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Pancreatic Neoplasms: HELP
Articles by Kristian Pietras
Based on 6 articles published since 2009
(Why 6 articles?)
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Between 2009 and 2019, K. Pietras wrote the following 6 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-β signaling. 2016

Eleftheriou, Nikolas M / Sjölund, Jonas / Bocci, Matteo / Cortez, Eliane / Lee, Se-Jin / Cunha, Sara I / Pietras, Kristian. ·Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden. · Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. ·Oncotarget · Pubmed #27741515.

ABSTRACT: Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-β family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown. Furthermore, the knockout of Gdf2 (BMP9), the primary ligand for ALK1 and endoglin, exhibited a mixed phenotype from each of ALK1 and endoglin deficiencies; overall primary tumor burden decreased, but hepatic metastases increased. Tumors lacking BMP9 display a hyperbranching vasculature, and an increase in vascular mesenchymal-marker expression, which may be implicit in the increase in metastases. Taken together, our work cautions against singular blockade of BMP9 and instead demonstrates the utility of dual blockade of ALK1 and endoglin as a strategy for anti-angiogenic therapy in PanNET.

2 Article Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD. 2016

Cortez, Eliane / Gladh, Hanna / Braun, Sebastian / Bocci, Matteo / Cordero, Eugenia / Björkström, Niklas K / Miyazaki, Hideki / Michael, Iacovos P / Eriksson, Ulf / Folestad, Erika / Pietras, Kristian. ·Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden; · Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden; · Department of Medicine, Karolinska Institutet, SE-14186, Stockholm, Sweden; · Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. · Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden; kristian.pietras@med.lu.se. ·Proc Natl Acad Sci U S A · Pubmed #26831065.

ABSTRACT: Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

3 Article Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. 2013

Anderberg, Charlotte / Cunha, Sara I / Zhai, Zhenhua / Cortez, Eliane / Pardali, Evangelia / Johnson, Jill R / Franco, Marcela / Páez-Ribes, Marta / Cordiner, Ross / Fuxe, Jonas / Johansson, Bengt R / Goumans, Marie-José / Casanovas, Oriol / ten Dijke, Peter / Arthur, Helen M / Pietras, Kristian. ·Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. ·J Exp Med · Pubmed #23401487.

ABSTRACT: Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.

4 Article Image-based 3D modeling study of the influence of vessel density and blood hemoglobin concentration on tumor oxygenation and response to irradiation. 2013

Lagerlöf, Jakob H / Kindblom, Jon / Cortez, Eliane / Pietras, Kristian / Bernhardt, Peter. ·Department of Radiation Physics, Göteborg University, Göteborg, Sweden. Jakob@radfys.gu.se ·Med Phys · Pubmed #23387780.

ABSTRACT: PURPOSE: Hypoxia is one of the most important factors influencing clinical outcome after radiotherapy. Improved knowledge of factors affecting the levels and distribution of oxygen within a tumor is needed. The authors constructed a theoretical 3D model based on histological images to analyze the influence of vessel density and hemoglobin (Hb) concentration on the response to irradiation. METHODS: The pancreases of a Rip-Tag2 mouse, a model of malignant insulinoma, were excised, cryosectioned, immunostained, and photographed. Vessels were identified by image thresholding and a 3D vessel matrix assembled. The matrix was reduced to functional vessel segments and enlarged by replication. The steady-state oxygen tension field of the tumor was calculated by iteratively employing Green's function method for diffusion and the Michaelis-Menten model for consumption. The impact of vessel density on the radiation response was studied by removing a number of randomly selected vessels. The impact of Hb concentration was studied by independently changing vessel oxygen partial pressure (pO(2)). For each oxygen distribution, the oxygen enhancement ratio (OER) was calculated and the mean absorbed dose at which the tumor control probability (TCP) was 0.99 (D(99)) was determined using the linear-quadratic cell survival model (LQ model). RESULTS: Decreased pO(2) shifted the oxygen distribution to lower values, whereas decreased vessel density caused the distribution to widen and shift to lower values. Combined scenarios caused lower-shifted distributions, emphasising log-normal characteristics. Vessel reduction combined with increased blood pO(2) caused the distribution to widen due to a lack of vessels. The most pronounced radiation effect of increased pO(2) occurred with tumor tissue with 50% of the maximum vessel density used in the simulations. A 51% decrease in D(99), from 123 to 60 Gy, was found between the lowest and highest pO(2) concentrations. CONCLUSIONS: Our results indicate that an intermediate vascular density region exists where enhanced blood oxygen concentration may be beneficial for radiation response. The results also suggest that it is possible to distinguish between diffusion-limited and anemic hypoxia from the characteristics of the pO(2) distribution.

5 Article Use of a mouse model of pancreatic neuroendocrine tumors to find pericyte biomarkers of resistance to anti-angiogenic therapy. 2011

Franco, M / Pàez-Ribes, M / Cortez, E / Casanovas, O / Pietras, K. ·Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden. ·Horm Metab Res · Pubmed #21960459.

ABSTRACT: The successful introduction of rationally targeted agents into standard cancer care is a testimony of the vast knowledge base in tumor biology. However, in order to provide individually tailored therapy to patients and to identify small subsets of patients with a high likelihood to benefit from treatment, the identification of biomarkers for response or resistance to a particular therapeutic regimen is imperative. Herein, by the use of a genetically engineered mouse model of pancreatic neuroendocrine tumors, we have assessed the utility of pericyte characteristics in terms of differential marker expression to serve as surrogate markers for response or evasive resistance to anti-angiogenic therapy. We found that tumors refractory to therapy following long-term treatment with a vascular endothelial growth factor receptor-2 blocking antibody contained blood vessels with a prolific investment of pericytes expressing α-smooth muscle actin. Further analysis by simultaneous immunostaining for different pericyte markers led to the conclusion that the increased abundance of this particular subtype of blood vessels most likely occurred by co-option of vessels from the surrounding exocrine pancreas. Our findings may form the basis for retrospective analysis of pancreatic neuroendocrine tumors from patients having undergone treatment with anti-angiogenic agents in order to validate the occurrence of pericytes expressing α-smooth muscle actin as a biomarker for tumors refractory to therapy.

6 Article Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis. 2010

Albrecht, Imke / Kopfstein, Lucie / Strittmatter, Karin / Schomber, Tibor / Falkevall, Annelie / Hagberg, Carolina E / Lorentz, Pascal / Jeltsch, Michael / Alitalo, Kari / Eriksson, Ulf / Christofori, Gerhard / Pietras, Kristian. ·Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland. ·PLoS One · Pubmed #21124841.

ABSTRACT: BACKGROUND: The family of vascular endothelial growth factors (VEGF) contains key regulators of blood and lymph vessel development, including VEGF-A, -B, -C, -D, and placental growth factor. The role of VEGF-B during physiological or pathological angiogenesis has not yet been conclusively delineated. Herein, we investigate the function of VEGF-B by the generation of mouse models of cancer with transgenic expression of VEGF-B or homozygous deletion of Vegfb. METHODOLOGY/PRINCIPAL FINDINGS: Ectopic expression of VEGF-B in the insulin-producing β-cells of the pancreas did not alter the abundance or architecture of the islets of Langerhans. The vasculature from transgenic mice exhibited a dilated morphology, but was of similar density as that of wildtype mice. Unexpectedly, we found that transgenic expression of VEGF-B in the RIP1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis retarded tumor growth. Conversely, RIP1-Tag2 mice deficient for Vegfb presented with larger tumors. No differences in vascular density, perfusion or immune cell infiltration upon altered Vegfb gene dosage were noted. However, VEGF-B acted to increase blood vessel diameter both in normal pancreatic islets and in RIP1-Tag2 tumors. CONCLUSIONS/SIGNIFICANCE: Taken together, our results illustrate the differences in biological function between members of the VEGF family, and highlight the necessity of in-depth functional studies of VEGF-B to fully understand the effects of VEGFR-1 inhibitors currently used in the clinic.