Perineural invasion in pancreatic cancer: proteomic analysis and <i>in vitro</i> modelling

Alrawashdeh, Wasfi; Jones, Richard C.; Dumartin, Laurent; Radon, Tomasz P.; Cutillas, Pedro R.; Feakins, Roger; Dmitrović, Branko; Demir, Ihsan Ekin; Ceyhan, Güralp O.; Crnogorac‐Jurčević, Tatjana

doi:10.1002/1878-0261.12463

Cited by 45 publications

(30 citation statements)

References 63 publications

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“…L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation 33 . Proteomic analysis also highlighted an increased expression of SCG2 and VGF in invaded compared to non-invaded nerves 34 . Previous research indicated that, in addition to functioning as a mitogen and a morphogen in non-neural systems, HGF can function as a guide and survival factor in the developing nervous system 7,8 .…”

Section: Discussionmentioning

confidence: 95%

Pancreatic Stellate Cells Facilitate Perineural Invasion of Pancreatic Cancer via HGF/c-Met Pathway

et al. 2019

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Pancreatic cancer (PC) is a highly lethal cancer that has a strong ability for invasion and metastasis, poor prognosis, and a stubbornly high death rate due to late diagnosis and early metastasis. Therefore, a better understanding of the mechanisms of metastasis should provide novel opportunities for therapeutic purposes. As a route of metastasis in PC, perineural invasion (PNI) occurs frequently; however, the molecular mechanism of PNI is still poorly understood. In this study, we show that the hepatocyte growth factor (HGF)/c-Met pathway plays a vital role in the PNI of PC. We found that HGF promotes PC cell migration and invasion by activating the HGF/c-Met pathway, and enhances the expression of nerve growth factor (NGF) and matrix metalloproteinase-9 (MMP9) in vitro. Furthermore, HGF significantly increased PC cell invasion of the dorsal root ganglia (DRG) and promoted the outgrowth of DRG in cocultured models of PC cells and DRG. In contrast, the capacity for invasion and the phenomenon of PNI in PC cells were reduced when the HGF/c-Met pathway was blocked by siRNA. In conclusion, PSCs facilitate PC cell PNI via the HGF/c-Met pathway. Targeting the HGF/c-Met signaling pathway could be a promising therapeutic strategy for PC.

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Section: Discussionmentioning

confidence: 95%

Pancreatic Stellate Cells Facilitate Perineural Invasion of Pancreatic Cancer via HGF/c-Met Pathway

et al. 2019

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“…Furthermore, single-cell transcription data analysis showed that perineural invasion relevant module genes were associated with EMT, invasion, and metastasis (64). Moreover, the overall proteomic profiles between perineural invasion and non-perineural invasion tumor samples appeared largely similar (65). Therefore, perineural infiltration is more likely a marker for the changes in tumor microenvironment than directly correlated with genomic alterations, and we can reasonably infer that pancreatic cancer cells with perineural invasion-associated mutations and CNVs in this study might be more invasive.…”

Section: [C > G] C and More T > G Mutations At C [T > G] G But Fewer C > A Mutations At T [C > A]mentioning

confidence: 97%

The Landscape of Genetic Alterations Stratified Prognosis in Oriental Pancreatic Cancer Patients

et al. 2021

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BackgroundPancreatic cancer is a life-threatening malignant disease with significant diversity among geographic regions and races leading to distinct carcinogenesis and prognosis. Previous studies mainly focused on Western patients, while the genomic landscape of Oriental patients, especially Chinese, remained less investigated.MethodsA total of 408 pancreatic cancer patients were enrolled. A panel containing 436 cancer-related genes was used to detect genetic alterations in tumor samples.ResultsWe profiled the genomic alteration landscape of pancreatic duct adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN), periampullary carcinoma (PVC), and solid-pseudopapillary tumor (SPT). Comparison with a public database revealed specific gene mutations in Oriental PDAC patients including higher mutation rates of DNA damage repair-related genes. Analysis of mutational signatures showed potential heterogenous carcinogenic factors caused by diabetes mellitus. KRAS mutation, especially KRAS G12D mutation, was associated with poor survival, while patients not harboring the 17 significant copy number variations (CNVs) had a better prognosis. We further identified multiple correlations between clinicopathologic variables and genetic mutations, as well as CNVs. Finally, by network-based stratification, three classes of PDAC patients were robustly clustered. Among these, class 1 (characterized by the Fanconi anemia pathway) achieved the best outcome, while class 2 (involved in the platinum drug resistance pathway) suffered from the worst prognosis.ConclusionsIn this study, we reported for the first time the genetic alteration landscape of Oriental PDAC patients identifying many Oriental-specific alterations. The relationship between genetic alterations and clinicopathological factors as well as prognosis demonstrated important genomic impact on tumor biology. This study will help to optimize clinical treatment of Oriental PDAC patients and improve their survival.

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“…Pancreatic ductal adenocarcinoma cells are able to induce neuronal plasticity (52). Interaction of PC with nerves is known to lead to nerve damage; described morphological changes are disrupted perineurium, distorted integrity of the whole nerve, and severely axonal edematous appearance, as a result of the invasion by pancreatic cancer cells (53).…”

Section: Pc Neurobiologymentioning

confidence: 99%

Pancreatic Cancer Related Pain: Review of Pathophysiology and Intrathecal Drug Delivery Systems for Pain Management

2021

Pain Phys

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BACKGROUND: Pancreatic cancer (PC) is one of the most lethal cancers and is the eleventh most common cancer worldwide. This disease is characterized by an often-fatal evolution and a high burden of symptoms, particularly pain. Several studies have demonstrated that pancreatic cancer patients have a high prevalence of pain, with up to 82% of patients reporting pain, often requiring systemic strong opioids as mainstay treatment. This comprehensive review of pancreatic cancer related pain (PCRP), focuses on current mechanisms that lead to pain including regional invasion processes, as well as the local secretion of factors that sensitize nociceptive nerves. OBJECTIVE: Our objective was to conduct a review of PCRP and provide updates on intrathecal drug delivery in PC therapeutic recommendations. STUDY DESIGN: We used a narrative review design. We present a novel perspective in the field of pain research by converging data from intrathecal drug delivery trials with previous elements of molecular pain research in PCRP. METHODS: The literature review relating to PCRP pathophysiology and intrathecal drug delivery systems (IDDS) was done with searches of English, French, and Spanish abstracts, using PubMed, Dynamed, EMBASE, SciELO, Uptodate, Google Scholar, and manual searches of the bibliographies of known primary and review articles from IDDS inception until August 2020. Different search strings based on MESH terms were used including: pain, chronic pain, cancer pain, prevalence, pathophysiology, pancreatic cancer, analgesia, invasive pain procedures, celiac plexus neurolysis, pancreatic neuropathy, intrathecal drug delivery, or a combination of these terms. A narrative review based on these sources was prepared. RESULTS: This paper reviews aspects related to pancreatic adenocarcinoma and PCRP prevalence and focuses on recent developments in pathophysiology with IDDS as a pain management strategy. We summarize the best available evidence regarding intrathecal therapy (IT) for PCRP management; 18 studies of IDDS including at least 236 PC patients are analyzed. LIMITATIONS: Some limitations include: IDDS studies heterogeneity regarding disease stage, patient population, and technical aspects, such as catheter placement and treatment regimen, do not allow integration of studies. CONCLUSION: This review analyzes both past and current literature with a critical analysis of findings and respective recommendations. Most studies of IDDS in PCRP evaluate outcomes on pain using one-dimensional pain scales, such as VAS. Other relevant results, such as performance status or quality of life, are not frequently reported. Burden of disease variables, such as cancer stage, location, and comorbidities, like depression and systemic analgesia co-prescription, are usually not presented in these studies. In the same way, most studies do not precisely inform IDDS titration and IT medication. These factors make integration of IDDS in PC studies difficult. Future studies regarding impact of IDDS on pain control on quality of life, in this particular population, may help clinicians in deciding the optimal time and approach for IDDS. The studies should report data on particular disease, comorbidities, and treatment regimens. KEY WORDS: Adenocarcinoma, cancer pain, pain, pancreatic carcinoma, pancreatic neoplasms, pain management, physiopathology, prevalence

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Perineural invasion in pancreatic cancer: proteomic analysis and in vitro modelling

Cited by 45 publications

References 63 publications

Pancreatic Stellate Cells Facilitate Perineural Invasion of Pancreatic Cancer via HGF/c-Met Pathway

Pancreatic Stellate Cells Facilitate Perineural Invasion of Pancreatic Cancer via HGF/c-Met Pathway

The Landscape of Genetic Alterations Stratified Prognosis in Oriental Pancreatic Cancer Patients

Pancreatic Cancer Related Pain: Review of Pathophysiology and Intrathecal Drug Delivery Systems for Pain Management

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