Pancreatic cancer has an insidious onset and lacks effective treatment methods, which is one of the tumors with the worst prognosis, so it is urgent to explore new treatment directions. Metabolic reprogramming is one of the important hallmarks of tumors. Pancreatic cancer cells in the harsh tumor microenvironment have comprehensively increased cholesterol metabolism in order to maintain strong metabolic needs, and cancer associated fibroblasts also provide cancer cells with a large amount of lipids. Cholesterol metabolism reprogramming involves the changes in the synthesis, uptake, esterification and metabolites of cholesterol, which are closely related to the proliferation, invasion, metastasis, drug resistance, and immunosuppression of pancreatic cancer. Inhibition of cholesterol metabolism has obvious anti-tumor effect. In this paper, the important effects and complexity of cholesterol metabolism in pancreatic cancer were comprehensively reviewed from perspectives of risk factors for pancreatic cancer, energy interaction between tumor-related cells, key targets of cholesterol metabolism and its targeted drugs. Cholesterol metabolism has a strict regulation and feedback mechanism, and the effect of single-target drugs in clinical application is not clear. Therefore, multi-target therapy of cholesterol metabolism is a new direction for pancreatic cancer treatment.
Humans ; Pancreatic Neoplasms/pathology* ; Cholesterol/metabolism* ; Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.
Humans ; Carcinoma, Pancreatic Ductal/pathology* ; Pancreatic Neoplasms/therapy* ; Signal Transduction ; Peripheral Nerves/metabolism* ; Tumor Microenvironment

Objective: To investigate the tumor immunity-related pathologic features and clinical significance in pancreatic ductal adenocarcinoma (PDAC). Methods: All pathologic materials and clinical information of 192 PDAC patients from the Cancer Hospital of the University of Chinese Academy of Sciences from January 2010 to December 2020 were collected. The onco-immune microenvironment associated morphologic features were evaluated, and MHC-Ⅰ, PD-L1, CD3, and CD8 expression were detected by immunohistochemistry (IHC). Then the correlation between the factors and their influence on prognosis was analyzed. Results: There were 163 cases of non-specific adenocarcinoma (163/192, 84.90%), 18 cases of adeno-squamous carcinoma (18/192, 9.37%), and 11 cases of other rare subtypes (11/192, 5.73%). Perineural invasion was observed in 110 cases (110/192, 57.29%) and vascular invasion in 86 cases (86/192, 44.79%). There were 84 cases (84/182, 46.15%) with severe chronic inflammation. Tumor infiltrating immune cell numbers (TII-N) were increased in 52 cases (52/192, 27.08%). Lymphocytes and plasma cells were the main infiltrating immune cells in 60 cases (60/192, 31.25%), whereas in 34 cases (34/192, 17.71%) the tumors were mainly infiltrated by granulocytes, and 98 cases (98/192, 51.04%) showed mixed infiltration. CD3⁺T cells were deficient in 124 cases (124/192, 66.31%). CD8⁺T cells were deficient in 152 cases (152/192, 79.58%). MHC-Ⅰ expression was down-regulated in 156 cases (156/192, 81.25%), and PD-L1 was positive (CPS≥1) in 46 cases (46/192, 23.96%). Statistical analysis showed that TII-N was negatively correlated with vascular invasion (P=0.035), perineural invasion (P=0.002), stage (P=0.004) and long-term alcohol consumption (P=0.039). The type of immune cells correlated positively with chronic pancreatic inflammation (P=0.002), and negatively with tumor differentiation (P=0.024). CD8⁺T cells were positively correlated with CD3⁺T cells (P=0.032), MHC-Ⅰ expression (P<0.001) and PD-L1 expression (P=0.001), and negatively correlated with long-term smoking (P=0.016). Univariate analysis showed that histological nonspecific type (P=0.013) and TII-N (P<0.001) were the factors for good prognosis. Vascular invasion (P=0.032), perineural invasion (P=0.001), high stage (P=0.003) and long-term alcohol consumption (P=0.004) were adverse prognostic factors. COX multivariate risk analysis found that TII-N was an independent favorable factor for PDAC, while perineural invasion was an independent adverse risk factor. Conclusions: TII-N is an independent superior prognostic factor for PDAC, and significantly correlated with many factors; chronic alcohol consumption and smoking may inhibit onco-immunity in PDAC patients.
Adenocarcinoma/pathology* ; B7-H1 Antigen/metabolism* ; Biomarkers, Tumor/metabolism* ; Carcinoma, Pancreatic Ductal/pathology* ; Humans ; Inflammation/pathology* ; Lymphocytes, Tumor-Infiltrating/metabolism* ; Pancreatic Neoplasms/pathology* ; Prognosis ; Tumor Microenvironment

Chromogranin A ; metabolism ; Gastrointestinal Neoplasms ; classification ; metabolism ; pathology ; Humans ; Immunohistochemistry ; Neuroendocrine Tumors ; classification ; metabolism ; pathology ; Pancreatic Neoplasms ; classification ; metabolism ; pathology ; Pathology ; standards ; Synaptophysin ; metabolism ; World Health Organization

OBJECTIVETo study the clinicopathological significance of the expression of carbonic anhydrase (CA)II protein and mRNA in primary invasive ductal cancer (IDC) of human pancreas.

METHODSThe expression of CAII protein in 33 paired paraffin embedded IDC specimens of the pancreas and paired adjacent non-cancerous pancreatic tissues was detected by immunohistochemistry. Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to examine the expression of CAII protein and mRNA level in 12 paired fresh IDC specimens of the pancreas and adjuvant non-cancerous pancreatic tissues. The relationship between the protein expression and clinicopathological features was analyzed.

RESULTSOverexpression of CAII protein was shown in 11 cases of pancreatic IDC tissues (33.3%, 11/33), which was much lower than that in paired non-cancerous pancreatic tissues (72.7%, t = 6.275, P = 0.000). The expression of CAII protein had no correlation with tumor position (χ² = 0.992, P = 0.319), differentiation (χ² = 0.866, P = 0.352), TNM stage (χ² = 1.210, P = 0.271) and Lymph node metastasis (χ² = 0.798, P = 0.372), but had bordering statistic sig with the prognosis of the patients (χ² = 3.233, P = 0.072). The median survival time in the patients with high expression of CAII protein was 540 days, while that in the patients with low expression was 320 days. The expression of CAII protein and mRNA was lower in IDC than that in paired non-cancerous pancreatic tissues detected by Western blot and RT-PCR respectively (t = 3.399, P = 0.006; t = 2.281, P = 0.043).

CONCLUSIONCAII is down regulated in pancreatic IDC and might be relative with the prognosis.

Carbonic Anhydrase II ; genetics ; metabolism ; Carcinoma, Pancreatic Ductal ; metabolism ; pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Pancreas ; metabolism ; Pancreatic Neoplasms ; metabolism ; pathology ; RNA, Messenger ; genetics

OBJECTIVETo study the clinicopathologic and immunohistochemical features, and the prognosis of intraductal papillary mucinous neoplasms (IPMN) of the pancreas.

METHODSThe clinical findings, morphologic features, immunophenotype and prognosis were investigated in 61 cases of IPMN.

RESULTSOf these 61 cases, 33 were in the pancreatic head and 14 were in the body and tail, and 14 in the entire pancreas. The average patients' age was 61.8 years. The initial symptom was abdominal pain in 37 cases, and the tumors were detected at routine checkup in 14 cases. The imaging examination showed dilated ducts and/or cystic and solid masses. Grossly, 32 cases were multi-loculated cystic masses containing mucin and papillary areas; 13 cases were solid. Microscopically, the IPMN showed four patterns, including gastric-type (16 cases), intestinal-type (21 cases), pancreatobiliary-type (21 cases) and eosinophilic-type (3 cases). The IPMN cohort included 13, 13 and 6 IPMN with low, intermediate and high-grade dysplasia respectively, and 29 IPMN associated with invasive carcinoma. The IPMN associated carcinomas were mainly ductal adenocarcinoma (23/29, 79.3%), followed by colloid carcinoma (4/29, 13.8%) and undifferentiated carcinoma (2/29, 6.9%). Immunohistochemically, IPMN expressed MUC5AC (51/57, 89.4%), MUC2 (21/57, 36.8%), and MUC1 (13/46, 28.3%). The mean postoperative follow-up period was 32 months (range 12-112 months). Six of 61 patients were lost to follow-up. Overall 5-year survival rate was 76%. The 5-year survival rate of IPMN with low, intermediate or high-grade dysplasia was 100%, and recurrence was local in 3 patients. The 3-year survival rate of IPMN associated with invasive carcinoma was 55%. 12 of 13 patients died within 2 years after operation.

CONCLUSIONSIPMN is a common cystic neoplasm of the pancreas located in the ducts. The pathologic types and classifications are clearly defined. MUC stains are helpful for the diagnosis and papillary typing. IPMN with invasive carcinoma was associated with significantly worse survival than IPMN with dysplasia.

Adenocarcinoma, Mucinous ; diagnosis ; pathology ; Carcinoma, Pancreatic Ductal ; diagnosis ; pathology ; Humans ; Middle Aged ; Mucins ; metabolism ; Neoplasm Recurrence, Local ; Pancreas ; pathology ; Pancreatic Neoplasms ; diagnosis ; pathology ; Prognosis ; Survival Rate

Aged ; Carcinoma, Squamous Cell ; metabolism ; pathology ; surgery ; Humans ; Immunohistochemistry ; Keratins ; metabolism ; Ki-67 Antigen ; metabolism ; Male ; Pancreas ; metabolism ; pathology ; Pancreatic Neoplasms ; metabolism ; pathology ; surgery ; Pancreaticoduodenectomy

OBJECTIVETo explore cytological parameters that may identify the primary sites of metastatic adenocarcinomas in serous fluid.

METHODSSerous fluid specimens from 89 cases of metastatic adenocarcinomas (40 metastatic adenocarcinomas of lung, 6 metastatic adenocarcinomas of breast, 21 metastatic ovary adenocarcinomas, 22 metastatic gastrointestinal and pancreatic adenocarcinomas) were studied by using multiple morphologic parameters. Immunocytochemical S-P method was used to detect the expression of CA125, CA199, SPB and TTF-1 in 75 cases.

RESULTSMetastatic adenocarcinomas of different primary sites displayed certain different morphologic features, including the total amount of tumor cells, size of clusters, ratio of clusters over single cells, configuration of tumor clusters and the background of the smear. Cell clusters of small to medium sizes represented 95% and 100% in the metastatic adenocarcinomas of lung and breast, respectively. Most of the ovarian metastatic adenocarcinomas (85.7%) presented some large cell clusters and larger amount of cells, whereas certain metastatic gastrointestinal and pancreatic adenocarcinomas (45.5%) presented smaller number of cells and predominantly to be single cell in distribution (40.9%). Psammoma bodies were found in metastatic adenocarcinomas of lung and ovary. SPB and TTF-1 expression supported the diagnosis of adenocarcinoma of pulmonary origin. CA125 expression supported an ovarian origin. Although CA199 was seen in all groups of metastatic adenocarcinomas, nevertheless, its appearance in tumor cells in ascitic fluid specimens supported gastrointestinal and pancreatic origins.

CONCLUSIONMorpho-logic features of the cytological smear, immunohistochemical staining and clinical history are equally important in determining the primary sites of metastatic adenocarcinomas in serous fluid.

Adenocarcinoma ; metabolism ; secondary ; Ascitic Fluid ; metabolism ; pathology ; Breast Neoplasms ; metabolism ; pathology ; Colonic Neoplasms ; metabolism ; pathology ; Female ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Male ; Nuclear Proteins ; metabolism ; Ovarian Neoplasms ; metabolism ; pathology ; Pancreatic Neoplasms ; metabolism ; pathology ; Pleural Effusion, Malignant ; metabolism ; pathology ; Proteins ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; Thyroid Nuclear Factor 1 ; Transcription Factors ; metabolism

Adolescent ; Adult ; Aged ; Chromogranin A ; metabolism ; Female ; Gastrointestinal Neoplasms ; metabolism ; pathology ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; metabolism ; Liver Neoplasms ; metabolism ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Neuroendocrine Tumors ; metabolism ; pathology ; Pancreatic Neoplasms ; metabolism ; pathology ; Synaptophysin ; metabolism ; Young Adult

Actins ; metabolism ; Angiomyolipoma ; pathology ; Carcinoma, Renal Cell ; pathology ; Diagnosis, Differential ; Epithelioid Cells ; metabolism ; pathology ; Female ; Gastrointestinal Neoplasms ; pathology ; Gastrointestinal Stromal Tumors ; pathology ; Humans ; Kidney Neoplasms ; metabolism ; pathology ; Lung Neoplasms ; pathology ; Lymphangioleiomyomatosis ; pathology ; Male ; Melanoma ; pathology ; Melanoma-Specific Antigens ; metabolism ; Pancreatic Neoplasms ; pathology ; Perivascular Epithelioid Cell Neoplasms ; metabolism ; pathology ; Sarcoma, Clear Cell ; pathology ; Skin Neoplasms ; pathology ; Uterine Neoplasms ; pathology