Periostin Limits Tumor Response to VEGFA Inhibition
Summary: Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matric...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-03-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471830216X |
| _version_ | 1811281700914724864 |
|---|---|
| author | Ioanna Keklikoglou Ece Kadioglu Stefan Bissinger Benoît Langlois Axel Bellotti Gertraud Orend Carola H. Ries Michele De Palma |
| author_facet | Ioanna Keklikoglou Ece Kadioglu Stefan Bissinger Benoît Langlois Axel Bellotti Gertraud Orend Carola H. Ries Michele De Palma |
| author_sort | Ioanna Keklikoglou |
| collection | DOAJ |
| description | Summary: Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs. : The molecular and cellular mechanisms underlying tumor resistance to VEGFA neutralization are diverse and incompletely understood. Keklikoglou et al. show that de novo deposition of the matrix protein periostin (POSTN) orchestrates tumor adaptation to chronic VEGFA inhibition by sustaining macrophage infiltration in a mouse model of pancreatic neuroendocrine tumor (PNET). Keywords: tumor angiogenesis, anti-angiogenic therapy, tumor-associated macrophage, stromal cell, VEGF, periostin, pancreatic tumor |
| first_indexed | 2024-04-13T01:38:19Z |
| format | Article |
| id | doaj.art-29a95bd83ae14772b54e6c822e55dbdb |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T01:38:19Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-29a95bd83ae14772b54e6c822e55dbdb2022-12-22T03:08:16ZengElsevierCell Reports2211-12472018-03-01221025302540Periostin Limits Tumor Response to VEGFA InhibitionIoanna Keklikoglou0Ece Kadioglu1Stefan Bissinger2Benoît Langlois3Axel Bellotti4Gertraud Orend5Carola H. Ries6Michele De Palma7Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, SwitzerlandSwiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, SwitzerlandRoche Innovation Center Munich, Roche Pharma Research and Early Development, 82377 Penzberg, GermanyINSERM U1109, MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, 3 Avenue Moliere, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, FranceSwiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, SwitzerlandINSERM U1109, MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, 3 Avenue Moliere, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, FranceRoche Innovation Center Munich, Roche Pharma Research and Early Development, 82377 Penzberg, GermanySwiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Corresponding authorSummary: Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs. : The molecular and cellular mechanisms underlying tumor resistance to VEGFA neutralization are diverse and incompletely understood. Keklikoglou et al. show that de novo deposition of the matrix protein periostin (POSTN) orchestrates tumor adaptation to chronic VEGFA inhibition by sustaining macrophage infiltration in a mouse model of pancreatic neuroendocrine tumor (PNET). Keywords: tumor angiogenesis, anti-angiogenic therapy, tumor-associated macrophage, stromal cell, VEGF, periostin, pancreatic tumorhttp://www.sciencedirect.com/science/article/pii/S221112471830216X |
| spellingShingle | Ioanna Keklikoglou Ece Kadioglu Stefan Bissinger Benoît Langlois Axel Bellotti Gertraud Orend Carola H. Ries Michele De Palma Periostin Limits Tumor Response to VEGFA Inhibition Cell Reports |
| title | Periostin Limits Tumor Response to VEGFA Inhibition |
| title_full | Periostin Limits Tumor Response to VEGFA Inhibition |
| title_fullStr | Periostin Limits Tumor Response to VEGFA Inhibition |
| title_full_unstemmed | Periostin Limits Tumor Response to VEGFA Inhibition |
| title_short | Periostin Limits Tumor Response to VEGFA Inhibition |
| title_sort | periostin limits tumor response to vegfa inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S221112471830216X |
| work_keys_str_mv | AT ioannakeklikoglou periostinlimitstumorresponsetovegfainhibition AT ecekadioglu periostinlimitstumorresponsetovegfainhibition AT stefanbissinger periostinlimitstumorresponsetovegfainhibition AT benoitlanglois periostinlimitstumorresponsetovegfainhibition AT axelbellotti periostinlimitstumorresponsetovegfainhibition AT gertraudorend periostinlimitstumorresponsetovegfainhibition AT carolahries periostinlimitstumorresponsetovegfainhibition AT micheledepalma periostinlimitstumorresponsetovegfainhibition |