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Japanese Journal of Clinical Oncology Mar 2024Pancreatic acinar cell carcinoma is a rare form (0.2-4.3%) of pancreatic neoplasm with unique clinical and molecular characteristics, which largely differ from... (Review)
Review
Pancreatic acinar cell carcinoma is a rare form (0.2-4.3%) of pancreatic neoplasm with unique clinical and molecular characteristics, which largely differ from pancreatic ductal adenocarcinoma. Pancreatic acinar cell carcinoma occurs more frequently in males and can occur in children. Serum lipase is elevated in 24-58% of patients with pancreatic acinar cell carcinoma. Pancreatic acinar cell carcinomas tend to be large at diagnosis (median tumour size: ~5 cm) and are frequently located in the pancreas head. Radiologically, pancreatic acinar cell carcinoma generally exhibits a solid appearance; however, necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions. Immunostaining is essential for the definitive diagnosis of pancreatic acinar cell carcinoma. Compared with pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma has a more favourable prognosis. Although radical surgery is recommended for patients with pancreatic acinar cell carcinoma who do not have distant metastases, the recurrence rate is high. The effectiveness of adjuvant therapy for pancreatic acinar cell carcinoma is unclear. The response to FOLFIRINOX is generally favourable, and some patients achieve a complete response. Pancreatic acinar cell carcinoma has a different genomic profile compared with pancreatic ductal adenocarcinoma. Although genomic analyses have shown that pancreatic acinar cell carcinoma rarely has KRAS, TP53 and CDKN2A mutations, it has a higher prevalence of homologous recombination-related genes, including BRCA1/2 and ATM, than pancreatic ductal adenocarcinoma, suggesting high sensitivity to platinum-containing regimens and PARP inhibitors. Targeted therapies for genomic alternations are beneficial. Therefore, genetic testing is important for patients with pancreatic acinar cell carcinoma to choose the optimal therapeutic strategy.
Topics: Male; Child; Humans; Pancreatic Neoplasms; Carcinoma, Acinar Cell; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Carcinoma, Pancreatic Ductal
PubMed: 38109477
DOI: 10.1093/jjco/hyad176 -
Frontiers in Bioscience (Landmark... Mar 2024Pancreatic adenocarcinoma (PDAC) is disease with a 5-year survival of only 12%. Many patients with PDAC present with late-stage disease and even early-stage disease can... (Review)
Review
Pancreatic adenocarcinoma (PDAC) is disease with a 5-year survival of only 12%. Many patients with PDAC present with late-stage disease and even early-stage disease can often be characterized by an aggressive tumor biology. Standard therapy for metastatic PDAC consists mainly of chemotherapy regimens like FOLFIRINOX, FOLFOX, or gemcitabine and nab-paclitaxel. Research has focused on sequencing PDAC tumors to understand better the mutational landscape and transcriptomics of PDAC with the goal to develop targeted therapies. Targeted therapies may potentially minimize the toxic risks of chemotherapy and provide a long-term survival benefit. We herein review the underlying molecular pathogenesis of PDAC, as well as the classification schema created from current sequencing data, and recent updates related to targeted therapy for PDAC.
Topics: Humans; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Adenocarcinoma; Gemcitabine
PubMed: 38538278
DOI: 10.31083/j.fbl2903101 -
Cell Death & Disease Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein...
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC.
Topics: Humans; Carcinoma, Pancreatic Ductal; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Centrosome; Microtubule-Associated Proteins; Mitosis; Pancreatic Neoplasms; Animals; Mice
PubMed: 38012214
DOI: 10.1038/s41419-023-06313-x -
Cell Death & Disease Jul 2023Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic...
Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic activity. Mutations of HPSE2 were identified in patients diagnosed with urofacial syndrome (UFS), a rare genetic disorder that exhibits abnormal facial expression and bladder voiding dysfunction, leading to renal damage and eventually renal failure. In order to reveal the role of HPSE2 in tissue homeostasis, we established a conditional Hpa2-KO mouse. Interestingly, the lack of Hpa2 was associated with a marked decrease in the expression of key pancreatic transcription factors such as PTF1, GATA6, and Mist1. This was associated with a two-fold decrease in pancreas weight, increased pancreatic inflammation, and profound morphological alterations of the pancreas. These include massive accumulation of fat cells, possibly a result of acinar-to-adipocyte transdifferentiation (AAT), as well as acinar-to-ductal metaplasia (ADM), both considered to be pro-tumorigenic. Furthermore, exposing Hpa2-KO but not wild-type mice to a carcinogen (AOM) and pancreatic inflammation (cerulein) resulted in the formation of pancreatic intraepithelial neoplasia (PanIN), lesions that are considered to be precursors of invasive ductal adenocarcinoma of the pancreas (PDAC). These results strongly support the notion that Hpa2 functions as a tumor suppressor. Moreover, Hpa2 is shown here for the first time to play a critical role in the exocrine aspect of the pancreas.
Topics: Mice; Animals; Pancreas; Acinar Cells; Pancreatic Neoplasms; Pancreatitis; Cell Differentiation; Inflammation; Carcinoma, Pancreatic Ductal
PubMed: 37491420
DOI: 10.1038/s41419-023-05990-y -
Cell Reports. Medicine Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, homeobox C6...
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, homeobox C6 (HOXC6), is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mammalian target of rapamycin (mTOR) pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth because of its ability to suppress apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated insulin-like growth factor 1 receptor (IGF1R) signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.
Topics: Mice; Animals; Cell Proliferation; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; TOR Serine-Threonine Kinases; Protein Kinase Inhibitors; Neoplasm Proteins; Mammals
PubMed: 37951219
DOI: 10.1016/j.xcrm.2023.101285 -
Gut Mar 2024Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.
DESIGN
To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.
RESULTS
Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92).
CONCLUSION
A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.
Topics: Humans; CA-19-9 Antigen; Biomarkers, Tumor; Cell-Free Nucleic Acids; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Pancreas; Adenocarcinoma; DNA Methylation
PubMed: 38123998
DOI: 10.1136/gutjnl-2023-331074 -
Cancer Biology & Therapy Dec 2023Despite recent advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year overall survival of only 10%. Since either... (Review)
Review
Despite recent advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year overall survival of only 10%. Since either at or within a few months of diagnosis, most patients with PDAC will present with metastatic disease, a more individualized approach to select patients who may benefit from more aggressive therapy has been suggested. Although studies have reported improved survival in PDAC and isolated pulmonary metastasis (ISP) compared to extrapulmonary metastases, such findings remain controversial. Furthermore, the added benefit of pulmonary metastasectomy and other lung-directed therapies remains unclear. In this review, we discuss the metastatic pattern of PDAC, evaluate the available evidence in the literature for improved survival in PDAC and ISP, evaluate the evidence for the added benefit of pulmonary metastasectomy and other lung-directed therapies, identify prognostic factors for survival, discuss the biological basis for the reported improved survival and identify areas for further research.
Topics: Humans; Retrospective Studies; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Lung Neoplasms; Prognosis
PubMed: 37526431
DOI: 10.1080/15384047.2023.2198479 -
PloS One 2023Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an aggressive growth profile that is often diagnosed at late stage and that has few curative or...
Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an aggressive growth profile that is often diagnosed at late stage and that has few curative or therapeutic options. PDAC growth has been linked to alterations in the pancreas microbiome, which could include the presence of the fungus Malassezia. We used RNA-sequencing to compare 14 matched tumor and normal (tumor adjacent) pancreatic cancer samples and found Malassezia RNA in both the PDAC and normal tissues. Although the presence of Malassezia was not correlated with tumor growth, a set of immune- and inflammatory-related genes were up-regulated in the PDAC compared to the normal samples, suggesting that they are involved in tumor progression. Gene set enrichment analysis suggests that activation of the complement cascade pathway and inflammation could be involved in pro PDAC growth.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Pancreas; RNA; Prognosis; Gene Expression Regulation, Neoplastic
PubMed: 37910468
DOI: 10.1371/journal.pone.0284232 -
Frontiers in Endocrinology 2023Pancreatic signet ring cell carcinoma (PSRCC) is a rare and aggressive cancer that has been reported primarily as case reports. Due to limited large-scale... (Observational Study)
Observational Study
BACKGROUND
Pancreatic signet ring cell carcinoma (PSRCC) is a rare and aggressive cancer that has been reported primarily as case reports. Due to limited large-scale epidemiological and prognostic analyses, the outcomes of PSRCC patients varies greatly in the absence of recognized first-line treatment strategies. This study aimed to compare the clinical features, treatment, and prognosis of PSRCC and pancreatic ductal cell carcinoma (PDAC), the most common subtype of pancreatic cancer, and to establish predictive models for these subtypes.
METHODS
The data on PSRCC and PDAC patients from 1998 to 2018 was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Thereafter, the clinical, demographic, and treatment characteristics of the two groups and the differences and influencing factors of the two groups were evaluated by propensity score matching (PSM), Kaplan-Meier survival curves, Cox risk regression analyses, and least absolute shrinkage and selection operator (LASSO) analysis. Next, prognosis models were constructed and validated by KM and ROC analysis. Finally, a nomogram was constructed, based on the results of these analyses, to predict survival outcomes of PSRCC and PDAC patients.
RESULTS
A total of 84,789 patients (432 PSRCC and 84357 PDAC patients) were included in this study. The results of the study revealed that, compared to the PDAC patients, PSRCC patients were more likely to be male, aged between 58-72 years, have larger tumor masses, and less likely to undergo chemotherapy. Before PSM, the overall survival and cancer-specific survival of the PSRCC group were significantly lower than those PDAC group, but there was no difference in the prognosis of the two groups after PSM. Additionally, lymph node ratio (LNR), log odds of positive lymph node (LODDS), tumor size, age, T-stage, marital status, and summary stage were found to be independent prognostic factors for PSRCC. Lastly, the prediction model and nomogram based on these prognostic factors could accurately predict the survival rate of the patients in SEER datasets and external validation datasets.
CONCLUSION
The prognosis of PSRCC and PDAC patients is similar under the same conditions; however, PSRCC patients may have more difficulty in receiving better treatment, thus resulting in their poor prognosis.
Topics: Humans; Male; Middle Aged; Aged; Female; Prognosis; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Carcinoma, Signet Ring Cell
PubMed: 37534212
DOI: 10.3389/fendo.2023.1205594 -
Cancer Science Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is physically palpated as a hard tumor with an unfavorable prognosis. Assessing physical features and their association with...
Pancreatic ductal adenocarcinoma (PDAC) is physically palpated as a hard tumor with an unfavorable prognosis. Assessing physical features and their association with pathological features could help to elucidate the mechanism of physical abnormalities in cancer tissues. A total of 93 patients who underwent radical surgery for pancreatic and bile duct cancers at a single center hospital during a 28-month period were recruited for this study that aimed to estimate the stiffness of PDAC tissues compared to the other neoplasms and assess relationships between tumor stiffness and pathological features. Physical alterations and pathological features of PDAC, with or without preoperative therapy, were analyzed. The immunological tumor microenvironment was evaluated using multiplexed fluorescent immunohistochemistry. The stiffness of PDAC correlated with the ratio of Azan-Mallory staining, α-smooth muscle actin, and collagen I-positive areas of the tumors. Densities of CD8 T cells and CD204 macrophages were associated with tumor stiffness in cases without preoperative therapy. Pancreatic ductal adenocarcinoma treated with preoperative therapy was softer than that without, and the association between tumor stiffness and immune cell infiltration was not shown after preoperative therapy. We observed the relationship between tumor stiffness and immunological features in human PDAC for the first time. Immune cell densities in the tumor center were smaller in hard tumors than in soft tumors without preoperative therapies. Preoperative therapy could alter physical and immunological aspects, warranting further study. Understanding of the correlations between physical and immunological aspects could lead to the development of new therapies.
Topics: Humans; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Prognosis
PubMed: 37337413
DOI: 10.1111/cas.15853