Most of the human genome consists of DNA genes that are translated into RNAs but not into proteins. These RNA molecules are named noncoding RNAs (ncRNA). While in the past it was thought that ncRNAs ...would be redundant without relevant functions, it is now well established that ncRNAs identify a class of regulatory molecules that finely tune cell homeostasis and are deregulated in disease states, including hepatocellular carcinoma (HCC). Of note, the number of ncRNAs within a cell increases progressively, with the complexity of the species indicating their essential role in the maintenance of regulatory networks that affect the intricacy of the organism. ncRNAs have been demonstrated to mediate HCC development and progression by affecting intrinsic cancer cell signaling and crosstalk between malignant cells and the microenvironment. Moreover, ncRNAs hold promise as clinical biomarkers, but further evidence is warranted before their translation and integration within clinical practice.
Here we show that Rab25 permits the sorting of ligand-occupied, active-conformation α5β1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally ...targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25-expressing cells and tumors, which colocalizes with active α5β1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo.
► Activated integrins move from late endosomes/lysosomes to the plasma membrane ► Spatial segregation of pathways recycling active and inactive integrins ► CLIC3 regulates cell migration and invasion ► CLIC3 dictates whether Rab25 functions as cancer progression suppressor or promoter
Objectives
Type 3c diabetes mellitus (T3cDM) occurring post pancreatectomy can be challenging to treat due to the frequent combination of decreased circulating levels of insulin and glucagon and ...concurrent exocrine insufficiency. Relatively, little is known regarding the risk factors for development of T3cDM post pancreatectomy. Our aim was to review the literature and assess what is known of the risk factors for the development of new‐onset DM following partial pancreatic resection and where possible determines the incidence, time of onset and the management approach to hyperglycaemia in this context.
Design
Medline and Embase databases were reviewed using specific keyword criteria. Original manuscripts published in 1990 or later included. Articles with study population <20, lacking information on new‐onset DM, follow‐up duration or specifically targeting rare procedures/pathology were excluded. The Newcastle Ottawa Quality Assessment form was applied. Results reported according to PRISMA guidelines. Pooled effect size calculated using random effects model.
Patients
Thirty six articles were identified that described a total of 5636 patients undergoing pancreaticoduodenectomy, 3922 patients having distal pancreatectomy and 315 with central pancreatectomy.
Results
The incidence of new‐onset DM was significantly different between different types of resection from 9% to 24% after pancreaticoduodenectomy (pooled estimate 16%; 95% CI: 14%‐17%), 3%‐40% after distal pancreatectomy (pooled estimate 21%; 95% CI: 16%‐25%) and 0%‐14% after central pancreatectomy (pooled estimate 6%; 95% CI: 3%‐9%). Surgical site, higher preoperative HbA1c, fasting plasma glucose and lower remnant pancreatic volume had strongest associations with new‐onset DM.
Conclusions
This systematic review supports that risk of development of T3cDM is associated with type of pancreatic resection, lower remnant pancreatic volume and higher preoperative HbA1c.
Integrin trafficking is key to cell migration, but little is known about the spatiotemporal organization of integrin endocytosis. Here, we show that α5β1 integrin undergoes tensin-dependent ...centripetal movement from the cell periphery to populate adhesions located under the nucleus. From here, ligand-engaged α5β1 integrins are internalized under control of the Arf subfamily GTPase, Arf4, and are trafficked to nearby late endosomes/lysosomes. Suppression of centripetal movement or Arf4-dependent endocytosis disrupts flow of ligand-bound integrins to late endosomes/lysosomes and their degradation within this compartment. Arf4-dependent integrin internalization is required for proper lysosome positioning and for recruitment and activation of mTOR at this cellular subcompartment. Furthermore, nutrient depletion promotes subnuclear accumulation and endocytosis of ligand-engaged α5β1 integrins via inhibition of mTORC1. This two-way regulatory interaction between mTORC1 and integrin trafficking in combination with data describing a role for tensin in invasive cell migration indicate interesting links between nutrient signaling and metastasis.
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•Tensin positions integrins for Arf4-dependent endocytosis•Photoactivation-in-TIRF microscopy pinpoints the site for integrin endocytosis•Integrin endocytosis dictates recruitment of mTORC1 to nearby late endosomes•Proinvasive trafficking pathway is regulated by nutrient status
Rainero et al. find that α5β1 integrins are first moved from the cell periphery to a region beneath the nucleus and from here are endocytosed and trafficked to late endosomes to support mTOR signaling. Control of this proinvasive pathway by nutrient status provides evidence for mechanistic links among ECM internalization, nutrient signaling, and metastasis.
Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of ...two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence, and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. Evidence is presented that this new understanding can be exploited in rational development and targeted application of prosenescence cancer therapies.
► Activated PIK3CA/AKT is a poor inducer of senescence ► Activated PIK3CA/AKT impairs RAS-induced senescence ► Activated PIK3CA/AKT counters RAS via mTOR activation and GSK3β inhibition ► Rapamycin restores senescence in tumors harboring activated RAS
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S ...transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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, p53R¹⁷⁵H, rather than complete loss of protein expression. In this study we elucidate the functions of mutant p53 (Trp53R¹⁷²H), compared to knockout p53 (Trp53fl), in a mouse model of PDAC. First we find that although KrasG¹²D is one of the major oncogenic drivers of PDAC, most KrasG¹²D-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 KrasG¹²D-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, p53R¹⁷²P, 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 p53R¹⁷²H, as compared with genetic loss of p53, specifically promotes metastasis. Moreover, only mutant p53R¹⁷²H-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 KrasG¹²D-induced senescence/growth arrest and second, the promotion of metastasis.
The rising incidence and the accumulating prevalence of neuroendocrine neoplasia (NEN) in the population makes this a common, prevalent and a clinically relevant disease group. Surgical resection ...represents the only potentially curative treatment for digestive NENs. Thus, resection should in principle be considered for all patients with NEN, although taking the patients age, relevant comorbidity, and performance status into account for operability. Patients with insulinomas, NEN of the appendix and rectal NENs are usually cured by surgery alone. However, less than a third of patients are amendable to curative surgery alone at time of diagnosis. Furthermore, recurrence is common and may occur years after primary surgery, hence the long follow-up time recommended in most NENs (>10 years). As many patients with NENs present with locoregional or metastatic disease, there is considerable debate regarding the role of debulking surgery in these settings. However, good long-term survival can be achieved in a considerable proportion of patients, with 50–70% alive up to 10 years after surgery. Location and grade are the main determinants of long-term survival. Here we present considerations to surgery for primary neuroendocrine tumors in the digestive tract.
High vagal nerve activity, reliability measured by HRV, is considered protective in cancer, reducing oxidative stress, inflammation and opposing sympathetic nerve activity. The present monocentric ...study examines the relationship between HRV, TNM stage, co-morbidity, systemic inflammation and survival in patients who underwent potentially curative resections for colorectal cancer (CRC). Time-domain HRV measures, Standard Deviation of NN-intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD), were examined as categorical (median) and continuous variables. Systemic inflammation was determined using systemic inflammatory grade (SIG) and co-morbidity using ASA. The primary end point was overall survival (OS) and was analysed using Cox regression. There were 439 patients included in the study and the median follow-up was 78 months. Forty-nine percent (n = 217) and 48% (n = 213) of patients were categorised as having low SDNN (< 24 ms) and RMSSD (< 29.8 ms), respectively. On univariate analysis, SDNN was not significantly associated with TNM stage (p = 0.830), ASA (p = 0.598) or SIG (p = 0.898). RMSSD was not significantly associated with TNM stage (p = 0.267), ASA (p = 0.294) or SIG (p = 0.951). Neither SDNN or RMSSD, categorical or continuous, were significantly associated with OS. In conclusion, neither SDNN or RMSSD were associated with TNM stage, ASA, SIG or survival in patients undergoing potentially curative surgery for CRC.
Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic ...iCCA, perihilar pCCA, and distal dCCA) in a pan-European cohort.
The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed.
Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival mOS = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors.
CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality.
This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic 2C12, perihilar 2C18, or distal 2C15 affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.
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•CCA subtypes present different risk factors and tumor features.•CA19-9 shows low sensitivity in early stages but increased sensitivity in advanced disease.•Under surgery, positive margins and lymph node invasion compromise survival.•ECOG-PS, disease status and CA19-9 are independent prognostic factors.
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