Quan Liao

Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer.

Glucose-regulated protein 78 (GRP78) is a member of the heat-shock protein 70 family. We evaluated the expression of GRP78 using tissue microarray-based immunohistochemistry in tumor tissues and adjacent nontumor tissues from 180 pancreatic ductal adenocarcinoma (PDAC) patients. The associations between the expression levels of GRP78, clinicopathological factors, and overall survival were evaluated. The results showed that the expression of GRP78 was significantly higher in PDAC cells than in normal pancreatic duct cells within adjacent nontumor tissues (p < 0.05). The increased expression of GRP78 in the tumor tissues was significantly correlated with a higher T-stage (p < 0.05) and a shorter overall survival (OS, p < 0.05). In an in vitro study, the regulation of GRP78 in the PDAC cell lines affected the proliferation, migration, and invasion of PDAC cells through the regulation of CyclinD1, cyclin-dependent kinase (CDK) 4, CDK6, phospho-signal transducer, activator of transcription 3 (p-STAT3), janus kinase 2 (JAK2), ras homolog gene family member A (RhoA), Rho-associated kinase 1 (ROCK1), and sterile alpha motif domain containing protein 4 (Smad4). The present data suggest that GRP78 plays a crucial role in the proliferation, migration, and invasion of pancreatic cancer cells and may be a suitable prognostic marker in PDAC.

Recent studies of 5-fluorouracil resistance in pancreatic cancer.

Resistance to 5-fluorouracil (5-FU), an important anticancer drug, is a serious challenge in the treatment of pancreatic cancer. Equilibrative nucleoside transporter 1 and multidrug-resistance protein (MRP) 5 and MRP8, rather than P-glycoprotein, play important roles in 5-FU transport. Thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidine phosphorylase are four key enzymes involved in 5-FU metabolism. Other metabolic enzymes, including uridine monophosphate synthetase, also contribute to chemoresistance. Intracellular signaling pathways are an integrated network, and nuclear factor kappa-light-chain-enhancer of activated B cells, AKT and extracellular signal-regulated kinases are signaling pathways that are particularly relevant to 5-FU resistance. In addition, recent reports indicate that STAT-3 is a crucial survival protein. Proteomic assays provide a powerful tool for identifying target proteins and understanding the role of microRNAs and stromal factors to facilitate the development of strategies to combat 5-FU resistance.

Primary pancreatic lymphoma: a clinical quandary of diagnosis and treatment.

Objective: To investigate the clinical feature and treatment strategy of primary pancreatic lymphoma. Methods: Thirty-nine cases of primary pancreatic lymphoma reported in China were reviewed retrospectively with their clinical characters, treatment, and outcome, as well as a literature review of worldwide reports. Results: The major clinical presentations included discomfort or pain in the upper abdomen and jaundice without specificity. Only 2 cases were identified correctly by computed tomography, and 5 cases obtained a positive finding in a biopsy before operation. Thirty-two patients accepted operation; 13 pancreatoduodenectomy and 6 distal pancreatectomy were performed. Thirty-one patients accepted postoperative chemotherapy. Until now, 26 patients are still alive at a range of 3 to 72 months; 5 patients died at 5 to 24 months after operation. Literature review revealed 85 additional cases of pancreatic lymphoma in English reports. Their diagnosis and treatment methods varied. Conclusions: Primary pancreatic lymphoma was misdiagnosed as pancreatic adenocarcinoma frequently. Fine needle aspiration biopsy is the most valuable method in preoperative diagnosis. The cyclophosphamide, doxorubicin, vincristine, and prednisone scheme was still the most commonly used regimen of chemotherapy. The value of surgery and radiotherapy remains controversial; an operation combining chemotherapy seems to be an appropriate method of treatment for a patient in whom malignancy cannot be ruled out.

Laparoscopic distal pancreatectomy with or without splenectomy: spleen-preservation does not increase morbidity.

BACKGROUND The indications for laparoscopic spleen-preserving distal pancreatectomy (LSPDP) and its morbidity compared with laparoscopic distal pancreatectomy with splenectomy (LDPS) are ill-defined. This study aimed to share the indications for spleen-preservation and investigate the safety and outcome of LSPDP at our institution. METHODS A retrospective review of patients who were scheduled to receive laparoscopic surgery for distal pancreatic lesions was conducted. The indications, surgical procedures, intra-operative data, and outcomes of the two procedures were collected and compared by statistical analysis. RESULTS LDPS and LSPDP were successfully performed in 16 and 21 patients respectively, whereas they were converted to open surgery in 9 patients. There were no significant differences in age, gender, operation time, blood loss, and conversion rate between the LDPS and LSPDP groups. The mean tumor size showed an inter-group difference (5.05 vs 2.53 cm, P<0.001). There were no significant differences in complication and morbidity rates between the two groups. All patients remained alive without recurrence during a follow-up of 9 to 67 months (median 35). CONCLUSION LSPDP has a morbidity and outcome comparable to LDPS.

Interleukin-27 inhibits malignant behaviors of pancreatic cancer cells by targeting M2 polarized tumor associated macrophages.

Graphical abstract Figure. No caption available. HighlightsM2 polarized TAMs expressed higher level of WSX‐1.IL‐27 could invert the polarization of M2 phenotype TAMs.IL‐27 inhibited malignant behaviors of PDAC cells via macrophages. ABSTRACT Pancreatic cancer is characterized as inflammatory malignancy with a dismal prognosis. There is abundant intratumoral infiltration of macrophages, and most of these tumor associated macrophages (TAM) are induced to be M2 phenotype. The M2 polarized TAM has been demonstrated to promote progression and induce chemo‐resistance of pancreatic cancer. Interleukin (IL)‐27 is a novel member of IL‐12 cytokine family and its roles in regulation of phenotypes and functions of TAM remain largely unknown. In this study, we demonstrated IL‐27 significantly inhibited the M2 macrophages polarization and dampened the proliferation, migration and metastasis of pancreatic cancer cells and as well enhanced the efficacy of gemcitabine. IL‐27 could be potential to improve the treatment of pancreatic cancer by targeting M2 polarized TAMs.

Chemotherapy and tumor microenvironment of pancreatic cancer

Pancreatic cancer is an extremely dismal malignance. Chemotherapy has been widely applied to treat this intractable tumor. It has exclusive tumor microenvironment (TME), characterized by dense desmoplasia and profound infiltrations of immunosuppressive cells. Interactions between stromal cells and cancer cells play vital roles to affect the biological behaviors of pancreatic cancer. Targeting the stromal components of pancreatic cancer has shown promising results. In addition to the direct toxic effects of chemotherapeutic drugs on cancer cells, they can also remodel the TME, eventually affecting their efficacy. Herein, we reviewed the following four aspects; (1) clinical landmark advances of chemotherapy in pancreatic cancer, since 2000; (2) interactions and mechanisms between stromal cells and pancreatic cancer cells; (3) remodeling effects and mechanisms of chemotherapy on TME; (4) targeting stromal components in pancreatic cancer.

Atorvastatin (Lipitor) attenuates the effects of aspirin on pancreatic cancerogenesis and the chemotherapeutic efficacy of gemcitabine on pancreatic cancer by promoting M2 polarized tumor associated macrophages.

BackgroundInteractions of inflammatory cells with pancreatic cancer cells play crucial roles in pancreatic cancer, however the dynamic changes of inflammatory cell populations in pancreatic cancerogensis and after chemotherapy have not been well eclucidated. The combinational use of aspirin and atrovastatin (Lipitor) have been widely prescribled for cardio-cerebral vascular diseases mainly by regulation of inflammations, and they have been also reported to have plausible anti-tumor effects, however their potential roles in pancreatic cancerogenesis and chemotherapeutic effects have been seldom investigated. We scanned the dynamic changes of pan-inflammatory cell populations in pancreatic cancerogensis and after chemotherapy and found the potential target cell populations. Then we tested the roles of aspirin and Lipitor to regulate these inflammatory cell populations and their effects on pancreatic cancerogenesis and chemotherapeutic effects.MethodsCancerogen, dimethylbenzanthracene (DMBA), was used to induce pancreatic cancerogenesis and subcatunous implantation of syngenic murine Panc02 pancreatic cancer cells was adopted as well. Gemcitabine was used for chemotherapy. The peripheral blood, pancreatic lesions and tumor samples were harvested and analyzed to search for the potential target cell populations. The roles of aspirin and Lipitor to regulate these cell populations and their potential effects on pancreatic cancerogenesis and chemotherapeutic efficacy were investigated both in vitro and in vivo.ResultsWe found progressive accumulations of myeloid-derived suppressor cells (MDSC) and M2-polarzied tumor associated macrophages(M2) in pancreatic lesions accompanied with dynamic reducations of cytotoxic T cells(CTL) and helper T cells(Th) in the progression of pancreatic cancerogenesis. After gemcitabine treatment, the MDSC significantly reduced, however M2 soared up unexpectedly. Aspirin could significantly inhibit the MDSC and M2 to prevent pancreatic cancerogenesis and improve chemotherapeutic effects of gemcitabine, however Lipitor did not significantly affect MDSC, instead it could promote M2 to attenuate the postive effects of aspirin and gemcitabine.ConclusionsMDSC and M2 accumulate in progression of pancreatic cancerogenesis and gemcitabine can induce M2. Aspirin could prevent pancreatic cancerogenesis and improve efficacy of gemcitabine partially by inhibiting MDSC and M2, however when used in combination, Lipitor could weaken the efficacy of aspirin and gemcitabine partially by promoting M2.

Propensity score‐matched analysis of robotic versus open surgical enucleation for small pancreatic neuroendocrine tumours

Enucleation of pancreatic neuroendocrine tumours (pNETs) via robotic surgery has rarely been described. This study sought to assess the safety and efficiency of robotic surgery for the enucleation of small pNETs.

G-protein-coupled receptor kinase 2 in pancreatic cancer: clinicopathologic and prognostic significance

G-protein-coupled receptor kinase 2 (GRK2) was found to regulate biological behaviors in some cancers, including pancreatic cancer (PC). However, its clinicopathologic and prognostic implications in cancer remain unclear. This study was designed to address the issues in PC. Expression of GRK2 was measured by Western blotting and tissue microarray-based immunohistochemical staining in 3 and 171 patients with PC, respectively. The H-score was used to evaluate the staining results. In addition, GRK2 expression was correlated with clinicopathologic variables and overall survival. Finally, the prognostic value of GRK2 was validated in a publically available PC dataset, GSE21501. It was suggested that GRK2 expression was highly up-regulated in 2 out of 3 tumor samples, in contrast to corresponding non-tumor ones. Furthermore, H-score of GRK2 staining was significantly higher in tumor than in non-tumor tissues. Tumoral expression of GRK2 was significantly associated with T stage. Univariate analysis showed that high GRK2 expression in tumor tissues was predictive for poor overall survival of PC. However, GRK2 expression was not identified as an independent prognostic marker in multivariate Cox regression test, although close to the statistical significance. In dataset GSE21501, GRK2 was also revealed to be prognostic. Our data establish that GRK2 is overexpressed in PC, and might serve as a potential indicator of unfavorable prognosis.

Myeloid-derived suppressor cells (MDSC) facilitate distant metastasis of malignancies by shielding circulating tumor cells (CTC) from immune surveillance

The mechanisms of distant metastasis of malignancies largely remain unknown. Circulating tumor cells (CTC) derived from the primary cancer initiate distant metastasis by entering and traversing the bloodstream. Current methods to detect CTC are based on the notion that CTC do not express the common leukocyte antigen CD45. However, these methods neglect the fact that CTC can directly adhere to platelets and immune cells and therefore appear to be CD45-positive. The potential effects of interactions between CTC and adhesive immune cells have been largely overlooked, despite the fact that most CTC are killed by immune effector cells and only those that evade immune surveillance result in clonal expansion and metastatic lesions. It is crucial to define the characteristics that allow a select CTC population to escape immune surveillance; particularly, it must be determined whether interactions between CTC and adhesive immune cells provide a protective effect on CTC survival. If interactions between CTC and adhesive immune cells offer a selective advantage to those CTC cells, the next consideration is which characteristics of a CTC-immune cell population allow sufficient protection to facilitate immune evasion. Myeloid-derived suppressor cells (MDSC) are a large heterogeneous population of immature myeloid cells that accumulate during cancer progression to induce extensively systemic and local immunosuppression, a phenomenon that has been demonstrated to facilitate cancer distant metastasis. We hypothesize, therefore, that CTC populations interacting with adhesive immune cells will have different biological behavior than CTC populations alone. Further, we hypothesize that CTC can create a defensive shield consisting of adhesive MDSC, which allows evasion of immune surveillance and therefore facilitates distant metastatic lesions. This possibility highlights the importance of direct interactions between CTC and adhesive immune cells and suggests the potential target that the CTC-MDSC cluster represents for prevention and treatment of distant metastasis of malignancies.