scholarly journals Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer

2021 ◽  
Vol 22 (8) ◽  
pp. 3953
Author(s):  
Tomas Koltai ◽  
Stephan Joel Reshkin ◽  
Tiago M. A. Carvalho ◽  
Rosa A. Cardone
Keyword(s):  
Pancreatic Cancer ◽  
Malignant Tumors ◽  
Low Cost ◽  
Surface Protein ◽  
Metastatic Potential ◽  
Ductal Adenocarcinoma ◽  
Over Expression ◽  
Average Survival ◽  
Repurposed Drugs ◽  
Hyaluronan Binding

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell’s proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.

scholarly journals HNF-1a promotes pancreatic cancer growth and apoptosis resistance via its target gene PKLR

2020 ◽  
Vol 52 (3) ◽  
pp. 241-250
Author(s):  
Zhiyao Fan ◽  
Kun Fan ◽  
Shengming Deng ◽  
Yitao Gong ◽  
Yunzhen Qian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Target Gene ◽  
Malignant Tumors ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Cancer Tissue ◽  
Apoptosis Resistance ◽  
Specific Expression ◽  
Pancreatic Cancer Cells

Abstract Pancreatic ductal adenocarcinoma is one of the deadliest malignant tumors, and many genes play important roles in its development. The hepatocyte nuclear factor-1a (HNF-1a) gene encodes HNF-1a, which is a transcriptional activator. HNF-1a regulates the tissue-specific expression of multiple genes, especially in pancreatic islet cells and in the liver. However, the role of the HNF-1a gene in the development of pancreatic cancer is still unclear. Here, we used immunohistochemical staining and real-time PCR to analyze HNF-1a expression in pancreatic cancer tissue. Stable cell lines with HNF-1a knockdown or overexpression were established to analyze the role of HNF-1a in pancreatic cancer cell proliferation and apoptosis by colony formation assay and flow cytometry. We also analyzed the L-type pyruvate kinase (PKLR) promoter sequence to identify the regulatory effect of HNF-1a on PKLR transcription and confirmed the HNF-1a binding site in the PKLR promoter via a chromatin immunoprecipitation assay. HNF-1a was found to be overexpressed in pancreatic cancer and promoted proliferation while inhibiting apoptosis in pancreatic cancer cells. PKLR was identified as the downstream target gene of HNF-1a and binding of HNF-1a at two sites in PKLR (−1931/−1926 and −966/−961) regulated PKLR transcription. In conclusion, HNF-1a is overexpressed in pancreatic cancer, and the transcription factor HNF-1a can promote pancreatic cancer growth and apoptosis resistance via its target gene PKLR.

scholarly journals Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Lidong Cao ◽  
Jiacheng Wu ◽  
Xianzhi Qu ◽  
Jiyao Sheng ◽  
Mengying Cui ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Biochemical Parameters ◽  
Malignant Tumors ◽  
Aerobic Glycolysis ◽  
Clinical Applications ◽  
Common Type ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Biomarkers

AbstractPancreatic cancer is one of the most malignant tumors worldwide, and pancreatic ductal adenocarcinoma is the most common type. In pancreatic cancer, glycolysis is the primary way energy is produced to maintain the proliferation, invasion, migration, and metastasis of cancer cells, even under normoxia. However, the potential molecular mechanism is still unknown. From this perspective, this review mainly aimed to summarize the current reasonable interpretation of aerobic glycolysis in pancreatic cancer and some of the newest methods for the detection and treatment of pancreatic cancer. More specifically, we reported some biochemical parameters, such as newly developed enzymes and transporters, and further explored their potential as diagnostic biomarkers and therapeutic targets.

scholarly journals Morbidity and mortality of pancreatic tumors undergoing surgical treatment

2014 ◽  
Vol 27 (4) ◽  
pp. 275-279 ◽  
Author(s):  
Luiza Bueno ZENI ◽  
Ricardo Fantazzini RUSSI ◽  
Alexandre Faleiro FIALHO ◽  
Ana Luiza Pagani FONSECA ◽  
Lyara Schaefer SOMBRIO ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Surgical Treatment ◽  
Postoperative Complications ◽  
Medical Records ◽  
Malignant Tumors ◽  
Surgical Techniques ◽  
Pancreatic Head ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Early Postoperative Complications

BACKGROUND: Pancreatic cancer has a high mortality rate due to late diagnosis and aggressive behavior. The prognosis is poor, with 5-year survival occurring in less than 5% of cases. AIM: To analyze demographic characteristics, comorbidities, type of procedure and early postoperative complications of patients with pancreatic cancer submitted to surgical treatment. METHODS: Cross-sectional study with analysis of 28 medical records of patients with malignant tumors of the pancreas in a 62 month. Data collection was performed from the medical records of the hospital. RESULTS: Of the total, 53,6% were male and the mean age was 60.25 years. According to the procedure, 53,6% was submitted to duodenopancreactectomy the remainder to biliodigestive derivation or distal pancreatectomy. The ductal adenocarcinoma occurred in 82,1% and 92,9% of tumors were located in the pancreatic head. Early postoperative complications occurred in 64,3% of cases and the most prevalent was intra-abdominal abscess (32,1%). Among duodenopancreactectomies 77,8% had early postoperative complications. CONCLUSION: Its necessary to encourage early detection of tumors of the pancreas to raise the number operations with curative intent. Refinements in surgical techniques and surgical teams can diminish postoperative complications and, so, operative morbimortality can also decrease over time.

scholarly journals Alterations in Glucose Metabolism Due to Decreased Expression of Heterogeneous Nuclear Ribonucleoprotein M in Pancreatic Ductal Adenocarcinoma

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 57
Author(s):  
Jun-ichi Takino ◽  
Takuma Sato ◽  
Isamu Hiraishi ◽  
Kentaro Nagamine ◽  
Takamitsu Hori
Keyword(s):  
Pancreatic Cancer ◽  
Glucose Metabolism ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Malignant Tumors ◽  
Glucose Consumption ◽  
Ductal Adenocarcinoma ◽  
Detailed Mechanism ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Low Glucose ◽  
Nuclear Ribonucleoprotein

The prognosis of pancreatic cancer is considerably worse than that of other cancers, as early detection of pancreatic cancer is difficult and due to its hypovascular environment, which involves low blood flow and a low supply of oxygen and nutrients. Moreover, pancreatic cancer demonstrates a mechanism that allows it to survive in a hypovascular environment. However, the detailed mechanism remains elusive. Recently, it has been reported that heterogeneous ribonuclear protein M (HNRNPM) is a splicing factor associated with malignant tumors. Thus, in this study, we investigated the expression and effects of HNRNPM in pancreatic ductal adenocarcinoma (PDA). We observed that HNRNPM expression, which is highly expressed in pancreatic tissues, was reduced in PDA tissues. Additionally, knockdown of HNRNPM under low-glucose conditions that mimic a hypovascular environment was shown to alter glucose metabolism and prolong cell survival by suppressing glucose consumption. These results suggest that the decreased expression of HNRNPM in PDA may be involved in its adaptation to a hypovascular environment.

scholarly journals Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yiu Huen Tsang ◽  
Yumeng Wang ◽  
Kathleen Kong ◽  
Caitlin Grzeskowiak ◽  
Oksana Zagorodna ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Malignant Tumors ◽  
Nutrient Deficiency ◽  
Ductal Adenocarcinoma ◽  
Mechanistic Insight ◽  
Cancer Initiation ◽  
Cancer Immunotherapeutic ◽  
Insight Into

The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Here we show that a number of cancer-associated MAGEA mutants that undergo proteasome-dependent degradation in vitro could negatively impact their utility as immunotherapeutic targets. Importantly, in pancreatic ductal adenocarcinoma cell models, MAGEA6 suppresses macroautophagy (autophagy). The inhibition of autophagy is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations. Using xenograft mouse models, we demonstrated that inhibition of autophagy is critical for tumor initiation whereas reinstitution of autophagy as a consequence of MAGEA6 degradation contributes to tumor progression. These findings could inform cancer immunotherapeutic strategies for targeting MAGEA antigens and provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression.

scholarly journals Scalp Metastasis as the First Presentation of an Underlying Aggressive Pancreatic Cancer

2020 ◽  
Vol 8 ◽  
pp. 232470962093166
Author(s):  
Preethi Ramachandran ◽  
Lakshmi Boyapati ◽  
Gardith Joseph
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Potential ◽  
Cutaneous Metastasis ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Umbilical Metastasis ◽  
Aggressive Cancer ◽  
Scalp Metastasis ◽  
Scalp Lesion ◽  
Subcutaneous Tissues

Pancreatic ductal adenocarcinoma, an extremely aggressive cancer, has high metastatic potential. Cutaneous metastasis is very uncommon, representing only <10% of all cases, presenting mostly around the umbilical region. Non-umbilical metastasis is even rarer, and the significance remains unknown. In this article, we describe a case of a 76-year-old gentleman who initially presented with an asymptomatic scalp lesion, which on biopsy revealed metastatic adenocarcinoma of pancreatic origin. Detailed workup revealed extremely high tumor burden with metastases involving muscles, subcutaneous tissues, bone, lung, spleen, liver, and colon. Cutaneous involvement in pancreatic cancer represents poor survival with widespread dissemination of the disease. The involvement of some sites and not others and the extreme degree of aggressiveness might reflect subgroups of this cancer with different molecular biology. Identifying these groups may have utility in determining prognosis and stratifying treatment for patients. This will hopefully translate into better diagnostic tests and therapies in the near future.

scholarly journals 5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT, and ERK Activity

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6932
Author(s):  
Wan-Chi Tsai ◽  
Wen-Hung Wang ◽  
Bo-Cian Huang ◽  
Chiung-Yao Huang ◽  
Jyh-Horng Sheu
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Metastatic Potential ◽  
Ductal Adenocarcinoma ◽  
M Cell ◽  
Cytotoxic Effects ◽  
Pancreatic Cancer Cells ◽  
Erk Phosphorylation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been demonstrated to possess cytotoxic activity against cancer cells. However, the cytotoxicity against pancreatic cancer cells and the related mechanisms are unknown. The aim of this study was to evaluate the anti-pancreatic cancer potential of 5-epi-sinuleptolide and to elucidate the underlying mechanisms. The inhibitory effects of 5-epi-sinuleptolide treatment on the proliferation of pancreatic cancer cells were determined and the results showed that 5-epi-sinuleptolide treatment inhibited cell proliferation, induced apoptosis and G2/M cell cycle arrest, and suppressed the invasion of pancreatic cancer cells. The results of western blotting further revealed that 5-epi-sinuleptolide could inhibit JAK2/STAT3, AKT, and ERK phosphorylation, which may account for the diverse cytotoxic effects of 5-epi-sinuleptolide. Taken together, our present investigation unveils a new therapeutic and anti-metastatic potential of 5-epi-sinuleptolide for pancreatic cancer treatment.

scholarly journals Molecular signatures of mu opioid receptor and somatostatin receptor 2 in pancreatic cancer

2016 ◽  
Vol 27 (22) ◽  
pp. 3659-3672 ◽  
Author(s):  
Raphael Jorand ◽  
Sunetra Biswas ◽  
Devin L. Wakefield ◽  
Steven J. Tobin ◽  
Ottavia Golfetto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Opioid Receptor ◽  
Somatostatin Receptor ◽  
Metastatic Potential ◽  
Mu Opioid Receptor ◽  
Ductal Adenocarcinoma ◽  
Mu Opioid ◽  
Pancreatic Cancer Cells ◽  
Epithelial Marker

Pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy, has been linked to atypical levels, certain mutations, and aberrant signaling of G-protein–coupled receptors (GPCRs). GPCRs have been challenging to target in cancer because they organize into complex networks in tumor cells. To dissect such networks with nanometer-scale precision, here we combine traditional biochemical approaches with superresolution microscopy methods. A novel interaction specific to PDAC is identified between mu opioid receptor (MOR) and somatostatin receptor 2 (SSTR2). Although MOR and SSTR2 did not colocalize in healthy pancreatic cells or matching healthy patient tissues, the pair did significantly colocalize in pancreatic cancer cells, multicellular tumor spheroids, and cancerous patient tissues. Moreover, this association in pancreatic cancer cells correlated with functional cross-talk and increased metastatic potential of cells. Coactivation of MOR and SSTR2 in PDAC cells led to increased expression of mesenchymal markers and decreased expression of an epithelial marker. Together these results suggest that the MOR-SSTR2 heteromer may constitute a novel therapeutic target for PDAC.

scholarly journals Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1572 ◽  
Author(s):  
Giulia Ambrosini ◽  
Elisa Dalla Pozza ◽  
Giuseppina Fanelli ◽  
Claudia Di Carlo ◽  
Andrea Vettori ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Potential ◽  
Ductal Adenocarcinoma ◽  
Live Cells ◽  
Quiescent State ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients.

Rare localization of renal cell carcinoma metastases in the paranasal sinuses and breast: a case report

2019 ◽  
Vol 22 (6) ◽  
pp. 13-22
Author(s):  
E. V. Kryaneva ◽  
N. A. Rubtsova ◽  
A. V. Levshakova ◽  
A. I. Khalimon ◽  
A. V. Leontyev ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Paranasal Sinuses ◽  
Renal Cell ◽  
Clinical Case ◽  
Clear Cell ◽  
Malignant Tumors ◽  
Metastatic Potential ◽  
Cell Renal Cell Carcinoma ◽  
Metastatic Lesions

This article presents a clinical case demonsratinga high metastatic potential of clear cell renal cell carcinoma combined with atypical metastases to breast and paranasal sinuses. The prevalence of metastatic lesions to the breast and paranasal sinuses in various malignant tumors depending on their morphological forms is analyzed. The authors present an analysis of data published for the last 30 years. The optimal diagnostic algorithms to detect the progression of renal cell carcinoma and to evaluate the effectiveness of the treatment are considered.

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