Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer.

BACKGROUND: Deciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment. METHODS: We examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes' expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR. RESULTS: Twenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies. CONCLUSIONS: By employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.

Predicting pancreatic fistula after central pancreatectomy using current fistula risk scores for pancreaticoduodenectomy and distal pancreatectomy.

BACKGROUND: The incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) after central pancreatectomy (CP) is high, yet an effective predictive method is currently lacking. This study aimed to predict CR-POPF after CP by utilizing existing fistula risk scores (FRSs) for pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: A retrospective analysis was conducted on patients undergoing CP at our institution between January 2010 and July 2022. The primary outcome was CR-POPF (grade B/C) according to the 2016 International Study Group of Pancreatic Surgery definition. To establish predictive models for CR-POPF after CP, we combined the FRSs for PD and DP using a calculation formula that considers the probability of the union of two events. As a result, we obtained twelve central FRS (C-FRS) models. The performance of each C-FRS was assessed using the area under the curves (AUC) and calibration plots. RESULTS: A total of 115 patients undergoing CP were included. Among them, 38 (33%) were male, with a median age of 53 years. CR-POPF occurred in 35 (30.4%) patients, specifically 33 (28.7%) with grade B and 2 (1.7%) with grade C. Multivariate analysis showed that body mass index (BMI) [odds ratio (OR) 1.260, 95% confidence interval (CI) 1.039-1.528, P = 0.019), pancreatic thickness at the cephalic transection site (OR 1.228, 95% CI 1.074-1.405, P = 0.003), cephalic main pancreatic duct (MPD) size (OR 41.872, 95%CI 7.614-230.265, P < 0.001), and distal MPD size (OR 0.142, 95% CI 0.036-0.561, P = 0.005) were independent predictive factors for CR-POPF. Discrimination was generally acceptable for all C-FRS models, with an AUC ranging from 0.748 (DISPAIR-a-FRS: 95% CI, 0.659-0.824) to 0.847 (Intraop-D-a-FRS: 95% CI, 0.768-0.907). The models were calibrated with adequate Brier scores ranging from 0.157 to 0.183. The performance in all subgroups was similar as that of the entire cohort. Three preoperative risk groups (low, intermediate, and high) were identified based on the clinical applicability of the Preop-D-Roberts-FRS, with corresponding incidences of CR-POPF as 0% (0/24), 30% (21/70), and 66.7% (14/21), respectively. CONCLUSION: The derived C-FRS models show potential for accurately predicting the development of CR-POPF after CP. However, further validation studies are required to determine the most effective model. In the meantime, the Preop-D-Roberts-FRS is recommended for clinical practice due to its ease of use and preoperative predictability.

Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis. DESIGN: C57BL/6 mice were 'educated' by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models. RESULTS: Pex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis. CONCLUSION: The Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.

The expression and survival significance of sodium glucose transporters in pancreatic cancer.

BACKGROUND: Sodium glucose transporters (SGLTs) play vital roles in glucose uptake in many solid cancers, including pancreatic cancer (PC). However, their expression profile in pancreatic cancer and correlation with prognosis are not clear. Thus, we aimed to analyse the expression profile and prognostic significance of SGLT-1 and SGLT-2 in PC. METHODS: Eighty-eight patients with pancreatic ductal adenocarcinoma (PDAC) undergoing surgery in Huashan Hospital, Fudan University, from July 2017 to June 2020 were enrolled in the study. Specimens for immunohistochemistry were obtained through surgical resection. Bioinformatics analysis was performed based on the Gene Expression Omnibus (GEO), Oncomine and The Cancer Genome Atlas (TCGA) databases. The statistics were calculated using IBM SPSS Statistics, version 20 and R 4.1.1. P values lower than 0.05 were considered to indicate statistical significance. RESULTS: SGLT-1 but not SGLT-2 was significantly overexpressed in PDAC. Survival analysis showed that the median overall survival (OS) and progression-free survival (PFS) of patients with high SGLT-1 expression were significantly longer than that of patients with low SGLT-1 expression. Cox regression indicated that high SGLT-1 expression was an independent predictor for a better prognosis, while residual tumour status (R1 and R2) was an independent risk factor for a poor prognosis. Finally, PDZK1-interacting protein 1 (PDZK1IP1), a protein participating in the generation of reactive oxygen species, was overexpressed in PDAC and its expression was significantly correlated with SGLT-1. CONCLUSIONS: SGLT-1 but not SGLT-2 was overexpressed in PDAC, and the overexpression of SGLT-1 could be a predictor of a better prognosis. Residual tumour status (R1 and R2) was a risk factor for poor prognosis and disease progression.

Prevalence and prognosis of increased pancreatic enzymes in patients with COVID-19: A systematic review and meta-analysis.

INTRODUCTION: The prevalence of increased pancreatic enzymes (elevated serum amylase and/or lipase) and its relationship to clinical outcomes in patients with coronavirus disease 2019 (COVID-19) infection is not known. METHODS: A systematic review and meta-analysis of relevant studies reporting prevalence and impact of increased pancreatic enzymes (defined as an elevation in amylase and/or lipase levels above the upper limit of normal [ULN] value) in COVID-19 was undertaken. RESULTS: A total of 36,496 patients from 21 studies were included for this meta-analysis. The overall prevalence and mortality for increased pancreatic enzymes (>ULN) in COVID-19 were 25.4% (95% CI, 15.8%-36.2%) and 34.6% (95% CI, 25.5%-44.4%), respectively. The overall prevalence and mortality for increased pancreatic enzymes (>3 × ULN) were 6.1% (95% CI, 3.6%-9.2%) and 39.2% (95% CI, 18.7%-61.6%), respectively. Patients with increased pancreatic enzymes, including elevated serum lipase or amylase of either type, had worse clinical outcomes, including need for ICU admission, mechanical ventilation and mortality. DISCUSSION: Increased pancreatic enzymes is frequent and may exacerbate the consequences of COVID-19 infection.

Basal microvilli define the metabolic capacity and lethal phenotype of pancreatic cancer.

Apical microvilli of polarized epithelial cells govern the absorption of metabolites and the transport of fluid in tissues. Previously, we reported that tall and dense basal microvilli present on the endothelial cells of pancreatic cancers, a lethal malignancy with a high metabolism and unusual hypomicrovascularity, contain nutrient trafficking vesicles and glucose; their length and density were related to the glucose uptake of pancreatic cancers in a small-scale analysis. However, the implications of basal microvilli on pancreatic cancers are unknown. Here, we evaluated the clinical implications of basal microvilli in 106 pancreatic cancers. We found that basal microvilli are a dominant change in pancreatic cancers. The presence of longer and denser basal microvilli on the microvessels in pancreatic cancer tissues positively correlated with increased glucose uptake and higher metastatic (or invasive) and proliferative potentials of neoplastic cells and vice versa. Clinically, postoperative patients with longer and denser basal microvilli were more prone to unfavorable pathological characteristics and dismal prognoses. They were even more refractory to adjuvant therapy than those with shorter and thinner basal microvilli were. Our findings show that basal microvilli define the metabolic capacity and lethal phenotype of pancreatic cancers. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Label-Free Histology and Evaluation of Human Pancreatic Cancer with Coherent Nonlinear Optical Microscopy.

Surgeries achieving maximal tumor resection remain the major effective treatment of pancreatic cancer. Rapid and precise intraoperative diagnosis of pancreatic tissues is critical for optimum surgical outcomes but is challenging for the current staining-based histological methods. We demonstrated that label-free coherent nonlinear optical microscopy with combined stimulated Raman scattering (SRS) and second harmonic generation (SHG) could reveal key diagnostic features of both normal and cancerous human pancreatic tissues. Adjacent pairs of tissue sections from resection margins of 37 patients were imaged by SRS and hematoxylin and eosin staining for direct comparison, demonstrating high diagnostic concordance (Cohen's kappa, κ > 0.97) between them. Fresh unprocessed tissues showed well-preserved histoarchitectures including pancreatic ducts, islets, acini, and nerves. Moreover, the area ratios of collagen fibers were analyzed and found to correlate with the drainage pancreatic amylase level (odds ratio = 28.0, p = 0.0017). Our results indicated that SRS/SHG histology provides potential for rapid intraoperative diagnosis of pancreatic cancer as well as a predictive value of postoperative pancreatic fistula.

Grading Solid Pseudopapillary Tumors of the Pancreas: the Fudan Prognostic Index.

BACKGROUND: Ki-67 has been shown to predict outcome of patients with solid pseudopapillary tumor of the pancreas (SPTP) but has not been incorporated into a formal classification system to predict recurrence-free survival (RFS). METHODS: This is a retrospective cohort study of patients with histologically confirmed diagnosis of SPTP who had at least 1 year of follow-up at two tertiary academic centers. Survival data were assessed by Kaplan-Meier method and multivariable Cox regression model. Prognostic performance was compared among various systems. RESULTS: A total of 193 consecutive patients were included, ranging in age from 12 to 70 years (median 33 years). Seven patients (3.6%) developed tumor recurrence. The 3-, 5-, and 10-year RFS rates were estimated at 96.9%, 96.1%, and 94.8%, respectively. For the AJCC staging system, patients with stage I had similar prognosis to those with stage II. For the ENETS staging system, patients with stage I to III had similar prognosis. Grade based on Ki-67 was superior to both the AJCC and ENETS systems for predicting survival. Multivariate analysis revealed that large tumor size [> 10 cm; hazard ratio (HR), 6.177 95% confidence interval (CI), 1.289-29.603; P = 0.023] and Ki-67 (HR, 17.199 95% CI, 4.001-73.930; P < 0.001) were independent predictors for RFS. The Fudan Prognostic Index based on the combination of Ki-67 and tumor size showed excellent discrimination for RFS and was more accurate and informative than other grading/staging systems. CONCLUSION: The Fudan Prognostic Index better predicts RFS compared with either Ki-67 alone or the current AJCC and ENETS TNM-based staging systems.

The Expression and Survival Significance of Glucose Transporter-1 in Pancreatic Cancer: Meta-Analysis, Bioinformatics Analysis and Retrospective Study.

To explore the expression profile and prognostic relevance of GLUT-1 in pancreatic cancer, a meta-analysis, bioinformatics analysis based on Gene Expression Omnibus (GEO), Oncomine dataset and The Cancer Genome Atlas (TCGA) database, and immunohistochemistry in tumor and normal tissue from 88 pancreatic ductal adenocarcinoma (PDAC) patients were performed. GLUT-1 was significantly overexpressed in pancreatic cancer but it could not be a significant biomarker for prognosis. TNM stage and pathological grade could be biomarker of poor prognosis of patients with pancreatic cancer.

LyP-1-fMWNTs enhanced targeted delivery of MBD1siRNA to pancreatic cancer cells.

Functionalized multi-walled carbon nanotubes have been extensively gained popularity in pancreatic cancer gene therapy. LyP-1, a peptide, has been proved to specifically bind pancreatic cancer cells. The potential therapeutic effect of LyP-1-conjugated functionalized multi-walled carbon nanotubes in treating pancreatic cancer is still unknown. In this study, LyP-1-conjugated functionalized multi-walled carbon nanotubes were successfully synthesized, characterized and showed satisfactory size distribution and zeta potential. Compared with functionalized multi-walled carbon nanotubes, cellular uptake of LyP-1-functionalized multi-walled carbon nanotubes was shown to be increased. Compound of LyP-1-functionalized multi-walled carbon nanotubes and MBD1siRNA showed superior gene transfection efficiency. Moreover, LyP-1-fMWNTs/MBD1siRNA complex could significantly decrease the viability and proliferation and promoted apoptosis of pancreatic cancer cells in vitro. Further xenograft assays revealed that the tumour burden in the nude mice injected with LyP-1-functionalized multi-walled carbon nanotubes/MBD1siRNA was significantly relieved. The study demonstrated that LyP-1-functionalized multi-walled carbon nanotubes/MBD1siRNA could be a promising candidate for tumour active targeting therapy in pancreatic cancer.

WD repeat-containing protein 1 maintains ß-Catenin activity to promote pancreatic cancer aggressiveness.

BACKGROUND: The molecular signature underlying pancreatic ductal adenocarcinoma (PDAC) progression may include key proteins affecting the malignant phenotypes. Here, we aimed to identify the proteins implicated in PDAC with different tumour-node-metastasis (TNM) stages. METHODS: Eight-plex isobaric tags coupled with two-dimensional liquid chromatography-tandem mass spectrometry were used to analyse the proteome of PDAC tissues with different TNM stages. A loss-of-function study was performed to evaluate the oncogenic roles of WD repeat-containing protein 1 (WDR1) in PDAC. The molecular mechanism by which WDR1 promotes PDAC progression was studied by real-time qPCR, Western blotting, proximity ligation assay and co-immunoprecipitation. RESULTS: A total of 5036 proteins were identified, and 4708 proteins were quantified with high confidence. Compared with normal pancreatic tissues, 37 proteins were changed significantly in PDAC tissues of different stages. Moreover, 64 proteins were upregulated or downregulated in a stepwise manner as the TNM stages of PDAC increased, and 10 proteins were related to tumorigenesis. The functionally uncharacterised protein, WDR1, was highly expressed in PDAC and predicted a poor prognosis. WDR1 knockdown suppressed PDAC tumour growth and metastasis in vitro and in vivo. Moreover, WDR1 knockdown repressed the activity of the Wnt/ß-Catenin pathway; ectopic expression of a stabilised form of ß-Catenin restored the suppressive effects of WDR1 knockdown. Mechanistically, WDR1 interacted with USP7 to prevent ubiquitination-mediated degradation of ß-Catenin. CONCLUSION: Our study identifies several previous functional unknown proteins implicated in the progression of PDAC, and provides new insight into the oncogenic roles of WDR1 in PDAC development.

Controlling Nutritional Status score is superior to Prognostic Nutritional Index score in predicting survival and complications in pancreatic ductal adenocarcinoma: a Chinese propensity score matching study.

Preoperative nutritional status plays an important role in predicting postoperative outcomes. Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) are good tools to assess patients' nutritional status. They have been used in predicting outcomes in various malignancies, but few studies have focused on pancreatic adenocarcinoma (PDAC) patients. Totally, 306 PDAC patients were enrolled. The propensity score matching (PSM) method was introduced to eliminate the baseline inequivalence. Patients with different PNI (or CONUT) scores showed inequivalence baseline characteristics, and patients with compromised nutritional status were related with a more advanced tumour stage. After PSM, the baseline characteristics were well balanced. Both low PNI (≤45) and high CONUT (≥3) were independent risk factors for poor overall survival (P < 0·05), and the result remained the same after PSM. Survival analysis demonstrated both patients with low PNI and high CONUT score were associated with poorer survival, and the result remained the same after PSM. The results of AUC indicated that CONUT might have a higher sensitivity and specificity in predicting complications and survival. Preoperative low PNI (≤45) and high CONUT (≥3) scores might be reliable predictors of prognosis and surgical complications in PDAC patients. Compared with PNI, CONUT might be more effective.

Preoperative neutrophil-to-lymphocyte ratio predicts malignancy and recurrence-free survival of solid pseudopapillary tumor of the pancreas.

BACKGROUND: Systemic inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be prognostic for many types of pancreatic malignancy. The aim of this study was to evaluate the prognostic role of these markers in patients with solid pseudopapillary tumor of the pancreas (SPTP). METHODS: Patients who underwent surgical resection for histologically confirmed SPTP were retrospectively reviewed in our institution. Preoperative NLR and PLR were calculated. Clinicopathologic data were correlated with the presence of malignant potential and recurrence-free survival (RFS). RESULTS: A total of 113 patients with SPTP were included in this study. Of them, 23 were men and 90 were women, with a median age of 35 years (interquartile range, 25-44). The optimal cut-off values for malignant SPTP were 3.22 for NLR, and 75.5 for PLR, respectively. Univariate analysis showed that high NLR (>3.22) and white blood cell count more than 9.96 × 109 /L were predictive of a malignant SPTP. Meanwhile, high NLR (P = 0.001) and age more than 35 years (P = 0.026) were associated with worse RFS. On multivariable analyses, high NLR was the only independent predictor of malignant SPTP (odd ratio 6.871; 95% confidence interval [CI], 1.482-31.864; P = 0.014) and RFS (hazard ratio 12.633; 95% CI, 1.758-90.790; P = 0.012). CONCLUSIONS: This study highlights the supportive role of preoperative NLR in predicting malignancy and RFS of SPTP patients. Further studies including a larger cohort of patients are needed to corroborate our findings.

Total pancreatectomy for pancreatic malignancy with preservation of the spleen.

BACKGROUND: Total pancreatectomy may be necessary to achieve margin-negative resection for pancreatic cancer. However, despite the desirability of saving the spleen, the feasibility, safety, and oncological outcomes of spleen-preserving total pancreatectomy have not been studied in patients with malignancy involving the pancreatic neck or proximal body. The aim of this study was to report the efficacy of spleen-preserving total pancreatectomy using the Warshaw technique for patients with pancreatic malignancies. METHODS: A retrospective analysis of patients who underwent total pancreatectomy for malignant pancreatic diseases between December 2006 and January 2018 focused on comparing the clinical outcomes between conventional operations with splenectomy and spleen-preserving total pancreatectomy using the Warshaw technique. RESULTS: Thirty-eight patients among a total of 59 total pancreatectomies had the spleen preservation by the Warshaw operation. In this series, the pancreatic ductal adenocarcinomas resected with the Warshaw technique were of smaller tumor size but had greater rates of vascular invasion, resulting in the more frequent vascular resection. No patients had splenic complications requiring splenectomy, but two patients intended to have the Warshaw operation were converted to splenectomy because of splenic malperfusion. Asymptomatic perigastric varices were noted in 4 patients. Postoperative morbidity and mortality were comparable between the Warshaw and conventional operation groups. Recurrence-free and overall survival was similar in both groups. CONCLUSION: In patients with pancreatic malignancy, total pancreatectomy with preservation of the spleen using the Warshaw technique achieves outcomes comparable with conventional total pancreatectomy with splenectomy in selected patients.

Pancreatectomy with Hepatic Artery Resection for Pancreatic Head Cancer.

BACKGROUND: To report our experiences and outcome of pancreatectomy with hepatic artery resection (PT-HAR) for advanced pancreatic head cancer. METHODS: A retrospective study of clinical data from 14 patients with advanced pancreatic ductal adenocarcinoma undergoing PT-HAR in a tertiary academic center between March 2010 and June 2017 was performed. Furthermore, a comparison in a match-pair analysis (1:3) with patients received standard pancreatectomy during the same period was conducted to evaluate the clinical outcome. RESULTS: The PT-HAR cohort included pancreaticoduodenectomy (n = 11) and total pancreatectomy (n = 3). Of them, six underwent portal/superior mesenteric vein resection and reconstruction and three underwent hepatic artery reconstruction. Four patients without arterial reconstruction developed liver perfusion failure. No perioperative mortality occurred, with a median postoperative hospital stay of 10.5 days (range 6-39). The median overall survival was 30 months (95% confidence interval 9.8-50.2 months), with the 1-, 2-, and 3-year survival rates of 81.8%, 63.6%, and 42.4%, respectively. The matched-pair data analysis showed no significant differences between PT-HAR and standard pancreatectomy, except that liver perfusion failure occurred more frequently after PT-HAR. CONCLUSIONS: PT-HAR can be performed with acceptable morbidity, mortality, and survival for advanced pancreatic head cancer. Considering the potential risk of liver perfusion failure, only highly selected patients are eligible for PT-HAR without reconstruction.

The roles of ID-1 in human pancreatic ductal adenocarcinoma and the therapeutic effects of 2-methoxyestradiol.

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis and high mortality rate. Inhibitor of differentiation-1 (ID-1) overexpression has already been reported to be associated with low survival, but the detailed roles of ID-1 in PDAC are unclear. As an ID-1 inhibitor, 2-methoxyestradiol (2-ME) has been shown effective in the antitumor therapies, but its effect on PDAC is unknown. In this study, ID-1 overexpression and knockdown stable SW1990 cells were used to examine proliferation, migration and invasion abilities. Effectiveness of 2-ME was estimated in vivo, as well as in vitro by survival analysis, magnetic resonance imaging and tissue analysis. PDAC patients were retrospectively reviewed to assess the ID-1 expression and prognosis. We found that ID-1 was closely associated with in vitro SW1990 cells proliferation, migration and invasion abilities, as well as the expression of HIF-1α, VEGF and MMP-9. 2-ME was shown to be effective on tumor suppression both in vivo and in vitro, perhaps mainly by ID-1 regulation. Moreover, the relevance between high ID-1 expression and poor prognosis was validated in PDAC patients. Our data collectively reveals the roles of ID-1 in PDAC malignancy, and suggests 2-ME treatment may be a potential alternative chemotherapeutic agent for PDAC patients.

Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown. METHODS: A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC). RESULTS: TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P < 0.001) and recurrence-free survival (RFS; all P < 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015). CONCLUSION: TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.

Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling.

Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies.