Lymph node metastasis and the physicochemical micro-environment of pancreatic ductal adenocarcinoma xenografts

Pancreatic ductal adenocarcinoma (PDAC) patients develop lymph node metastases early and have a particularly poor prognosis. The poor prognosis has been shown to be associated with the physicochemical microenvironment of the tumor tissue, which is characterized by desmoplasia, abnormal microvasculature, extensive hypoxia, and highly elevated interstitial fluid pressure (IFP). In this study, we searched for associations between lymph node metastasis and features of the physicochemical microenvironment in an attempt to identify mechanisms leading to metastatic dissemination and growth. BxPC-3 and Capan-2 PDAC xenografts were used as preclinical models of human PDAC. In both models, lymph node metastasis was associated with high IFP rather than high fraction of hypoxic tissue or high microvascular density. Seven angiogenesis-related genes associated with high IFP-associated lymph node metastasis were detected by quantitative PCR in each of the models, and these genes were all up-regulated in high IFP/highly metastatic tumors. Three genes were mutual for the BxPC-3 and Capan-2 models: transforming growth factor beta, angiogenin, and insulin-like growth factor 1. Further comprehensive studies are needed to determine whether there is a causal relationship between the up-regulation of these genes and high IFP and/or high propensity for lymph node metastasis in PDAC.

• Publication year

  2017

• Venue

  OncoTarget

• Publication date

  2017-05-26

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.18632/oncotarget.18231PMID 28624797PMCID 5564626
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective

  2019cited by this paper
• Functional intratumoral lymphatics in patient-derived xenograft models of squamous cell carcinoma of the uterine cervix: implications for lymph node metastasis

  2016cited by this paper
• Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma.

  2016cited by this paper
• The lymphatic system and pancreatic cancer.

  2016cited by this paper
• Diffusion-weighted and dynamic contrast-enhanced MRI of pancreatic adenocarcinoma xenografts: associations with tumor differentiation and collagen content

  2016cited by this paper
• Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue

  2016cited by this paper
• Pancreatic cancer biology and genetics from an evolutionary perspective

  2016cited by this paper
• Pathophysiological Basis for the Formation of the Tumor Microenvironment

  2016cited by this paper
• TNF-alpha promotes lymphangiogenesis and lymphatic metastasis of gallbladder cancer through the ERK1/2/AP-1/VEGF-D pathway

  2016cited by this paper
• Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase.

  2016cited by this paper
• The conflicting roles of tumor stroma in pancreatic cancer and their contribution to the failure of clinical trials: a systematic review and critical appraisal

  2015cited by this paper
• Cancer statistics, 2015

  2015cited by this paper
• The clinical significance of hypoxia in human cancers.

  2015cited by this paper
• Analysis of the intra- and intertumoral heterogeneity of hypoxia in pancreatic cancer patients receiving the nitroimidazole tracer pimonidazole

  2015cited by this paper
• Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

  2015cited by this paper
• Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer

  2015cited by this paper
• Recent advances in pancreatic cancer: biology, treatment, and prevention.

  2015cited by this paper
• Pancreatic cancer: from state-of-the-art treatments to promising novel therapies

  2015cited by this paper
• Pancreatic ductal adenocarcinoma: From genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic.

  2015cited by this paper
• Lymphangiogenic factors, mechanisms, and applications.

  2014cited by this paper
• Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.

  2014cited by this paper
• Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

  2014cited by this paper
• Tumor Interstitial Fluid Pressure—A Link between Tumor Hypoxia, Microvascular Density, and Lymph Node Metastasis

  2014cited by this paper
• Tumor necrosis factor-α promotes the lymphangiogenesis of gallbladder carcinoma through nuclear factor-κB-mediated upregulation of vascular endothelial growth factor-C

  2014cited by this paper
• Hypoxia signaling and the metastatic phenotype.

  2014cited by this paper
• Role of lymphatic vasculature in regional and distant metastases.

  2014cited by this paper
• The role of mechanical forces in tumor growth and therapy.

  2014cited by this paper
• Pancreatic adenocarcinoma.

  2014cited by this paper
• TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

  2014cited by this paper
• Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure.

  2014cited by this paper
• Insulin-like growth factor-1 induces lymphangiogenesis and facilitates lymphatic metastasis in colorectal cancer.

  2013cited by this paper
• Vascular proliferation is associated with survival in pancreatic ductal adenocarcinoma

  2013cited by this paper
• High Interstitial Fluid Pressure Is Associated with Tumor-Line Specific Vascular Abnormalities in Human Melanoma Xenografts

  2012cited by this paper
• Interstitial fluid pressure and associated lymph node metastasis revealed in tumors by dynamic contrast-enhanced MRI.

  2012cited by this paper
• Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity

  2012cited by this paper
• The Pancreas Cancer Microenvironment

  2012cited by this paper
• Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer

  2012cited by this paper
• Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.

  2012cited by this paper
• Only women with symptoms need to have their breast implants removed, says government

  2012cited by this paper
• VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics.

  2012cited by this paper
• Current Treatment Options for Pancreatic Carcinoma

  2011cited by this paper
• Growth Factors and their receptors in cancer metastases.

  2011cited by this paper
• Lymphangiogenesis and cancer metastasis.

  2011cited by this paper
• Tumorigenesis and Neoplastic Progression Overexpression of CXCL5 Is Associated With Poor Survival in Patients With Pancreatic Cancer

  2011cited by this paper
• Survival after Resection of Pancreatic Adenocarcinoma: Results from a Single Institution over Three Decades

  2011cited by this paper
• Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer.

  2011cited by this paper
• Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma

  2011cited by this paper
• Hypoxia, inflammation, and the tumor microenvironment in metastatic disease

  2010cited by this paper
• Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models

  2010cited by this paper
• Stromal biology and therapy in pancreatic cancer

  2010influential reference
• CXC chemokines in cancer angiogenesis and metastases.

  2010cited by this paper
• Associations between Radiocurability and Interstitial Fluid Pressure in Human Tumor Xenografts without Hypoxic Tissue

  2010cited by this paper
• The pathology and genetics of metastatic pancreatic cancer.

  2009cited by this paper
• The basics of epithelial-mesenchymal transition.

  2009cited by this paper
• Lymphangiogenesis and cancer metastasis

  2009cited by this paper
• Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

  2009influential reference
• Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure.

  2009cited by this paper
• Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan.

  2008cited by this paper
• Twenty-five years of quantitative PCR for gene expression analysis.

  2008cited by this paper
• Evolutionary-new centromeres preferentially emerge within gene deserts

  2008cited by this paper
• Chapter 14. Measuring intratumoral microvessel density.

  2008cited by this paper
• Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours

  2008influential reference
• Fluctuating and Diffusion-Limited Hypoxia in Hypoxia-Induced Metastasis

  2007cited by this paper
• Tumor-stroma interactions in pancreatic ductal adenocarcinoma

  2007influential reference
• The Integrin-Extracellular Matrix Axis in Pancreatic Cancer

  2007cited by this paper
• The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling

  2007cited by this paper
• Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling.

  2007cited by this paper
• Hypoxia in cancer: significance and impact on clinical outcome

  2007cited by this paper
• NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2

  2007cited by this paper
• A therapeutic target for prostate cancer based on angiogenin-stimulated angiogenesis and cancer cell proliferation

  2006cited by this paper
• Pancreatic adenocarcinoma

  2006cited by this paper
• Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis.

  2006cited by this paper
• Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis

  2005cited by this paper
• The human tumor microenvironment: invasive (needle) measurement of oxygen and interstitial fluid pressure.

  2004cited by this paper
• Invasion and metastasis in pancreatic cancer

  2003cited by this paper
• Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor.

  2002cited by this paper
• Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts.

  2002cited by this paper
• Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours.

  2002cited by this paper
• Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements.

  2001cited by this paper
• Pancreatic tumors show high levels of hypoxia.

  2000cited by this paper
• The relationship between elevated interstitial fluid pressure and blood flow in tumors: a bioengineering analysis.

  1999influential reference
• Measuring Intratumoral Microvessel Density

  1998cited by this paper
• Vessel counts and vascular endothelial growth factor expression in pancreatic adenocarcinoma.

  1998cited by this paper
• Interstitial fluid pressure, perfusion rate and oxygen tension in human melanoma xenografts.

  1996cited by this paper
• Intratumor microvessel density as a prognostic factor in cancer.

  1995cited by this paper
• Lack of general correlation between interstitial fluid pressure and oxygen partial pressure in solid tumors.

  1995cited by this paper
• Cancer statistics

  1989cited by this paper

• Lymphatic metastasis in pancreatic cancer: from bedside to bench and back

  2025cites this paper
• Vascular regional analysis unveils differential responses to anti-angiogenic therapy in pancreatic xenografts through macroscopic photoacoustic imaging

  2025cites this paper
• Can cancer cells inform us about the tumor microenvironment?

  2023cites this paper
• Predictive Design and Analysis of Drug Transport by Multiscale Computational Models Under Uncertainty

  2022cites this paper
• Fluid-sensitive migration mechanisms predict association between metastasis and high interstitial fluid pressure in pancreatic cancer.

  2022cites this paper
• In silico investigations of intratumoral heterogeneous interstitial fluid pressure.

  2021cites this paper
• Assessment of Intratumor Heterogeneity in Parametric Dynamic Contrast-Enhanced MR Images: A Comparative Study of Novel and Established Methods

  2021cites this paper
• Mathematical modeling of cancer cell migration - from in vitro to in vivo

  2020influential citation
• Collective tumor cell migration in the presence of fibroblasts.

  2019cites this paper
• Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts12

  2019cites this paper
• Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation

  2018cites this paper
• DCE-MRI of Sunitinib-Induced Changes in Tumor Microvasculature and Hypoxia: A Study of Pancreatic Ductal Adenocarcinoma Xenografts12

  2018cites this paper
• Metastatic pathway and the microvascular and physicochemical microenvironments of human melanoma xenografts

  2017cites this paper