The lymphatic system and pancreatic cancer

Fink, Darci M.; Steele, Maria M.; Hollingsworth, Michael A.

doi:10.1016/j.canlet.2015.11.048

Cited by 52 publications

(41 citation statements)

References 385 publications

(440 reference statements)

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“…Increased lymphangiogenesis in pancreatic tumors or their draining nodes is generally believed to relate directly to the extent of lymphatic involvement [52, 53]. However, some studies suggest that intratumoral lymphatic vessel density (LVD) is not associated with lymphatic invasion or metastasis [11, 54].…”

Section: Discussionmentioning

confidence: 99%

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

et al. 2016

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Pancreatic ductal adenocarcinomas (PDAC) are aggressive with frequent lymphatic spread. By analysis of data from The Cancer Genome Atlas, we determined that ∼35% of PDACs have a pro-angiogenic gene signature. We now show that the same PDACs exhibit increased expression of lymphangiogenic genes and lymphatic endothelial cell (LEC) markers, and that LEC abundance in human PDACs correlates with endothelial cell microvessel density. Lymphangiogenic genes and LECs are also elevated in murine PDACs arising in the KRC (mutated Kras; deleted RB) and KIC (mutated Kras; deleted INK4a) genetic models. Moreover, pancreatic cancer cells (PCCs) derived from KRC tumors express and secrete high levels of lymphangiogenic factors, including the EGF receptor ligand, amphiregulin. Importantly, TGF-β1 increases lymphangiogenic genes and amphiregulin expression in KRC PCCs but not in murine PCCs that lack SMAD4, and combinatorial targeting of the TGF-β type I receptor (TβRI) with LY2157299 and EGFR/HER2 with lapatanib suppresses tumor growth and metastasis in a syngeneic orthotopic model, and attenuates tumor lymphangiogenesis and angiogenesis while reducing lymphangiogenic genes and amphiregulin and enhancing apoptosis. Therefore, this combination could be beneficial in PDACs with lymphangiogenic or angiogenic gene signatures.

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Section: Discussionmentioning

confidence: 99%

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

et al. 2016

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“…Thus, accurate knowledge of the CC and TD anatomies is needed. Furthermore, the prognostic importance of lymph-node status in patients with digestive cancers (Fink et al 2016) and the high rate of regional lymph-node recurrence after cancer resection, even after extended lymphadenectomy (Riediger et al 2009), have created an interest in anatomical knowledge of the abdominal lymphatic circulation (Borghi et al 1998;Samra et al 2008).…”

Section: Discussionmentioning

confidence: 99%

A radio‐anatomical correlation study of the cisterna chyli

et al. 2018

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Surgical laparoscopic procedures in the retroperitoneal and supramesocolic spaces are increasingly frequent. There is a high risk of iatrogenic intraoperative injury of the retroperitoneal lymphatic structures during these procedures. A precise understanding of the anatomy of the thoracic duct (TD) and the cisterna chyli (CC) is essential for safe surgical procedures in this area. However, routine imaging procedures rarely and often incorrectly visualize the CC. The objective of this study was to evaluate the feasibility of a retrograde injection of the TD to fill the CC with a contrast agent in 16 human cadavers. Both magnetic resonance lymphography (MRI) and computed tomography (CT) studies could be performed on the same anatomical specimen, using a contrast medium which hardened, allowing gross dissection. MRI and CT detectability were evaluated, and imaging results were compared with the anatomical dissection. The CC of 12/16 cadavers were successfully injected, and four were unsuccessful due to technical difficulties, showing the effectiveness of the method. This technique can improve understanding of the anatomy of the TD and CC and provides an original option to study the complex anatomy of these structures by correlating precise cadaveric dissections with cross-sectional imaging.

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“…Peritumoral LNS are often observed in patients with PDAC. Some reported a correlation with improved outcome and others a correlation with a worse outcome 34,35 . Here we found peritumoral LNS in the NAM+GEM group (4/4) with CD4 and CD8 T cells (Fig 4a), and less frequently intratumoral LNS in NAM (3/5) and GEM (2/5) groups but not in the saline group (Fig S8).…”

Section: Nam+gem Affects the Stromal Architecture With Reduced Extracmentioning

confidence: 99%

Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice

Selvanesan

Meena

Beck

et al. 2020

Preprint

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Treatments for pancreatic ductal adenocarcinoma (PDAC) are poorly effective, at least partly due to the tumor's immune-suppressive stromal compartment. New evidence of positive effects on immune responses in the tumor microenvironment, compelled us to test the combination of gemcitabine (GEM), a standard chemotherapeutic for pancreatic cancer, with nicotinamide (NAM), the amide form of niacin (vitamin B3), in various mouse tumor models of pancreatic cancer, i.e. peritoneal or orthotopic of Panc-02 (Kras G12D ) and orthotopic KPC (Kras G12D , p53 R172H , Pdx1-Cre) grafts. A significant reduction in tumor weight and number of metastases was found, as well as a significant improved survival of the NAM+GEM group compared to all control groups. Immunohistochemistry and flow cytometry of pancreatic tumors showed a significant decrease in tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC), an increase in the number of CD4 and CD8 T cells and the production of granzyme B in the NAM+GEM group. Moreover, T cell responses to tumorassociated antigen survivin were observed in spleens of the mice that received NAM+GEM but not in those that received single agents or saline. In addition, remodeling of the tumor stroma was observed with decreased collagen I and expression of hyaluronic acid binding protein, reorganization of the immune cells into lymph node like structures, and CD31 positive vessels.Expression profiling for a panel of immuno-oncology genes revealed significant changes in genes involved in migration and activation of T cells, attraction of dendritic cells, and epitope spreading. This study highlights the potential of NAM+GEM as immunotherapy for advanced pancreatic cancer.

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The lymphatic system and pancreatic cancer

Cited by 52 publications

References 385 publications

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

A radio‐anatomical correlation study of the cisterna chyli

Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice

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