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

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22083953 ◽

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.

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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 ◽

10.3390/molecules26226932 ◽

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.

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

Molecular Biology of the Cell ◽

10.1091/mbc.e16-06-0427 ◽

2016 ◽

Vol 27 (22) ◽

pp. 3659-3672 ◽

Cited By ~ 13

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.

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Oxaliplatin-Induced Peripheral Neuropathy Can Be Minimized By Pressurized Regional Intravascular Delivery In An Orthotopic Murine Pancreatic Cancer Model.

10.21203/rs.3.rs-1226505/v1 ◽

2022 ◽

Author(s):

Jayanth Surya Narayanan Shankara Narayanan ◽

Katie Frizzi ◽

Suna Erdem ◽

Partha Ray ◽

David Jaroch ◽

...

Keyword(s):

Pancreatic Cancer ◽

Peripheral Neuropathy ◽

Tumor Burden ◽

Cytotoxic Agents ◽

Ductal Adenocarcinoma ◽

Tumor Control ◽

Cancer Model ◽

Functional Assays ◽

Venous Infusion ◽

Regional Delivery

Abstract Purpose: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice.Methods: We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays.Results: Tumor weights in mice treated with 2 mg/Kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/Kg systemic dose required to achieve similar tumor control.Conclusion: Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.

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

Cells ◽

10.3390/cells9071572 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1572 ◽

Cited By ~ 1

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.

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Chylous Ascites, Unusual Association with Ductal Pancreatic Adenocarcinoma with Plasmacytoid Morphology: A Case Report and Literature Review

The Surgery Journal ◽

10.1055/s-0041-1728651 ◽

2021 ◽

Vol 07 (03) ◽

pp. e158-e162

Author(s):

Catalin Bogdan Satala ◽

Ioan Jung ◽

Tivadar Jr. Bara ◽

Vlad Tudorache ◽

Simona Gurzu

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Surgical Intervention ◽

Chylous Ascites ◽

Distal Portion ◽

Ductal Adenocarcinoma ◽

Lymph Vessels ◽

Lymphangiosis Carcinomatosa ◽

Ductal Pancreatic Adenocarcinoma ◽

Tumor Emboli

AbstractChylous ascites represents a relatively uncommon condition. In this paper, we present a case of chyloperitoneum associated with pancreatic ductal adenocarcinoma (PDAC) and a review of literature regarding chylous ascites. A 76-year-old male patient was admitted in emergency department with acute abdomen. A pancreatic cancer was suspected. Subtotal spleno-pancreatectomy, for a nodular mass infiltrating the mild and distal portion of the pancreas, was necessary. During surgical intervention in the peritoneal cavity, a moderate quantity of whitish and thick consistency fluid with milk-like appearance was observed to be accumulated. After examination of the fluid, chyloperitoneum was diagnosed. The histologic examination showed a PDAC, with multiple emboli in lymph vessels, with tumor cells with plasmacytoid morphology, diagnosed as lymphangiosis carcinomatosa. The patient died at 3 weeks after surgical intervention. In patients with pancreatic cancer and chylous ascites, suspicion of tumor-related blockage of the lymphatic flow should be suspected. Prognosis of PDAC should be evaluated not only based on the number of lymph node metastases, but also considering the number of lymph vessels with tumor emboli and the architecture of tumor cells. This is the first reported case of a PDAC with plasmacytoid morphology of lymphangiosis carcinomatosa.

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A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

Journal of Nanotheranostics ◽

10.3390/jnt2020006 ◽

2021 ◽

Vol 2 (2) ◽

pp. 82-93

Author(s):

Luca Digiacomo ◽

Francesca Giulimondi ◽

Daniela Pozzi ◽

Alessandro Coppola ◽

Vincenzo La Vaccara ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Protein Corona ◽

Detection Sensitivity ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Ca 19.9 ◽

Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

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Exercise efficacy and prescription during treatment for pancreatic ductal adenocarcinoma: a systematic review

BMC Cancer ◽

10.1186/s12885-020-07733-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dominic O’Connor ◽

Malcolm Brown ◽

Martin Eatock ◽

Richard C. Turkington ◽

Gillian Prue

Keyword(s):

Quality Of Life ◽

Systematic Review ◽

Pancreatic Cancer ◽

Adjuvant Therapy ◽

Physical Function ◽

Meta Analysis ◽

Ductal Adenocarcinoma ◽

Key Stakeholders ◽

The Impact

Abstract Background Surgical resection remains the only curative treatment for pancreatic cancer and is associated with significant post-operative morbidity and mortality. Patients eligible for surgery, increasingly receive neo-adjuvant therapy before surgery or adjuvant therapy afterward, inherently exposing them to toxicity. As such, optimizing physical function through exercise during treatment remains imperative to optimize quality of life either before surgery or during rehabilitation. However, current exercise efficacy and prescription in pancreatic cancer is unknown. Therefore, this study aims to summarise the published literature on exercise studies conducted in patients with pancreatic cancer undergoing treatment with a focus on determining the current prescription and progression patterns being used in this population. Methods A systematic review of four databases identified studies evaluating the effects of exercise on aerobic fitness, muscle strength, physical function, body composition, fatigue and quality of life in participants with pancreatic cancer undergoing treatment, published up to 24 July 2020. Two reviewers independently reviewed and appraised the methodological quality of each study. Results Twelve studies with a total of 300 participants were included. Heterogeneity of the literature prevented meta-analysis. Exercise was associated with improvements in outcomes; however, study quality was variable with the majority of studies receiving a weak rating. Conclusions High quality evidence regarding the efficacy and prescription of exercise in pancreatic cancer is lacking. Well-designed trials, which have received feedback and input from key stakeholders prior to implementation, are required to examine the impact of exercise in pancreatic cancer on key cancer related health outcomes.

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Ca2+ Signaling and Its Potential Targeting in Pancreatic Ductal Carcinoma

Cancers ◽

10.3390/cancers13123085 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3085

Author(s):

Louay Bettaieb ◽

Maxime Brulé ◽

Axel Chomy ◽

Mel Diedro ◽

Malory Fruit ◽

...

Keyword(s):

Pancreatic Cancer ◽

Exocrine Pancreas ◽

Ductal Carcinoma ◽

Ductal Adenocarcinoma ◽

Molecular Devices ◽

Pancreatic Ductal Carcinoma ◽

Aberrant Expression ◽

Common Cause ◽

Cancer Hallmarks ◽

Cancer Mutations

Pancreatic cancer (PC) is a major cause of cancer-associated mortality in Western countries (and estimated to be the second cause of cancer deaths by 2030). The main form of PC is pancreatic adenocarcinoma, which is the fourth most common cause of cancer-related death, and this situation has remained virtually unchanged for several decades. Pancreatic ductal adenocarcinoma (PDAC) is inherently linked to the unique physiology and microenvironment of the exocrine pancreas, such as pH, mechanical stress, and hypoxia. Of them, calcium (Ca2+) signals, being pivotal molecular devices in sensing and integrating signals from the microenvironment, are emerging to be particularly relevant in cancer. Mutations or aberrant expression of key proteins that control Ca2+ levels can cause deregulation of Ca2+-dependent effectors that control signaling pathways determining the cells’ behavior in a way that promotes pathophysiological cancer hallmarks, such as enhanced proliferation, survival and invasion. So far, it is essentially unknown how the cancer-associated Ca2+ signaling is regulated within the characteristic landscape of PDAC. This work provides a complete overview of the Ca2+ signaling and its main players in PDAC. Special consideration is given to the Ca2+ signaling as a potential target in PDAC treatment and its role in drug resistance.

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Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival

Cancers ◽

10.3390/cancers13071612 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1612

Author(s):

Julie Earl ◽

Emma Barreto ◽

María E. Castillo ◽

Raquel Fuentes ◽

Mercedes Rodríguez-Garrote ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Somatic Mutation ◽

Disease Status ◽

Clinical Analysis ◽

Cytotoxic Agents ◽

Disease Stage ◽

Ductal Adenocarcinoma ◽

Familial Pancreatic Cancer ◽

Circulating Free Dna

Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10–15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.

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