Roles of gastrointestinal hormones in pancreatic cancer

Several gastrointestinal (GI) hormones, such as gastrin, cholecystokinin, and bombesin, have been reported to affect the development of pancreatic cancer. The receptors for these hormones are found in normal and neoplastic pancreatic cells. Activation of these receptors enhances pancreatic carcinogenesis and promotes the growth of established pancreatic carcinoma either in vitro or in vivo. On the other hand, some studies have shown that these GI hormones may have no effect or may play an inhibitory role in the development of pancreatic cancer. The reasons for the apparent discrepancies in the published literature are discussed in this review. In recent years, increasing emphasis has been placed on the effects of GI hormones on cancer invasion and metastasis. As the transition from noninvasion to the invasive state is the crucial event in cancer development, further investigation of the way in which GI hormones affect the invasion and metastasis of pancreatic cancer may be important for the development of new therapeutic approaches with eventual clinical utility.     

Advances in understanding the molecular mechanism of pancreatic cancer metastasis

BACKGROUND: Pancreatic cancer (PC) is usually diagnosed at the late-stage and therefore, has widespread metastasis and a very high mortality rate. The mechanisms underlying PC metastasis are not well understood. Recent advances in genomic sequencing have identiifed groups of gene mutations that affect PC metastasis, but studies elucidating their roles are lacking. The present review was to investigate the molecu-lar mechanisms of PC metastasis.
DATA SOURCES: Relevant articles on PC metastasis were searched in MEDLINE via PubMed prior to April 2015. The search was limited in English publications.
RESULTS: PC metastatic cascades are multi-factorial events including both intrinsic and extrinsic elements. This review highlights the most important genetic alterations and other mechanisms that account for PC invasion and metastasis, with particular regard to epithelial-mesenchymal transition, inlfammation, stress response, and circulating tumor cells.
CONCLUSIONS: Analyses of relevant gene functions and signaling pathways are needed to establish the gene regula-tory network and to deifne the pivotal modulators. Another promising area of study is the genotyping and phenotyping of circulating tumor cells, which could lead to a new era of per-sonalized therapy by identifying speciifc markers and targets.     

Hepatobiliary and Pancreatic: Rapid growing cystic ovarian metastasis from pancreatic cancer

Pancreatic cancer rarely develops cystic ovarian metastasis. We present a 63‐year‐old female patient with unresectable pancreas head cancer. Seven months after the introduction of the chemoradiotherapy, a giant intrapelvic cystic tumor with rapid growth was found. The tumor was resected because the patient complained of severe bloating and no other new metastatic sites could be identified. Postoperative pathological examination diagnosed it as an ovarian metastasis from the pancreas cancer.     

The role of Fyn kinase in the release from metaphase in mammalian oocytes

Meiosis in mammalian oocytes starts during embryonic life and arrests for the first time before birth, at prophase of the first meiotic division. The second meiotic arrest occurs after spindle formation at metaphase of the second meiotic division (MII) in selected oocytes designated for ovulation. The fertilizing spermatozoon induces the release from MII arrest only after the oocyte's spindle assembly checkpoint (SAC) was deactivated.     

Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer

TP53 mutation occurs in 50–75% of human pancreatic ductal adenocarcinomas (PDAC) following an initiating activating mutation in the KRAS gene. These p53 mutations frequently result in expression of a stable protein, p53^R175H, rather than complete loss of protein expression. In this study we elucidate the functions of mutant p53 (Trp53^R172H), compared to knockout p53 (Trp53^fl), in a mouse model of PDAC. First we find that although Kras^G12D is one of the major oncogenic drivers of PDAC, most Kras^G12D-expressing pancreatic cells are selectively lost from the tissue, and those that remain form premalignant lesions. Loss, or mutation, of Trp53 allows retention of the Kras^G12D-expressing cells and drives rapid progression of these premalignant lesions to PDAC. This progression is consistent with failed growth arrest and/or senescence of premalignant lesions, since a mutant of p53, p53^R172P, which can still induce p21 and cell cycle arrest, is resistant to PDAC formation. Second, we find that despite similar kinetics of primary tumor formation, mutant p53^R172H, as compared with genetic loss of p53, specifically promotes metastasis. Moreover, only mutant p53^R172H-expressing tumor cells exhibit invasive activity in an in vitro assay. Importantly, in human PDAC, p53 accumulation significantly correlates with lymph node metastasis. In summary, by using ‘knock-in’ mutations of Trp53 we have identified two critical acquired functions of a stably expressed mutant form of p53 that drive PDAC; first, an escape from Kras^G12D-induced senescence/growth arrest and second, the promotion of metastasis.     

Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer

Tumor angiogenesis is a process that requires migration, proliferation, and differentiation of endothelial cells. We hypothesized that decrease in pancreatic tumor growth due to inhibition of Src activity is associated with the inability of Src kinase to trigger a network of such signaling processes, which finally leads to endothelial cell death and angiogenesis-restricted tumor dormancy. The therapeutic efficacy of Src kinase inhibitor AZM475271 was tested in nude mice orthotopically xenografted with L3.6pl pancreatic carcinoma cells. No liver metastases and peritoneal carcinosis were detected and a significant effect on the average pancreatic tumor burden was observed following treatment with AZM475271, which in turn correlated with a decrease in cell proliferation and an increase in apoptotic endothelial cells. AZM475271 was shown to significantly inhibit migration of human umbilical vein endothelial cells in an in vitro Boyden Chamber cell migration assay. In a rat aortic ring assay we could demonstrate as well inhibition of endothelial cell migration and sprouting following therapy with Src kinase inhibitor at similar doses. The most conclusive anti-angiogenic activity of AZM475271 was demonstrated in vivo (mouse corneal micropocket assay) by showing a marked inhibition of basic fibroblast growth factor-induced neovascularization in response to systemic administration of AZM475271. Furthermore, we could show reduced proliferation of HUVECs determined with the TACS MTT Cell Viability Assay Kit. The blockade of Src kinase significantly reduced the level of VEGF in L3.6pl medium, the effect which was found also in the cell culture supernate from HUVECs. Inhibition of Src kinase by AZM475271 also showed prevention of survival signaling from VEGF and EGF receptors. Treatment with AZM475271 resulted in VEGF - dependent inhibition of tyrosine phosphorylation of FAK. HUVECs were also examined using propidium iodide staining for cell cycle analysis by FACS. Inhibition of Src kinase promoted HUVEC apoptosis in a dose-dependent manner. Taken together, our results suggest that the Src kinase inhibitor AZM475271, in addition to its effects on tumor cells, suppresses tumor growth and metastasis in vitro and in vivo potentially also by anti-angiogenic mechanisms.     

血清肿瘤标志物和肝功能指标联合检测在胰腺癌肝转移诊断中的价值

目的探讨肿瘤标志物和肝功能指标联合检测在胰腺癌肝转移早期诊断中的临床价值。方法选取125例胰腺癌患者,其中肝转移58例,无肝转移67例。检测患者血清肿瘤标志物和肝功能指标水平,并对结果进行分析。结果胰腺癌肝转移者血清中癌胚抗原（CEA）、糖类抗原19-9（CA19-9）、糖类抗原242（CA242）和乳酸脱氢酶（LDH）水平显著高于无肝转移者（P〈0.05）。ROC曲线分析显示CEA、CA19-9、CA242与LDH诊断肝转移的最佳上限为6.0μg/L、842 U/m l、64.48 U/L与220 U/L。CEA和LDH单独检测肝转移的敏感性为64.2%和51.9%,特异性为71.4%和74.2%。而CEA与LDH联合检测的敏感性和特异性为77.6%和93.5%。结论肿瘤标志物和肝功能指标联合检测特异性高,有助于胰腺癌肝转移的早期诊断。     

Appendicular metastasis from pancreatic adenocarcinoma

We present a 78-yr-old man with appendicular metastases from pancreatic adenocarcinoma. Barium enema X-ray showed incomplete filling of a distended appendix in a patient with abdominal discomfort. Colonoscopic evaluation revealed firm nodules in appendicular orifice. Histopathological examination of the nodule in the appendix revealed a metastatic adenocarcinoma. Abdominal computed tomography showed a low-density mass in the body of the pancreas. Endoscopic ultrasonography disclosed a hypoechoic mass in the body of the pancreas. Appendicular metastasis is extremely rare. To our knowledge, this is the second case of adenocarcinoma of the pancreas metastatic to the appendix in English language literature. A brief review of relevant literature is presented.     

Establihment of an experimental liver metastasis model by intraportal injection of a newly derived human pancreatic cancer cell line (KLM-1)

Summary Conclusion It is suggested that this liver metastasis model formed by a highly metastatic variant (KLM-1) is valuable for the study of the liver metastatic processes of human pancreatic cancer. Background Liver metastasis in the early postoperative period is one of the causes for the poor prognosis of patients with resected pancreatic cancer. Therefore, it is necessary to establish an experimental model to study the mechanisms of liver metastasis in pancreatic cancer. Methods Human pancreatic cancer cell lines (PK-1, PK-9, and KLM-1) were injected into the portal vein of nude mice with or without pretreatment with antiasialo GM1, and colonies of liver metastases were counted for comparison of metastatic ability of these cell lines. Biological and histopathological characteristics of the highly liver metastatic cell line (KLM-1) were compared with its parent cell line (PK-1). Results PK-1 cells and PK-9 cells rarely formed liver metastasis foci, but pretreatment with antiasialo GM1 promoted liver metastasis. KLM-1 cells formed liver metastases at the rate of 70% even without antiasialo GM1 pretreatment. KLM-1 cells had such biological characteristics as short doubling time, short lag phase, and resistance to NK cytotoxicity. After intraportal injection of¹²⁵I-labeled KLM-1 cells, radioactivitiy as well as micrometastases were detected in the liver at 72 h.     

The pretreatment platelet and plasma fibrinogen level correlate with tumor progression and metastasis in patients with pancreatic cancer

Abstract

Cancer patients frequently present with activated coagulation pathways and thrombocytosis, which are potentially associated with tumor progression and prognosis. However, the prognostic value of abnormal plasma fibrinogen and platelet levels for the treatment of pancreatic cancer is unclear. The purpose of our study was to evaluate the prognostic value of plasma fibrinogen and platelet levels in pancreatic cancer, and to devise a prognostic model to identify the patients with greatest risk for a poor overall survival. One hundred and twenty-five patients diagnosed with pancreatic ductal adenocarcinoma in our hospital between May 2000 and June 2005 were included in this study. The plasma fibrinogen and platelet levels were examined before treatment and analyzed along with patient clinicopathological parameters and overall survival. The foundation of prognostic model was based on the risk factors according to the Cox proportional hazard model. The incidence of hyperfibrinogenemia and thrombocytosis was 24.8% (31/125) and 15.2% (19/125), respectively. The mean fibrinogen concentration differed significantly between the early (I/II) and late (III/IV) stage patients (3.19?±?0.70 vs. 3.65?±?0.90?g/l, p?=?0.008). Patients with a higher concentration of plasma fibrinogen and platelets had a worse prognosis (p?<?0.05). There also existed a significant correlation between higher fibrinogen/platelet levels and distant organ metastasis (p?<?0.05, respectively). Bivariate correlation analysis showed that plasma fibrinogen levels correlated significantly with platelet levels (p?=?0.000). Multivariate analysis revealed that pretreatment plasma fibrinogen levels (p?=?0.027), tumor stage (p?=?0.026) and distant metastasis (p?=?0.027) were independent prognostic factors. The median survival time for the low-, intermediate-, and high-risk groups was 9.6 months (95% CI 6.2–13.0), 3.8 months (95% CI 2.3–5.3), and 2.3 months (95% CI 0.9–3.7), respectively (p?=?0.000). Pretreatment plasma fibrinogen and platelet levels closely correlated with tumor progression, metastasis and overall survival in pancreatic cancer. The foundation of prognostic model may help us identify the greatest risk populations with pancreatic cancer.     

Src, Fyn and Yes play differential roles in VEGF-mediated endothelial cell events

Widely coexpressed Src family kinase (SFK) members Src, Fyn and Yes are involved in various cellular events, often acting downstream of receptor tyrosine kinases, such as vascular endothelial growth factor (VEGF) receptors. They are well known for their functional redundancy; any unique features remain largely undefined. Utilizing RNA interference, we have selectively knocked down Src, Fyn and Yes in human retinal microvascular endothelial cells (HRMECs). Cells with single SFK knockdown showed that all three kinases were required for VEGF mitogenic signaling. VEGF-induced cell migration was significantly increased in Fyn-deficient cells and decreased in Yes-deficient cells. Selective interference of Fyn, but not Src or Yes, impaired VEGF-induced tube formation in HRMECs. Cells in which all three SFKs were targeted showed significant inhibition of all three cellular events. In addition, interference of Src, Fyn and Yes did not affect the anti-apoptotic effect of VEGF in HRMECs, as determined by DNA fragmentation analysis. These results provide direct evidence that Src, Fyn and Yes maintain distinct properties in the regulation of VEGF-mediated endothelial cell events.     

Improved prognosis of pancreatic cancer patients with peritoneal metastasis

BackgroundPeritoneal metastasis is one of the most important poor prognostic factors in advanced pancreatic cancer (PC). Whether the prognosis of PC with peritoneal metastasis has improved with the advent of gemcitabine plus nab-paclitaxel (GnP) and modified FOLFIRINOX (mFFX) is uncertain. The aim of this study was to evaluate the improvements in treatment outcomes of PC with peritoneal metastasis.MethodsWe retrospectively investigated consecutive PC patients with peritoneal metastasis treated with chemotherapy at our institution between 2010 and 2019. We compared the clinical characteristics and survival outcomes according to the period of diagnosis (group A, 2010–2014; group B, 2015–2019) and chemotherapy regimen. We also examined the prognostic factors for overall survival (OS).ResultsAmong 180 patients included (GnP 88; mFFX 14; other regimens 78), distant metastasis was confined to the peritoneum in 89 patients. Although group B had a worse performance status compared to group A, median OS was significantly longer in group B. GnP and mFFX showed a significantly higher objective response rate and disease control rate in addition to longer progression free survival and OS compared to other regimens. The administration of GnP or mFFX, performance status, and neutrophil to lymphocyte ratio ≥5 were identified as independent prognostic factors for OS. Furthermore, the amount of ascites and extent of peritoneal metastasis were significantly associated with OS in patients with distant metastasis confined to the peritoneum.ConclusionsThe prognosis of PC with peritoneal metastasis has significantly improved over time with the advent of GnP and mFFX.     

Hereditary factors in pancreatic cancer

The incidence and the mortality rates for pancreatic cancer are the same, indicating its dismal outlook. Its natural history remains elusive. Cigarette smoking appears to be the most significant environmental culprit. Hereditary factors may account for approximately 5% of the total pancreatic cancer burden. However, when its extant heterogeneity and the reduced penetrance of causal germline mutations are considered, the hereditary incidence may significantly exceed this estimate. Even when endoscopic ultrasound (EUS), the gold standard for pancreatic cancer screening, is utilized, early detection with surgical cure has rarely been accomplished. Needed to ameliorate this problem is research into genetic and environmental risk factors and their interaction. The identification of tumor biomarkers which signal early pathogenetic events, thereby enabling pancreatic cancer to be diagnosed at its earliest possible stage before it has spread to regional lymph nodes or to more distant sites, will improve the outlook. We discuss our research approaches to this problem. Members of families with thep16 germline mutation will undergo EUS coupled with the collection of pancreatic juice for the study of a possible gradient for telomerase activity, K‐ras mutations, and cytology. If changes in these putative biomarkers are observed, endoscopic retrograde cholangiopancreatography (ERCP) would be the next diagnostic step. We conclude with a discussion of ethical concerns about this research.     

AKT2在胰腺癌组织中的表达及意义

目的 探讨胰腺癌组织中蛋白激酶B（AKT）2的表达及其在胰腺癌发生、发展中的作用。方法 采用免疫组化SABC法检测63例胰腺癌组织和23例胰腺良性病变组织中AKT2的表达,分析其与胰腺癌临床病理因素的关系。结果 AKT2在胰腺癌组织中的阳性表达率为39．7％（25／63）,明显高于胰腺良性病变组织的13％（3／23）,P〈0．05。AKT2表达与胰腺癌组织学分级、淋巴结转移、TNM分期有关（P〈0．05）。结论 AKT2在胰腺癌组织中表达增高,可能在胰腺癌发生、发展、转移中起重要作用。     

Protein kinase D enzymes: novel kinase targets in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by advanced stage desmoplastic tumors with a high prevalence of genetic abnormalities. Occurrence of PDA is linked to activating Kras mutations and aberrant epidermal growth factor receptor signaling, leading to additional activation of wild-type Kras. As Kras is difficult to target, there is a constant need to identify novel targets acting downstream of this molecule in driving the formation or progression of PDA. Recently, it was shown that protein kinase D enzymes not only are increasingly expressed in PDA but also causatively linked to the development and progression of this cancer. They act downstream of both mutant Kras and growth factors and therefore may represent ideal novel targets.     

Ethanol-Induced Cas Tyrosine Phosphorylation and Fyn Kinase Activation in Rat Brain

Background Tyrosine phosphorylation signaling has been reported to be involved in regulatory mechanisms of ethanol-induced modulation of the central nervous system.
Methods We investigated the effect of ethanol administration on tyrosine phosphorylation signaling in rat brain and also examined the possible involvement of Fyn kinase in the process.
Results Immunoprecipitation experiments showed that Crk -associated src substrate (Cas) was tyrosine-phosphorylated in response to ethanol administration. Fyn kinase was shown to be activated by ethanol administration and to phosphorylate Cas on tyrosine residue in vitro. Furthermore, Fyn kinase was co-localized with Cas in rat cerebellum and cerebral cortex.
Conclusions Cas was tyrosine-phosphorylated in rat brain by ethanol administration, and Fyn kinase was most likely involved in the process.     

Translational evidence on the role of Src kinase and activated Src kinase in invasive breast cancer

Src kinase is a member of a non-receptor tyrosine kinase family. It has been implicated as a regulator of cell proliferation and survival and plays a complex role in cell adhesion and motility. In vitro evidence for a role for Src in breast cancer is compelling. However, only a few translational clinical studies have been undertaken in this field. This review summarises translational evidence on expression and activation of Src kinase in breast cancer patient cohorts exploring clinical significance and the possibility of identifying key biomarkers. There is strengthened translational proof for a definitive role of Src in breast cancer. Nevertheless, there remains a need to find a robust biomarker to identify patients responsive to Src inhibitors for clinical trials.