Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive form of cancer with a low survival rate. A successful treatment strategy should not be limited to targeting cancer cells alone, but should adopt a more comprehensive approach, taking into account other influential factors. These include the extracellular matrix (ECM) and immune microenvironment, both of which are integral components of the tumor microenvironment. The present review describes the roles of pancreatic stellate cells, differentiated cancer‑associated fibroblasts and the interleukin family, either independently or in combination, in the progression of precursor lesions in pancreatic intraepithelial neoplasia and PDAC. These elements contribute to ECM deposition and immunosuppression in PDAC. Therapeutic strategies that integrate interleukin and/or stromal blockade for PDAC immunomodulation and fibrogenesis have yielded inconsistent results. A deeper comprehension of the intricate interplay between fibrosis, and immune responses could pave the way for more effective treatment targets, by elucidating the mechanisms and causes of ECM fibrosis during PDAC progression.

Pancreatic surveillance can detect early-stage pancreatic cancer and achieve long-term survival, but currently involves annual endoscopic ultrasound and MRI/MRCP, and is recommended only for individuals who meet familial/genetic risk criteria. To improve upon current approaches to pancreatic cancer early detection and to expand access, more accurate, inexpensive, and safe biomarkers are needed, but finding them has remained elusive. Newer approaches to early detection, such as using gene tests to personalize biomarker interpretation, and the increasing application of artificial intelligence approaches to integrate complex biomarker data, offer promise that clinically useful biomarkers for early pancreatic cancer detection are on the horizon.

Synchronous primary neoplasms of Meckel\'s diverticulum and colon malignancies are rarely reported in the literature. We present three patients with synchronous primary neoplasms of Meckel\'s diverticulum and colon malignancies. All tumors located in Meckel\'s diverticulum were incidentally found at laparotomy and the definitive diagnosis was made with microscopic examination of surgical specimens. Synchronous primary neoplasms of Meckel\'s diverticulum and colon malignancies are rarely encountered. Moreover, this is the first case of synchronous colon cancer and pancreatic intraepithelial neoplasia (PanIN) arising from pancreatic heterotopia within Meckel\'s diverticulum. The diagnosis of Meckel\'s diverticulum should be kept in mind in patients who underwent laparotomy for any reason; when found incidentally at laparotomy, it should be carefully examined for any suspicious abnormality and surgery should be considered that it can be performed without any problems.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression.

Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of Klf5 and the activation of KrasG12D mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and KrasG12D mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with Klf5 loss (with or without KrasG12D) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of Klf5 reduced the expression level of cytokines and fibrotic components such as Il1b, Il6, Tnf, Tgfb1, Timp1, and Mmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of Il1b, Il6, and Tgfb1 genes. In summary, the inactivation of Klf5 inhibits ADM and PanIN formation and the development of pancreatic fibrosis.

Metaplasia, dysplasia, and cancer arise from normal epithelia via a plastic cellular transformation, typically in the setting of chronic inflammation. Such transformations are the focus of numerous studies that strive to identify the changes in RNA/Protein expression that drive such plasticity along with the contributions from the mesenchyme and immune cells. However, despite being widely utilized clinically as biomarkers for such transitions, the role of glycosylation epitopes is understudied in this context. Here, we explore 3\'-Sulfo-Lewis A/C, a clinically validated biomarker for high-risk metaplasia and cancer throughout the gastrointestinal foregut: esophagus, stomach, and pancreas. We discuss the clinical correlation of sulfomucin expression with metaplastic and oncogenic transformation, as well as its synthesis, intracellular and extracellular receptors and suggest potential roles for 3\'-Sulfo-Lewis A/C in contributing to and maintaining these malignant cellular transformations.

UNASSIGNED: Although pancreatic cancer (PC) has an extremely poor prognosis, the 5-year survival rate of patients with pancreatic high-grade precancerous lesion without invasive carcinoma (PHP) is favorable. PHP diagnosis and identification of patients requiring intervention are needed. We aimed to validate a modified PC detection scoring system regarding its detection ability for PHP and PC in the general population.
UNASSIGNED: We modified an existing PC detection scoring system that incorporates low-grade risk (LGR) factors (family history, presence of diabetes mellitus [DM] or worsening DM, heavy drinking, smoking, stomach symptoms, weight loss, and pancreatic enzyme) and high-grade risk (HGR) factors (new-onset DM, familial PC, jaundice, tumor biomarkers, chronic pancreatitis, intraductal papillary mucinous neoplasm, cysts, hereditary PC syndrome, and hereditary pancreatitis). Each factor was scored as one point; LGR score ≥3 points and/or HGR score ≥1 point (positive scores) were indicative of PC. The newly modified scoring system incorporated main pancreatic duct dilation as an HGR factor. The PHP diagnosis rate using this scoring system combined with EUS was prospectively analyzed.
UNASSIGNED: Among 544 patients with positive scores, 10 had PHP. The diagnosis rates were 1.8% for PHP and 4.2% for invasive PC. Although the number of LGR and HGR factors tended to increase with PC progression, none of the individual factors were significantly different between patients with PHP and those without lesions.
UNASSIGNED: The newly modified scoring system evaluating multiple factors associated with PC could potentially identify patients with higher risk of PHP or PC.

Pancreatic cancer is among the leading causes of cancer death in the United States of America. Early detection and intervention are critical as a large majority of patients have either local or distant metastatic disease at the time of diagnosis. However, groove pancreatitis, a rare form of chronic pancreatitis, presents as a challenge for adequate and efficient differential diagnosis of pancreatic cancer as a result of similar clinical symptoms and imaging features. Furthermore, intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasia are 2 of the precursor lesions that have been identified with pancreatic ductal adenocarcinoma. Intraductal papillary mucinous neoplasms are cystic tumors of the pancreas characterized by excessive mucin production in either the main pancreatic duct or its branches. Conversely, pancreatic intraepithelial neoplasia are microscopic lesions in the smaller pancreatic ducts. In this article, we report the case of a 46-year-old male with a diagnosis of groove pancreatitis, main duct intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia whose tumor was excised by means of a Whipple procedure. We focus on optimizing diagnosis and treatment through the application of radiological modalities.

UNASSIGNED: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has no effective early detection method or treatment to date.
UNASSIGNED: The normal cell type that initiates PDAC, or its cellular origin, is still unknown. To investigate the contribution of distinct normal epithelial cell types to PDAC tumorigenesis, genetically engineered mouse models were used to show that both acinar and ductal cells are capable of giving rise to PDAC. These studies indicated that genetic mutations and pancreatic injury interact differently with each cellular origin to affect their predilection and process for forming PDAC. In this review, we summarize recent findings using various genetically engineered mouse models in the identification and characterization of the PDAC cell of origin. We also discuss potential implications for cellular origin on tumor development, PDAC transcriptional subtype, and disease prognosis of patients.
UNASSIGNED: Although it is clear that both ductal and acinar cells have the potential to form PDAC, whether cellular origin can indeed influence patient prognosis and whether knowledge of cellular origin will aid in the diagnosis or treatment of patients in the future will need further study.

Activated pancreatic stellate cells (PSCs) are the main cells involved in chronic pancreatitis and pancreatic intraepithelial neoplasia lesion (PanIN). Fine-tuning the precise molecular targets in PSC activation might help the development of PSC-specific therapeutic strategies to tackle progression of pancreatic cancer-related fibrosis. miR-301a is a pro-inflammatory microRNA known to be activated by multiple inflammatory factors in the tumor stroma. Here, we show that miR-301a is highly expressed in activated PSCs in mice, sustained tissue fibrosis in caerulein-induced chronic pancreatitis, and accelerated PanIN formation. Genetic ablation of miR-301a reduced pancreatic fibrosis in mouse models with chronic pancreatitis and PanIN. Cell proliferation and activation of PSCs was inhibited by downregulation of miR-301a via two of its targets, Tsc1 and Gadd45g. Moreover, aberrant PSC expression of miR-301a and Gadd45g restricted the interplay between PSCs and pancreatic cancer cells in tumorigenesis. Our findings suggest that miR-301a activates two major cell proliferation pathways, Tsc1/mTOR and Gadd45g/Stat3, in vivo, to facilitate development of inflammatory-induced PanIN and maintenance of PSC activation and desmoplasia in pancreatic cancer.