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Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4464-9. doi: 10.1073/pnas.1600007113. Epub 2016 Mar 31.

Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors.

Author information

1
Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; krampitz@stanford.edu irv@stanford.edu.
2
Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
3
Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
4
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
5
Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
6
Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
7
Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 krampitz@stanford.edu irv@stanford.edu.

Abstract

Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a "don't eat me" signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90(hi)cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo.

KEYWORDS:

CD47; CD90; MET; cancer stem cell; pancreatic neuroendocrine tumor

Comment in

PMID:
27035983
PMCID:
PMC4843455
DOI:
10.1073/pnas.1600007113
[Indexed for MEDLINE]
Free PMC Article

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