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

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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Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1722434115 ◽

2018 ◽

Vol 115 (16) ◽

pp. E3769-E3778 ◽

Cited By ~ 37

Author(s):

Carlos A. Orozco ◽

Neus Martinez-Bosch ◽

Pedro E. Guerrero ◽

Judith Vinaixa ◽

Tomás Dalotto-Moreno ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Cancer Progression ◽

Pancreatic Tumor ◽

Therapeutic Potential ◽

Tumor Formation ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Regulatory Pathways

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53−/−) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

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Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives

Cancers ◽

10.3390/cancers11111659 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1659 ◽

Cited By ~ 6

Author(s):

Verena Martini ◽

Sylvia Timme-Bronsert ◽

Stefan Fichtner-Feigl ◽

Jens Hoeppner ◽

Birte Kulemann

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Prognostic Markers ◽

Cancer Prognosis ◽

Detection Methods ◽

Ductal Adenocarcinoma ◽

Detection Tool ◽

The Usa ◽

New Biomarkers

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and Europe; early symptoms and screenings are lacking, and it is usually diagnosed late with a poor prognosis. Circulating tumor cells (CTCs) have been promising new biomarkers in solid tumors. In the last twenty years (1999–2019), 140 articles have contained the key words “Circulating tumor cells, pancreatic cancer, prognosis and diagnosis.” Articles were evaluated for the use of CTCs as prognostic markers and their correlation to survival in pancreatic ductal adenocarcinoma (PDAC). In the final selected 17 articles, the CTC detection rate varied greatly between different enrichment methodologies and ranged from 11% to 92%; the majority of studies used the antigen-dependent CellSearch© system for CTC detection. Fifteen of the reviewed studies showed a correlation between CTC presence and a worse overall survival. The heterogeneity of CTC-detection methods and the lack of uniform results hinder a comparison of the evaluated studies. However, CTCs can be detected in pancreatic cancer and harbor a hope to serve as an early detection tool. Larger studies are needed to corroborate CTCs as valid biomarkers in pancreatic cancer.

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The Immune Microenvironment in Pancreatic Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21197307 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7307 ◽

Cited By ~ 1

Author(s):

Magdalena Huber ◽

Corinna U. Brehm ◽

Thomas M. Gress ◽

Malte Buchholz ◽

Bilal Alashkar Alhamwe ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Immune Cells ◽

Tumor Stroma ◽

Ductal Adenocarcinoma ◽

Cancer Type ◽

Cellular Interactions ◽

Therapeutic Approaches ◽

Immune Microenvironment ◽

Cellular Immune

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care.

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Tumor Cell Thrombin/PAR-1 Signaling Drives Pancreatic Ductal Adenocarcinoma Growth and Dissemination

Blood ◽

10.1182/blood.v126.23.1070.1070 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1070-1070

Author(s):

Matthew J. Flick ◽

Cheryl Rewerts ◽

Carolina Cruz ◽

Joseph S. Palumbo ◽

James P. Luyendyk ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Coagulation System ◽

Ductal Adenocarcinoma ◽

Parental Line ◽

Experimental Metastasis ◽

Primary Tumor Growth ◽

Wild Type

Abstract Pancreatic ductal adenocarcinoma (PDAC) accounts for ~85% of diagnosed pancreatic cancers and is among the most lethal malignancies. The 5-year survival rate for pancreatic cancer patients has improved only marginally in the last 40 years (3% → 7%), with effectively no change in survival profile for patients with metastatic disease (2%). High mortality is linked to the aggressive and invasive nature of the malignancy and poor efficacy of limited treatment options, which collectively highlight the need for novel treatment strategies. Notably, analyses of pancreatic cancer in patients and animal models have demonstrated that PDAC is associated with robust coagulation system activity. Previous work has shown that patient PDAC tumor cells often express high levels of tissue factor (TF) and protease-activated receptor (PAR)-1. To determine the potential contribution of tumor cell derived-TF and PAR-1 to PDAC growth and metastasis, a novel tumor cell line (termed KPC2) was derived from mice in which PDAC tumorigenesis was induced by activation of two established pancreatic cancer alleles, KrasG12D and Trp53R172H. In transplant studies, tumor growth and experimental metastasis were evaluated using KPC2 cells in which TF or PAR-1 expression was suppressed by shRNA knockdown. In addition, the interplay of tumor-derived TF and PAR-1 with host factors in promoting tumor growth and experimental metastasis were evaluated in mice with genetically imposed deficits in coagulation system components. TF knockdown (to ~10% of the parental line) in KPC2 cells resulted in a significant diminution of both primary tumor growth and experimental metastasis. This reduction appeared to be linked to thrombin activity as primary tumor growth and experimental metastasis of parental KPC2 cells were significantly reduced in fIIlow mice (which constitutively express 10% of normal prothrombin) relative to wild-type mice. PAR-1 knockout mice displayed similar KPC2 growth and experimental metastasis to wild-type animals indicating that stromal cell-derived PAR-1 was not significant determinant. In stark contrast, shRNA-mediated knockdown of PAR-1 in KPC2 (to ~10% of the parental line) cells resulted in significantly diminished tumor growth and experimental metastasis. Diminished tumor growth was linked to reduced expression of the macrophage chemokine MCP-1 and the metalloproteinase MMP9 by the tumor cells as well as reduced thrombin-stimulated ERK phosphorylation. Our results suggest that a major mechanism of PDAC growth and dissemination is through TF/thrombin-driven PAR-1 signaling on tumor cells. Disclosures No relevant conflicts of interest to declare.

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Evaluation of cancer invasion markers determining the risk of lymph node metastasis in pancreatic cancer

Experimental and Clinical Gastroenterology ◽

10.31146/1682-8658-ecg-175-3-60-65 ◽

2020 ◽

pp. 60-65

Author(s):

M. V. Zavyalova ◽

S. V. Vtorushin ◽

N. V. Krakhmal ◽

Yu. Yu. Rakina ◽

A. P. Koshel

Keyword(s):

Pancreatic Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Cancer Invasion ◽

Ductal Adenocarcinoma ◽

Morphological Parameters ◽

Integrin Β1 ◽

Node Metastasis ◽

Ductal Pancreatic Adenocarcinoma ◽

Immunohistochemical Studies

The aim of the study was to evaluate the expression features of cancer invasion markers in ductal pancreatic adenocarcinoma and determine their relationship with the frequency of lymph node metastasis.Materials and methods: 84 cases of pancreatic ductal adenocarcinoma were studied with morphological and immunohistochemical studies using antibodies MMP2, Integrin β1 and β3, β-catenin, Twist and Snail, which associated with increased invasive properties of the tumor according to the literature.Results: The study showed the presence of relationships between the expression indicators of the studied markers in different structures of the parenchymal component of the tumor with the frequency of lymph node metastasis in pancreatic cancer.Conclusion: The results of the study show the possibility of using these markers as additional morphological parameters that allow us to assess and predict the risk of lymphogenous dissemination of pancreatic cancer.

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Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Cancers ◽

10.3390/cancers13164173 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4173

Author(s):

Faustino Mollinedo ◽

Consuelo Gajate

Keyword(s):

Pancreatic Cancer ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Cancer Cells ◽

Tumor Cells ◽

Apoptotic Cell ◽

Ether Lipid ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

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The systemic activin response to pancreatic cancer: Implications for effective cancer cachexia therapy

10.1101/343871 ◽

2018 ◽

Author(s):

Xiaoling Zhong ◽

Marianne Pons ◽

Christophe Poirier ◽

Yanlin Jiang ◽

Jianguo Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Weight Loss ◽

Pancreatic Ductal Adenocarcinoma ◽

Conditioned Medium ◽

Tumor Cells ◽

Stromal Cells ◽

Cancer Cachexia ◽

Dominant Negative ◽

Prolonged Survival ◽

Ductal Adenocarcinoma

AbstractPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with high rates of cachexia. Serum activin correlates with PDAC cachexia and mortality, while activin administration causes cachexia in mice. We studied activin in human tumors and in mice with orthotopic or genetic PDAC. Cachexia severity correlated with activin expression in tumor lines. Activins were expressed in both cancer and tumor stromal cells, but also in organs in murine PDAC cachexia. Tumor cells expressed activin-βA, or Inhba, while organs expressed both activin-βA and activin-βB, or Inhbb. PDAC elicits activin expression; PDAC conditioned medium induced activin and atrophy of myotubes. Treatment with the activin trap, ACVR2B/Fc, reduced cachexia and prolonged survival in mice with activin-low tumors, and reduced cachexia in activin-high tumors, without affecting activin expression in organs. Mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not survival. Overall our results indicate that PDAC induces a systemic activin response, leading to cachexia, and that activin targets might include organs beyond muscle. Targeting of both tumor-derived and host-derived activins could improve cachexia therapy.

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Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.655152 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xinglong Geng ◽

Hongze Chen ◽

Liang Zhao ◽

Jisheng Hu ◽

Wenbo Yang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Smooth Muscle Actin ◽

Ductal Adenocarcinoma ◽

Alpha Smooth Muscle Actin ◽

Cancer Proliferation ◽

Paracrine Factors ◽

Targeting Therapy ◽

Desmoplastic Reaction ◽

Negative Results

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA)high interleukin-6 (IL-6)low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMAlow IL-6high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.

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Novel 3D µtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics

Cancers ◽

10.3390/cancers13195006 ◽

2021 ◽

Vol 13 (19) ◽

pp. 5006

Author(s):

Kunal P. Pednekar ◽

Marcel A. Heinrich ◽

Joop van Baarlen ◽

Jai Prakash

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Treatment Options ◽

Treatment Strategies ◽

Collagen Gel ◽

Current Treatment ◽

Ductal Adenocarcinoma ◽

Tumor Type ◽

Cellular Interactions

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future.

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Clinical significance of circulating tumor cells identified by cell-surface vimentin in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14562 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14562-e14562

Author(s):

Tao Wei ◽

Qi Zhang ◽

Tingbo Liang ◽

Xueli Bai

Keyword(s):

Pancreatic Cancer ◽

Cell Surface ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Clinical Significance ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Epithelial Tumor ◽

Mesenchymal Phenotype

e14562 Background: Identification of circulating tumor cells (CTCs) largely rely on epithelial tumor cell marker. Here we sought to interrogate whether cell-surface vimentin could be a biomarker for isolating CTCs potentially with mesenchymal phenotype in pancreatic ductal adenocarcinoma (PDAC). Methods: In total, 100 PDAC patients, 16 patients with intraductal papillary mucinous neoplasm (IPMN), and 30 healthy individuals were enrolled between December 2016 and November 2017. Potential CTCs were captured in 4 ml blood samples by vimentin antibody-coated microfluidic chip. CTCs were defined as vimentin+CD45-Hoechst+. Results: In vitro experiment showed that vimentin was highly expressed on the surface of pancreatic tumor cells with mesenchymal phenotype. Overall, vimentin+ CTCs were detected in 76% of patients with PDAC, but only in 2 out 30 healthy donors. Besides, five patients (31.3%) with IPMN had vimentin+ CTCs, and 10 CTCs were identified in one case. Using a cut-off value of two cells/4 ml of blood, 65% PDAC patients were positive for vimentin+ CTCs , while the positivity rates for the patients with IPMN and the healthy controls were 25% and 0%, respectively. Combined vimentin+ CTCs and CA19-9 offered a favorable diagnostic potency with area under curve of 0.968. Vimentin+ CTCs counts correlated with change of tumor burden for patients undergoing resection ( P < 0.01). Significant reduction of CTCs counts was observed after chemotherapy for subjects responding to treatment ( P < 0.05). The paired analysis showed that CTC counts was higher in portal vein blood than peripheral blood for 10 patients with available samples ( P < 0.05). Patients with 2 or more CTCs detected had more advanced disease and poorer differentiated tumor. In addition, preoperative higher CTCs counts correlated with shortened recurrence-free survival (Log-rank test: P = 0.02). Conclusions: Vimentin+ CTCs serves as a reliable biomarker in pancreatic cancer. The enrichment of potential mesenchymal CTCs could complement the strategy capturing epithelial CTCs, and provides a way to more thoroughly interrogate the biology and clinical significance of CTCs in PDAC.

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