Prognosis Of Pancreatic Cancer Research Articles

Critical Role of Preoperative Hyperglycemia in Association with GFAT-1 Expression in Resected Pancreatic Cancer.

Hyperglycemia is involved in malignant transformation of pancreatic cancer via the hexosamine biosynthetic pathway (HBP). However, few studies have verified this mechanism based on clinical data. This study investigated the complementary effects of hyperglycemia and HBP on pancreatic cancer prognosis using detailed clinical data. The study analyzed data of 477 patients with pancreatic cancer who underwent pancreatectomy between 2006 and 2020. The patients were divided into normoglycemia and hyperglycemia groups based on their HbA1c levels. Immunostaining for glutamine fructose-6-phosphate transaminase-1 (GFAT-1), the rate-limiting enzyme in HBP, CD4, CD8, and Foxp3, was performed to evaluate the association between survival outcomes, HBP, and local tumor immunity. Overall survival (OS) was significantly poorer in the hyperglycemia group than in the normoglycemia group (mean survival time [MST]: 35.0 vs. 47.9months; p = 0.007). The patients in the hyperglycemia group with high GFAT-1 expression had significantly poorer OS than those with low GFAT-1 expression (MST, 49.0 vs. 27.6months; p < 0.001). However, the prognosis did not differ significantly between the patients with high and low GFAT-1 expression in the normoglycemia group. In addition, the patients with hyperglycemia and high GFAT-1 expression had fewer CD4+ (p = 0.015) and CD8+ (p = 0.017) T cells and a lower CD8+/Foxp3+ ratio (p = 0.032) than those with hyperglycemia and low GFAT-1 expression. The patients with hyperglycemia and high GFAT-1 expression levels had an extremely poor prognosis. Furthermore, the tumors in these patients were characterized as immunologically cold tumors.

Deep learning predicts the 1-year prognosis of pancreatic cancer patients using positive peritoneal washing cytology

Peritoneal washing cytology (CY) in patients with pancreatic cancer is mainly used for staging; however, it may also be used to evaluate the intraperitoneal status to predict a more accurate prognosis. Here, we investigated the potential of deep learning of CY specimen images for predicting the 1-year prognosis of pancreatic cancer in CY-positive patients. CY specimens from 88 patients with prognostic information were retrospectively analyzed. CY specimens scanned by the whole slide imaging device were segmented and subjected to deep learning with a Vision Transformer (ViT) and a Convolutional Neural Network (CNN). The results indicated that ViT and CNN predicted the 1-year prognosis from scanned images with accuracies of 0.8056 and 0.8009 in the area under the curve of the receiver operating characteristic curves, respectively. Patients predicted to survive 1 year or more by ViT showed significantly longer survivals by Kaplan–Meier analyses. The cell nuclei found to have a negative prognostic impact by ViT appeared to be neutrophils. Our results indicate that AI-mediated analysis of CY specimens can successfully predict the 1-year prognosis of patients with pancreatic cancer positive for CY. Intraperitoneal neutrophils may be a novel prognostic marker and therapeutic target for CY-positive patients with pancreatic cancer.

Pancreatic cancer screening in high-risk individuals.

The incidence of pancreatic cancer is increasing, although globally it represents less than 3% of all cancers. Despite advances in medical and surgical management, survival rates have not significantly improved in recent years. Consequently, pancreatic cancer, though relatively uncommon, is the third leading cause of cancer-related deaths. This is primarily due to the disease´s late detection. Symptoms appear late and are nonspecific, and over 80% of cases are diagnosed at an advanced stage and unsuitable for curative surgery, resulting in a five-year survival rate below 10%. However, the exceptional cases that are diagnosed early show five-year survival rates exceeding 80%. Therefore, one of the keys to improving pancreatic cancer prognosis lies in early detection, making screening in high-risk individuals a potentially crucial strategy.

Prognostic and therapeutic value of the Eph/Ephrin signaling pathway in pancreatic cancer explored based on bioinformatics

Pancreatic cancer (PC) is one of the most common malignant tumors of the digestive tract and has a very high mortality rate worldwide. Different PC patients may respond differently to therapy and develop therapeutic resistance due to the complexity and variety of the tumor microenvironment. The Eph/ephrin signaling pathway is extensively involved in tumor-related biological functions. However, the key function of the Eph/ephrin signaling pathway in PC has not been fully elucidated. We first explored a pan-cancer overview of Eph/ephrin signaling pathway genes (EPGs). Then we grouped the PC patients into 3 subgroups based on EPG expression levels. Significantly different prognoses and tumor immune microenvironments between different subtypes further validate Eph/ephrin's important role in the pathophysiology of PC. Additionally, we estimated the IC50 values for several commonly used molecularly targeted drugs used to treat PC in the three clusters, which could help patients receive a more personalized treatment plan. Following a progressive screening of optimal genes, we established a prognostic signature and validated it in internal and external test sets. The receiver operating characteristic (ROC) curves of our model exhibited great predictive performance. Meanwhile, we further validated the results through qRT-PCR and immunohistochemistry. Overall, this research provides fresh clues on the prognosis and therapy of PC as well as the theoretical groundwork for future Eph/ephrin signaling pathway research.

The Long Noncoding RNA PANDAR as a Prognostic and Diagnostic Biomarker in Panceratic Cancer ‏‏.

Pancreatic cancer (PC) is a lethal complication in the world, affecting around half a million individuals each year. The treatment of PC is relatively difficult due to the difficulty in making an early diagnosis. Most PC patients are confronted with locally metastatic or advanced diseases in the asymptomatic phase, and about 80% have late diagnosis with metastasis. Recently, long noncoding RNAs (lncRNAs) have drawn attention as a novel biological regulation layer. They take part in the regulation of mRNA and can be used as a prognostic factor or drug target. Based on their functions as regulators of PC initiation and progress, the lncRNAs can be categorized as tumor suppressors or oncogenic. They can be considered as a target for finding new biomarkers for prognosis, diagnosis, monitoring, and treating drug response in PC. Therefore, the present study summarizes the lncRNAs role in PC and the probable strategies to deal with their expression and controlling tumorigenesis and detection of the prognosis of PC.

Evaluating surgeon communication of pancreatic cancer prognosis using the VitalTalk ADAPT framework.

Few data exist to guide optimal communication practices for surgical oncologists. VitalTalk, an evidence-based communication skills training model for clinicians, offers the five-step ADAPT tool for discussing prognosis. This study aimed to characterize surgeon communication of pancreatic cancer prognosis using VitalTalk's ADAPT framework. Contemporaneous audio recordings from 12 initial surgeon-patient encounters for borderline resectable pancreatic cancer were transcribed. Directed qualitative content analysis based on ADAPT (Ask, Discover, Anticipate, Provide, and Track) was used to deductively code transcripts. All encounters contained at least one ADAPT step while only one (8%) incorporated four or five steps. Surgeons provided prognostic information (Provide) in all but one encounter (92%); most was qualitative and clustered into themes: serious illness, surgical candidacy, prognostic ambiguity, and cancer recurrence. Surgeons elicited understanding (Ask), requested information preferences (Discover), anticipated ambivalence (Anticipate), and responded to emotion (Track) in a minority of encounters (25%-42%); of 15 patient emotional cues, six were not addressed by surgeons. During an initial encounter for pancreatic cancer, surgeons focus heavily on providing information but omit critical prognostic communication steps. Future studies are needed to investigate if surgeon training in palliative care-based communicationis feasible and impacts patient-perceived quality of communication.

Preoperative metabolic syndrome and prognosis after pancreatectomy for pancreatic cancer: A retrospective study.

We conducted a retrospective study to investigate the impact of metabolic syndrome (MetS), its individual components, and the number of metabolic risk factors on the prognosis of pancreatic cancer (PC) following pancreatectomy. MetS was defined as meeting any three of the following criteria: (1) waist circumference ≥85cm in men or ≥80cm in women; (2) triglycerides ≥150mg/dL or receiving drug treatment for elevated triglycerides; (3) high-density lipoprotein cholesterol <40mg/dL in men or <50mg/dL in women or receiving drug treatment for reduced HDL-C; (4) systolic blood pressure ≥130mmHg and/or diastolic blood pressure ≥85mmHg or receiving drug treatment for hypertension; and (5) fasting glucose, (FG) ≥100mg/dL or receiving drug treatment for elevated glucose. The hazard ratio (HR) and 95% confidence interval (CI) were calculated by the Cox regression model. Six hundred and seven patients who underwent radical resection for PC were enrolled in this study. Among them, 352 patients presented with preoperative MetS. MetS was associated with shorter overall survival (OS) but not with shorter disease-free survival (DFS). The adjusted HR (95% CI) for the poor OS in patients with 3, 4, and 5 metabolic risk components (vs.≤2) were 1.32 (1.03-1.84), 1.64 (1.18-2.29), and 1.96 (1.27-3.04), respectively (p<0.05). Elevated FG emerged as a significant predictor for poor OS and DFS. This study highlights that preoperative MetS serves as a significant predictor for OS in patients with PC, with its predictive value escalating as the number of metabolic risk components increases.

A prognostic model for anoikis-related genes in pancreatic cancer

Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation and progression of cancer cells. This study aimed to establish an anoikis-related prognostic model to predict the prognosis of pancreatic cancer (PC) patients. Gene expression data and patient clinical profiles were sourced from The Cancer Genome Atlas (TCGA-PAAD: Pancreatic Adenocarcinoma) and the International Cancer Genome Consortium (ICGC-PACA: Pancreatic Ductal Adenocarcinoma). Non-cancerous pancreatic tissue gene expression data were obtained from the Genotype-Tissue Expression (GTEx) project. The R package was used to construct anoikis-related PC prognostic models, which were later validated with the ICGC-PACA database. Survival analyses demonstrated a poorer prognosis for patients in the high-risk group, consistent across both TCGA-PAAD and ICGC-PACA datasets. A nomogram was designed as a predictive tool to estimate patient mortality. The study also analyzed tumor mutations and immune infiltration across various risk groups, uncovering notable differences in tumor mutation patterns and immune landscapes between high- and low-risk groups. In conclusion, this research successfully developed a prognostic model centered on anoikis-related genes, offering a novel tool for predicting the clinical trajectory of PC patients.

Significance of signal recognition particle 9 nuclear translocation: Implications for pancreatic cancer prognosis and functionality.

Signal recognition particles (SRPs) are essential for regulating intracellular protein transport and secretion. Patients with tumors with high SRP9 expression tend to have a poorer overall survival. However, to the best of our knowledge, no reports have described the relationship between SRP9 localization and prognosis in pancreatic cancer. Thus, the present study aimed to investigate this relationship. Immunohistochemical staining for SRP9 using excised specimens from pancreatic cancer surgery cases without preoperative chemotherapy or radiotherapy showed that SRP9 was preferentially expressed in the nucleus of the cancerous regions in some cases, which was hardly detected in other cases, indicating that SRP9 was transported to the nucleus in the former cases. To compare the prognosis of patients with SRP9 nuclear translocation, patients were divided into two groups: Those with a nuclear translocation rate of >50% and those with a nuclear translocation rate of ≤50%. The nuclear translocation rate of >50% group had a significantly better recurrence‑free survival than the nuclear translocation rate of ≤50% group (P=0.037). Subsequent in vitro experiments were conducted; notably, the nuclear translocation rate of SRP9 was reduced under amino acid‑deficient conditions, suggesting that multiple factors are involved in this phenomenon. To further study the function of SRP9 nuclear translocation, in vitro experiments were performed by introducing SRP9 splicing variants (v1 and v2) and their deletion mutants lacking C‑terminal regions into MiaPaCa pancreatic cancer cells. The results demonstrated that both splicing variants showed nuclear translocation regardless of the C‑terminal deletions, suggesting the role of the N‑terminal regions. Given that SRP9 is an RNA‑binding protein, the study of RNA immunoprecipitation revealed that signaling pathways involved in cancer progression and protein translation were downregulated in nuclear‑translocated v1 and v2. Undoubtedly, further studies of the nuclear translocation of SRP9 will open an avenue to optimize the precise evaluation and therapeutic control of pancreatic cancer.

Emerging Nanotechnology in Preclinical Pancreatic Cancer Immunotherapy: Driving Towards Clinical Applications.

The high malignant degree and poor prognosis of pancreatic cancer (PC) pose severe challenges to the basic research and clinical translation of next-generation therapies. The rise of immunotherapy has improved the treatment of a variety of solid tumors, while the application in PC is highly restricted by the challenge of immunosuppressive tumor microenvironment. The latest progress of nanotechnology as drug delivery platform and immune adjuvant has improved drug delivery in a variety of disease backgrounds and enhanced tumor therapy based on immunotherapy. Based on the immune loop of PC and the status quo of clinical immunotherapy of tumors, this article discussed and critically analyzed the key transformation difficulties of immunotherapy adaptation to the treatment of PC, and then proposed the rational design strategies of new nanocarriers for drug delivery and immune regulation, especially the design of combined immunotherapy. This review also put forward prospective views on future research directions, so as to provide information for the new means of clinical treatment of PC combined with the next generation of nanotechnology and immunotherapy.

Identification and model construction of survival-associated proteins for pancreatic cancer based on deep learning

Pancreatic cancer (PC) is a malignancy typified by its insidious onset, rapid progression, limited resectability, poor treatment response, and exceedingly dismal prognosis. The transition from precursor lesions to infiltrating malignant tumors in pancreatic cancer is concomitant with the accrual of genetic mutations. The elucidation of proteins linked to the prognosis of pancreatic cancer holds paramount importance in the realm of pancreatic cancer management. Herein, we introduce DeepPCSA, a model tailored for the screening of target proteins and the prediction of survival time, employing both conventional methodologies and deep learning techniques for patient survival analysis. This framework leverages the LASSOCOX regression approach on differentially expressed genes (DEGs) to discern pivotal genes, succeeded by the development of a prognostic model employing convolutional and fully connected layers to prognosticate patient survival duration. Furthermore, we account for covariates such as age, gender, and other pertinent factors for independent prognostic scrutiny, affirming the autonomy of our model as a prognostic determinant. Employing unsupervised clustering methodologies, we delineated two molecular subtypes delineated by disparate biological processes. Ultimately, via drug sensitivity analysis, we delineated the interrelation between survival duration and pharmaceuticals, substantiating the necessity for tailored drug interventions catering to patients of varying risk strata.

Alterations in genes involved in glycolysis and hypoxia affect the prognosis of pancreatic cancer

PurposeTo construct a prognostic model for pancreatic cancer based on glycolytic and hypoxic metabolic subtypes. To analyze the biological characteristics of these subtypes and explore potential therapeutic options. MethodsWe obtained mRNA, simple nucleotide variation (SNP), and clinical data for pancreatic cancer from The Cancer Genome Atlas (TCGA). Patients were classified into four metabolic subtypes. We focused on glycolysis and hypoxia subtypes. Single-sample gene set enrichment analysis (ssGSEA) assessed immune cell infiltration. We evaluated the effects of immunotherapy and chemotherapy on these subtypes. Cox regression and random survival forest algorithms were used to build a prognostic model. Validation was performed using data from the International Cancer Genome Consortium (ICGC) and ArrayExpress database. ResultsWe identified four subtypes. Kaplan-Meier survival analysis showed the glycolytic subtype had the longest survival, while the hypoxic subtype had the shortest. The glycolytic subtype exhibited higher immune cell infiltration. Immunotherapy and chemotherapy appeared more beneficial for the glycolytic subtype. KRAS mutations were more frequent in the hypoxic subtype. Our prognostic model indicated a worse prognosis for high-risk groups, validated by external data. ConclusionThe glycolytic metabolic subtype of pancreatic cancer is associated with longer survival and better response to chemotherapy and immunotherapy compared to the hypoxic subtype.

MMP11 as a prognostic biomarker correlated with immune infiltrates in pancreatic adenocarcinoma.

Matrix metalloproteinase 11 (MMP11) plays a vital role in cell proliferation, apoptosis, tumor angiogenesis, migration, and other basic processes. Currently, few studies have examined the value of MMP11 in pancreatic cancer in relation to prognostic risk, diagnostic indicators, and immunotherapy. This study aims to explore the association between MMP11 and the tumor immune microenvironment in pancreatic adenocarcinoma (PAAD). We selected clinical samples and data downloaded from The Cancer Genome Atlas and Genotype-Tissue Expression, in addition, we use other online data for further analysis. Through a comprehensive bioinformatics investigation, we systematically analyzed the clinical significance and expression level of MMP11 in pancreatic cancer. MMP11 was overexpressed in many cancers, and a higher expression of MMP11 was associated with a poorer prognosis in pancreatic cancer. Conversely, the hypermethylation of MMP11 was associated with better overall survival. The MMP11 expression network had widespread effects on the prognosis and immune activation of PAAD. The expression of MMP11 was significantly associated with a variety of tumor-infiltrating immune cells. An association was also found between MMP11 expression and chemokines in PAAD. High MMP11 expression might be involved in immune cell migration to the tumor microenvironment. MMP11 is a prognostic biomarker for patients in pancreatic cancer and may regulate the tumor immune microenvironment. The potential effects and mechanisms of MMP11 in PAAD require further exploring.

Identification of gemcitabine resistance-related AHNAK2 gene associated with prognosis and immune infiltration in pancreatic cancer

PurposeGemcitabine is a basic chemotherapy drug for pancreatic cancer (PC), but resistance is common and causes tumor recurrence and metastasis. Therefore, it is significant to explore gemcitabine resistance-related molecules for individualized treatment and prognosis assessment of PC. MethodsIn this study, transcriptome sequencing and TCGA database analysis were performed, and a differentiated gene AHNAK2 was screened. MEXPRESS database, tissue microarray analysis, and CIBERSORT and TIMER databases were used to correlate AHNAK2 expression with clinicopathological features and prognosis and immune infiltration of PC. Enrichment analysis was used to investigate the significant biological processes associated with AHNAK2. ResultsAHNAK2 was highly expressed in gemcitabine-resistant cells. High expression of AHNAK2 increased the risk of poor overall survival (OS) and progression-free survival (PFS) in PC. Clinicopathologic analysis revealed that AHNAK2 correlated with KRAS, TP53 mutations, histologic type, short OS, N stage, and elevated CA199 levels in PC. Knockdown of AHNAK2 inhibited the ability of cell proliferation and colony formation and enhanced the toxic effect of gemcitabine in PC. Meanwhile, the knockdown of AHNAK2 expression enhanced cell-ECM adhesion, inhibited cell-cell adhesion, and downregulated the KRAS/p53 signaling pathway in PC. Furthermore, AHNAK2 was correlated with immune infiltration, especially B cells and macrophages. ConclusionsOur study unveils for the first time the pivotal role of AHNAK2 in PC, particularly its association with gemcitabine resistance, clinical prognosis, and immune infiltration. AHNAK2 not only drives the proliferation and drug resistance of PC cells by potentially activating the KRAS/p53 pathway but also significantly impacts cell-cell and cell- ECM adhesion. Additionally, AHNAK2 plays a crucial role in modulating the tumor immune microenvironment. These insights underscore AHNAK2's unique potential as a novel therapeutic target for overcoming gemcitabine resistance, offering new perspectives for PC treatment strategies.

The Complexity of the Pancreatic Lymphatic System and the Key Role of Para-Aortic Lymph Node Metastasis in Pancreatic Cancer Prognosis Prediction: A Comprehensive Review

The pancreas is a vital organ nestled deep within the abdomen, playing a crucial role in both endocrine and exocrine functions. It is elongated and tadpole-shaped, with a head, body, and tail. The intricate connections to adjacent structures through a network of blood vessels, ducts, and supportive tissue transform pancreatic cancer into one of the most fatal malignancies globally as a result of a typically late diagnosis and metastatic form of the disease. Lymph node metastasis (LNM) is prevalent in the majority of individuals diagnosed with pancreatic cancer, signifying a critical factor influencing prognostic outcomes. The para-aortic lymph nodes (PALN) play an important role in the lymphatic drainage of various organs, including the kidneys, pancreas, and parts of the gastrointestinal tract. In pancreatic cancer, the risk of PALN metastasis holds considerable clinical significance, and diagnosing your involvement is primordial to therapeutic decisions and to increase the survival expectations of these patients.

Phase I/II first-in-human study to evaluate the safety and efficacy of tissue factor-ADC MRG004A in patients with solid tumors.

3002 Background: Tissue factor (TF) overexpression is associated with thrombosis, metastasis and poor prognosis in solid tumors, including cervical and pancreatic cancer. MRG004A is a novel anti-TF monoclonal antibody conjugated (ADC) to MMAE payload (drug-to-antibody ratio: 3.8), utilizing Glycoconnect site-specific conjugation technology. Herein, we present the preliminary safety and efficacy data from phase I/II MRG004A-001. Methods: This is an interim report (Data cutoff: Dec 15, 2023) of first-in-human, dose-escalation and expansion study ongoing in the USA and China. Pts with ECOG 0-1 with unresectable/metastatic solid tumor with measurable disease per RECIST v1.1 that progressed on prior systemic therapy, received MRG004A monotherapy Q3W intravenously. The primary objectives were to assess the safety, activity, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Baseline tissue was evaluated for the association of TF expression with objective response rate (ORR) and disease control rate (DCR). Results: Sixty-three pts were enrolled with 43 in dose-escalation phase (8 dose levels [0.3-2.6mg/kg]) and 20 in dose-expansion phase (15 at 2.0mg/kg and 5 at 2.4mg/kg). Median age 58 (38-75). ECOG0: 8 (13%) pts. Female: 37 (59%) pts. Median 3 prior lines of therapy: 3 (1-10). MTD was not reached. Sixteen baseline samples were evaluated for overall % membrane positivity by immunohistochemistry. Nineteen were pancreatic cancer (PC) and 68% (13/19) had TF ≥50% and 2 or 3 (+). Five received dose &lt;2 mg/kg Q3W. Significant anti-tumor activity of MRG004A was observed in pts with PC. Among 12 evaluable pts with PC in the 2.0mg/kg cohort, who have received median 3 lines of prior therapy, there were 4 PR and 6 SD. ORR was 33.3% (4/12) and DCR was 83.3% (10/12). Among them, 5 pts with PC of TF expression ≥50% and 3+ intensity and ≤2 prior lines of therapy received MRG004A at 2mg/kg. 4 of 5 TF-overexpressed PC achieved PR and 1 SD. Also, MRG004A showed efficacy in other cancers. In 4 pts with heavily-treated triple-negative breast cancer (TNBC), ORR and DCR were 25% (1/4) and 50% (2/4), respectively. In 2 pts with cervical cancer with four prior therapy lines, 1 PR and 1 SD. Common treatment-related adverse events (TRAE) of any grade include conjunctivitis (27%), anemia (17%), and hypoalbuminemia (13%) and 7.9% (5/63) pts had serious adverse events. One pt with TNBC treated at 1.8mg/kg experienced G3 Steven Johnson Syndrome, a dose-limiting toxicity (DLT), but resolved. No other DLT was observed and dose expansion and matured outcome evaluation is ongoing. Conclusions: MRG004A demonstrated a manageable toxicity and a striking antitumor activity across multiple tumor types with high TF expression in heavily pretreated setting, including pancreatic cancers. These encouraging findings warrant further evaluation of MRG004A, particularly in the context of TF-overexpressed solid tumors. Clinical trial information: NCT03941574 .

Genetic and immune identification and functional analysis of TRPM8 as a potential biomarker for pancreatic adenocarcinoma proliferation.

Pancreatic adenocarcinoma (PAAD), a member of highly lethal malignant tumors, has a poor outcome and extremely poor prognosis. The transient receptor potential (TRP) superfamily, a group of nonselective cation channels, is capable of influencing cellular functions by regulating calcium homeostasis. In addition, it has been shown that TRP channels can also affect various cellular phenotypes by regulating gene transcription levels and are involved in the development of a variety of malignant tumors. In order to find new therapeutic targets and biomarkers to improve the clinical prognosis of pancreatic cancer, we performed genetic and immunological characterization of TRP channels in PAAD, as well as related functional and prognostic analyses. We investigated the expression, genetic alterations, methylation levels, and immune infiltration levels of TRP channels in PAAD, and further also analyzed the function of TRP channels in PAAD and their prognostic value for PAAD patients. Our results suggest that TRPM8 may contribute to tumor proliferation by controlling the PI3K-AKT-mTOR signaling pathway in PAAD. After careful evaluation of the accumulated data, we concluded that TRPM8 has potential as a prognostic indicator and prospective therapeutic target in PAAD.

Placental growth factor promotes neural invasion and predicts disease prognosis in resectable pancreatic cancer

BackgroundSurgery represents the only curative treatment option for pancreatic ductal adenocarcinoma (PDAC), but recurrence in more than 85% of patients limits the success of curative-intent tumor resection. Neural invasion (NI), particularly the spread of tumor cells along nerves into extratumoral regions of the pancreas, constitutes a well-recognized risk factor for recurrence. Hence, monitoring and therapeutic targeting of NI offer the potential to stratify recurrence risk and improve recurrence-free survival. Based on the evolutionary conserved dual function of axon and vessel guidance molecules, we hypothesize that the proangiogenic vessel guidance factor placental growth factor (PlGF) fosters NI. To test this hypothesis, we correlated PlGF with NI in PDAC patient samples and functionally assessed its role for the interaction of tumor cells with nerves.MethodsSerum levels of PlGF and its soluble receptor sFlt1, and expression of PlGF mRNA transcripts in tumor tissues were determined by ELISA or qPCR in a retrospective discovery and a prospective validation cohort. Free circulating PlGF was calculated from the ratio PlGF/sFlt1. Incidence and extent of NI were quantified based on histomorphometric measurements and separately assessed for intratumoral and extratumoral nerves. PlGF function on reciprocal chemoattraction and directed neurite outgrowth was evaluated in co-cultures of PDAC cells with primary dorsal-root-ganglia neurons or Schwann cells using blocking anti-PlGF antibodies.ResultsElevated circulating levels of free PlGF correlated with NI and shorter overall survival in patients with PDAC qualifying for curative-intent surgery. Furthermore, high tissue PlGF mRNA transcript levels in patients undergoing curative-intent surgery correlated with a higher incidence and greater extent of NI spreading to tumor-distant extratumoral nerves. In turn, more abundant extratumoral NI predicted shorter disease-free and overall survival. Experimentally, PlGF facilitated directional and dynamic changes in neurite outgrowth of primary dorsal-root-ganglia neurons upon exposure to PDAC derived guidance and growth factors and supported mutual chemoattraction of tumor cells with neurons and Schwann cells.ConclusionOur translational results highlight PlGF as an axon guidance factor, which fosters neurite outgrowth and attracts tumor cells towards nerves. Hence, PlGF represents a promising circulating biomarker of NI and potential therapeutic target to improve the clinical outcome for patients with resectable PDAC.Graphical

The serum tenascin C level is a marker of metabolic disorder-related inflammation affecting pancreatic cancer prognosis

Obesity is a risk factor for pancreatic cancer development, partly due to the tissue environment of metabolic disorder-related inflammation. We aimed to detect a tissue environment marker triggered by obesity-related metabolic disorders related to pancreatic cancer progression. In murine experiments, Bl6/j mice fed a normal diet (ND) or a high-fat diet (HFD) were orthotopically injected with mPKC1, a murine-derived pancreatic cancer cell line. We used stocked sera from 140 pancreatic cancer patients for analysis and 14 colon polyp patients as a disease control. Compared with ND-fed mice, HFD-fed mice exhibited obesity, larger tumors, and worse prognoses. RNA sequencing of tumors identified tenascin C (TNC) as a candidate obesity-related serum tissue environment marker with elevated expression in tumors of HFD-fed mice. Serum TNC levels were greater in HFD-fed mice than in ND-fed mice. In pancreatic cancer patients, serum TNC levels were greater than those in controls. The TNC-high group had more metabolic disorders and greater CA19-9 levels than did the TNC-low group. There was no relationship between serum TNC levels and disease stage. Among 77 metastatic patients treated with chemotherapy, a high serum TNC concentration was an independent poor prognostic factor. Pancreatic cancer patients with high serum TNC levels experienced progression more rapidly.

Unveiling the role of interleukin-6 in pancreatic cancer occurrence and progression.

Pancreatic cancer is difficult to diagnose early and progresses rapidly. Researchers have found that a cytokine called Interleukin-6 (IL-6) is involved in the entire course of pancreatic cancer, promoting its occurrence and development. From the earliest stages of pancreatic intraepithelial neoplasia to the invasion and metastasis of pancreatic cancer cells and the appearance of tumor cachexia, IL-6 drives oncogenic signal transduction pathways and immune escape that accelerate disease progression. IL-6 is considered a biomarker for pancreatic cancer diagnosis and prognosis, as well as a potential target for treatment. IL-6 antibodies are currently being explored as a hot topic in oncology. This article aims to systematically explain how IL-6 induces the deterioration of normal pancreatic cells, with the goal of finding a breakthrough in pancreatic cancer diagnosis and treatment.