-STAT signaling activation. Our results suggest two possible mechanisms underlying enhancement of islet graft function with myoblast cells cotransplantation: "indirect effects" mediated by angiogenesis and "direct effects" of myoblast cells on islets via the JAK-STAT cascade. Overall, these findings suggest that skeletal myoblast cells enhance the function of transplanted islets, implying clinical potential for a novel ITx procedure involving myoblast cells for patients with diabetes.
Subject(s)
Diabetes Mellitus, Experimental , Insulin , Islets of Langerhans Transplantation , Myoblasts, Skeletal , Neovascularization, Physiologic , Animals , Islets of Langerhans Transplantation/methods , Diabetes Mellitus, Experimental/metabolism , Myoblasts, Skeletal/transplantation , Myoblasts, Skeletal/metabolism , Mice , Male , Insulin/metabolism , Hepatocyte Growth Factor/metabolism , Mice, Inbred C57BL , Vascular Endothelial Growth Factor A/metabolism , Islets of Langerhans/metabolism , Islets of Langerhans/blood supply , Chemokine CXCL12/metabolism , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 1/surgery , Signal Transduction , Insulin Secretion , Cell DifferentiationABSTRACT
Aim: The number of elderly patients with liver cancer is increasing with the aging society. The Geriatric Prognostic Scoring System is useful in predicting the postoperative prognosis for elderly patients with gastrointestinal cancer. The aim of the present study was to assess the predictive ability of the geriatric prognostic scoring system for postoperative survival in elderly patients with liver cancer. Methods: Eighty-eight patients aged ≥75 years who were treated for primary liver cancer and metastatic liver tumor were retrospectively analyzed. The Geriatric Prognostic Score (GPS) was created by several clinical parameters such as age, sex, type of cancer, stage, performance status, body mass index, and comprehensive geriatric assessment. Each patient was divided into two groups of high-risk to low-risk according to their GPS: â§30 high-risk group and <30 low-risk. The predictive ability of geriatric prognostic scoring system for postoperative survival was assessed in univariate and multivariate analyses. Results: Of the 88 patients, 75 were diagnosed as hepatocellular carcinoma and 13 as colorectal liver metastasis. After geriatric prognostic scoring system assessments, 26 patients were diagnosed as high-risk and the remaining 62 as low-risk. The 3-year overall survival rates were 78.5% in the low-risk group and 35.1% in the high-risk group (p < 0.001). The univariate and multivariate analyses of overall survival identified high GPS as an independent significant factor (p < 0.001). Conclusions: We could conclude that the geriatric prognostic scoring system is useful in predicting patients' prognosis after hepatectomy and it can provide helpful information to surgeons for determining treatment strategies for elderly patients with liver cancer.
Subject(s)
Antimetabolites, Antineoplastic , Carcinoma, Pancreatic Ductal , Cell Movement , Deoxycytidine , Fibronectins , Gemcitabine , Muscle, Skeletal , Pancreatic Neoplasms , Humans , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Fibronectins/metabolism , Fibronectins/pharmacology , Cell Movement/drug effects , Antimetabolites, Antineoplastic/pharmacology , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Cell Proliferation/drug effectsABSTRACT
N6-methyladenosine (m6A) is an RNA modification involved in RNA processing and widely found in transcripts. In cancer cells, m6A is upregulated, contributing to their malignant transformation. In this study, we analyzed gene expression and m6A modification in cancer tissues, ducts, and acinar cells derived from pancreatic cancer patients using MeRIP-seq. We found that dozens of RNAs highly modified by m6A were detected in cancer tissues compared with ducts and acinar cells. Among them, the m6A-activated mRNA TCEAL8 was observed, for the first time, as a potential marker gene in pancreatic cancer. Spatially resolved transcriptomic analysis showed that TCEAL8 was highly expressed in specific cells, and activation of cancer-related signaling pathways was observed relative to TCEAL8-negative cells. Furthermore, among TCEAL8-positive cells, the cells expressing the m6A-modifying enzyme gene METTL3 showed co-activation of Notch and mTOR signaling, also known to be involved in cancer metastasis. Overall, these results suggest that m6A-activated TCEAL8 is a novel marker gene involved in the malignant transformation of pancreatic cancer.
Subject(s)
Adenosine , Biomarkers, Tumor , Gene Expression Regulation, Neoplastic , Methyltransferases , Pancreatic Neoplasms , RNA, Messenger , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Adenosine/analogs & derivatives , Adenosine/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Methyltransferases/genetics , Methyltransferases/metabolism , Signal Transduction/genetics , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Cell Line, Tumor , Receptors, Notch/genetics , Receptors, Notch/metabolism , Gene Expression Profiling/methodsABSTRACT
BACKGROUND: Cell-derived sheets are of global interest for regenerative therapy. Transplanting a sheet for abdominal organs requires a device for laparoscopic delivery to minimize invasiveness. Here, using a porcine model, we aimed to confirm the feasibility of a device developed to deliver sheets to the thoracic cavity in a laparoscopic transplantation procedure. MATERIAL AND METHODS: We used the device to transplant human skeletal myoblast cell sheets onto the liver and measured extra-corporeal, intra-abdominal, and total procedure times for sheet transplantation. Tissues, including the liver and the sheet, were collected two days after transplantation and analyzed histologically. RESULTS: In all experiments (n = 27), all sheets were successfully placed at target locations. The mean (± standard deviation) extra-corporeal, intra-abdominal, and total procedure times were 44 ± 29, 33 ± 12, and 77 ± 36 s, respectively. We found no difference between the two surgeons in procedure times. Histological analyses showed no liver damage with the transplantation and that sheets were transplanted closely onto the liver tissue without gaps. CONCLUSION: We confirmed the feasibility of a simple universal device to transplant cell-derived sheets via laparoscopic surgery. This device could support a minimally invasive procedure for sheet transplantation.
Subject(s)
Laparoscopy , Liver , Animals , Laparoscopy/methods , Swine , Liver/surgery , Humans , Feasibility Studies , Myoblasts, Skeletal/transplantation , Models, Animal , Operative Time , Cell Transplantation/methods , Cell Transplantation/instrumentationABSTRACT
Tumor endothelial cells (TECs), which are thought to be structurally and functionally different from normal endothelial cells (NECs), are increasingly attracting attention as a therapeutic target in hypervascular malignancies. Although colorectal liver metastasis (CRLM) tumors are hypovascular, inhibitors of angiogenesis are a key drug in multidisciplinary therapy, and TECs might be involved in the development and progression of cancer. Here, we analyzed the function of TEC in the CRLM tumor microenvironment. We used a murine colon cancer cell line (CT26) and isolated TECs from CRLM tumors. TECs showed higher proliferation and migration than NECs. Coinjection of CT26 and TECs yielded rapid tumor formation in vivo. Immunofluorescence analysis showed that coinjection of CT26 and TECs increased vessel formation and Ki-67+ cells. Transcriptome analysis identified kallikrein-related peptide 10 (KLK10) as a candidate target. Coinjection of CT26 and TECs after KLK10 downregulation with siRNA suppressed tumor formation in vivo. TEC secretion of KLK10 decreased after KLK10 downregulation, and conditioned medium after KLK10 knockdown in TECs suppressed CT26 proliferative activity. Double immunofluorescence staining of KLK10 and CD31 in CRLM tissues revealed a significant correlation between poor prognosis and positive KLK10 expression in TECs and tumor cells. On multivariate analysis, KLK10 expression was an independent prognostic factor in disease-free survival. In conclusion, KLK10 derived from TECs accelerates colon cancer cell proliferation and hematogenous liver metastasis formation. KLK10 in TECs might offer a promising therapeutic target in CRLM.
Subject(s)
Cell Proliferation , Colonic Neoplasms , Endothelial Cells , Kallikreins , Liver Neoplasms , Animals , Female , Humans , Male , Mice , Cell Line, Tumor , Cell Movement , Colonic Neoplasms/pathology , Colonic Neoplasms/metabolism , Colonic Neoplasms/genetics , Endothelial Cells/metabolism , Endothelial Cells/pathology , Kallikreins/metabolism , Kallikreins/genetics , Liver Neoplasms/secondary , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/genetics , Mice, Inbred BALB C , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Tumor MicroenvironmentABSTRACT
BACKGROUND: High skeletal muscle mass might be a prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC); however, the underlying reason is unclear. We hypothesized that myokines, which are cytokines secreted by the skeletal muscle, function as suppressors of PDAC. We specifically examined irisin, a myokine, which plays a critical role in the modulation of metabolism, to clarify the anticancer mechanisms. METHODS: First, the effect of the conditioned medium (CM) from skeletal muscle cells and from irisin-knockdown skeletal muscle cells on PDAC cell lines was evaluated. We then investigated the effects and anticancer mechanism of irisin in PDAC cells, and evaluated the anticancer effect of recombinant irisin in a PDAC xenograft mouse model. Finally, patients undergoing pancreatic resection for PDAC were divided into two groups based on their serum irisin level, and the long-term outcomes were evaluated. RESULTS: The CM enhanced gemcitabine sensitivity by inducing apoptosis and decreasing cell migration by inhibiting epithelial-mesenchymal transition (EMT) in PDAC cell lines. The CM derived from irisin-knockdown skeletal muscle cells did not affect the PDAC cell lines. The addition of recombinant irisin to PDAC cell lines facilitated sensitivity to gemcitabine by inhibiting the mitogen-activated protein kinase (MAPK) pathway, and decreased migration by inhibiting EMT via the transforming growth factor-ß/SMAD pathway. Xenografts injected with gemcitabine and recombinant irisin grew slower than the xenografts injected with gemcitabine alone. The overall survival was prolonged in the high-irisin group compared with that in the low-irisin group. CONCLUSIONS: Skeletal muscle-derived irisin may affect PDAC by enhancing its sensitivity to gemcitabine and suppressing EMT.
Subject(s)
Antimetabolites, Antineoplastic , Apoptosis , Carcinoma, Pancreatic Ductal , Cell Movement , Cell Proliferation , Deoxycytidine , Epithelial-Mesenchymal Transition , Fibronectins , Gemcitabine , Muscle, Skeletal , Pancreatic Neoplasms , Xenograft Model Antitumor Assays , Animals , Female , Humans , Male , Mice , Antimetabolites, Antineoplastic/pharmacology , Apoptosis/drug effects , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Cell Proliferation/drug effects , Culture Media, Conditioned/pharmacology , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Fibronectins/metabolism , Fibronectins/pharmacology , Mice, Nude , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscle, Skeletal/drug effects , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Prognosis , Survival Rate , Tumor Cells, Cultured , AgedABSTRACT
BACKGROUND: Appropriate re-evaluation after neoadjuvant treatment (NAT) is important for optimal treatment selection. Nonetheless, determining the operative eligibility of patients with a modest radiologic response remains controversial. This study aimed to assess the prognostic significance of biologic factors for patients showing a modest radiologic response to NAT and investigate the tumor markers (TMs), CA19-9 alone, DUPAN-II alone, and their combination, to create an index that combines these sialyl-Lewis antigen-related TMs associated with treatment outcomes. METHODS: This study enrolled patients deemed to have a "stable disease" by RECIST classification with slight progression (tumor size increase rate, ≤20%) as their radiologic response after NAT. A sialyl-Lewis-related index (sLe index), calculated by adding one fourth of the serum DUPAN-II value to the CA19-9 value, was created. The prognostic significances of CA19-9, DUPAN-II, and the sLe index were assessed in relation to postoperative outcomes. RESULTS: An sLe index lower than the cutoff value (45.25) was significantly associated with favorable disease-free survival. Moreover, the post-NAT sLe index had a higher area under the curve value for recurrence within 24 months than the post-NAT levels of CA19-9 or DUPAN-II alone. Multivariable analysis showed that a post-NAT sLe index higher than 45.25 was the single independent predictive factor for recurrence within 24 months. CONCLUSIONS: Additional evaluation of biologic factors can potentially enhance patient selection, particularly for patients showing a limited radiologic response to NAT. The authors' index is a simple indicator for the biologic evaluation of multiple combined sialyl-Lewis antigen-related TMs and may offer a better predictive significance.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Humans , Biomarkers, Tumor , CA-19-9 Antigen , Lewis Blood Group Antigens , Prognosis , Biological Factors , Neoadjuvant Therapy , Antigens, Neoplasm , Pancreatic Neoplasms/surgery , Adenocarcinoma/surgery , Retrospective StudiesABSTRACT
AIM: Tumor Ki-67 expression reflects prognosis and cancer grade, and biopsy-based preoperative assessment of Ki-67 expression is key to treatment. Apparent diffusion coefficient (ADC) values obtained with this imaging may noninvasively predict Ki-67 by reflecting tumor cell density and limited water molecule movement from irregular alignment. This study aimed to investigate the ability of ADC values to predict Ki-67 expression in intrahepatic cholangiocarcinoma (ICC). METHOD: We retrospectively analyzed 39 cases of ICC confirmed by surgical pathology. All patients had undergone magnetic resonance imaging, and ADC values (mean, minimum, and maximum) were calculated. Ki-67 expression was assessed by immunohistochemistry, and patients were divided into groups of high (n = 18) and low (n = 21) Ki-67 expression. To assess the diagnostic performance of the ADC values for Ki-67 expression, we used the receiver operating characteristic curve and compared the areas under the curve (AUC). RESULTS: The mean and minimum ADC values were significantly lower in the group with high Ki-67 expression. For predicting high Ki-67 expression, the AUC values were 0.701 for mean ADC, 0.818 for minimum ADC, and 0.571 for maximum ADC. The diagnostic sensitivity and specificity of the minimum ADC values were 88.9% and 76.2%, respectively. In addition, with ADC values combined, the AUC increased to 0.831. Apparent diffusion coefficient is a useful predictor of Ki-67 expression level in ICC. CONCLUSION: Apparent diffusion coefficient values, especially minimum ADC values, can noninvasively predict ICC associated with high Ki-67 expression.
ABSTRACT
Clinical verification of adoptively transferred regulatory T cell (Treg) efficacy in transplantation remains challenging. Here, we examined the influence of autologous ex vivo-expanded polyclonal Tregs on kidney graft survival in a clinically relevant non-human primate model. Peripheral blood Tregs were isolated and expanded using artificial antigen presenting cells. Immunosuppression was comprised of tapered tacrolimus and CTLA4 immunoglobulin, in five animals each without or with Treg infusions. Escalating Treg doses were administered 6, 10, 13, 16, 20, 23, 27 and 30 days after transplant. Infused Tregs were monitored for Treg signature, anti-apoptotic (Bcl-2) and proliferation (Ki67) marker expression. Treg infusions prolonged median graft survival time significantly from 35 to 70 days. Treg marker (Ki67 and Bcl-2) expression by infused Tregs diminished after their infusion but remained comparable to that of circulating native Tregs. No major changes in circulating donor-reactive T cell responses or total Treg percentages, or in graft-infiltrating T cell subsets were observed with Treg infusion. However, Treg infusion was associated with significant increases in CD163 expression by circulating HLA-DR+ myeloid cells and elevated levels of circulating soluble CD163. Further, graft-infiltrating CD163+ cells were increased with Treg infusion. Thus, multiple Treg infusions were associated with M2-like myeloid cell enhancement that may mediate immunomodulatory, anti-inflammatory and graft reparative effects.
Subject(s)
Primates , T-Lymphocytes, Regulatory , Animals , Ki-67 Antigen/metabolism , Kidney , Allografts , Myeloid Cells , Proto-Oncogene Proteins c-bcl-2/metabolismABSTRACT
Insufficient cancer treatment can induce senescent cancer cell formation and treatment resistance. The characteristics of induced senescent cancer (iSnCa) cells remain unclear. Pancreatic ductal adenocarcinoma (PDAC) has a low and nondurable response rate to current treatments. Our study aimed to analyze the properties of iSnCa cells and the relationship between cellular senescence and prognosis in PDAC. We evaluated the characteristics of gemcitabine-induced senescent cancer cells and the effect of senescence-associated secretory phenotype (SASP) factors released by iSnCa cells on surrounding PDAC cells. The relationship between cellular senescence and the prognosis was investigated in 50 patients with PDAC treated with gemcitabine-based neoadjuvant chemotherapy. Exposure to 5 ng/mL gemcitabine-induced senescence, decreased proliferation and increased senescence-associated ß-galactosidase-cell staining without cell death in PDAC cells; the expression of glutaminase1 (GLS1) and SASP factors also increased and caused epithelial-mesenchymal transition in surrounding PDAC cells. iSnCa cells were selectively removed by the GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) through apoptosis induction. Cellular senescence was induced in PDAC cells via insufficient gemcitabine in subcutaneous tumor model mice. GLS1 expression was an independent prognostic factor in patients with PDAC who received gemcitabine-based neoadjuvant chemotherapy. This is the first study to identify the relationship between senescence and GLS1 in PDAC. Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.