Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • CD47 Antigen / immunology
  • Female
  • Humans
  • Isoenzymes / immunology
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis
  • Neoplasm Proteins / immunology
  • Neuroendocrine Tumors* / immunology
  • Neuroendocrine Tumors* / pathology
  • Neuroendocrine Tumors* / therapy
  • Pancreatic Neoplasms* / immunology
  • Pancreatic Neoplasms* / pathology
  • Pancreatic Neoplasms* / therapy
  • Retinal Dehydrogenase / immunology
  • Thy-1 Antigens / immunology
  • Tumor Escape*
  • Xenograft Model Antitumor Assays

Substances

  • CD47 Antigen
  • CD47 protein, human
  • Isoenzymes
  • Neoplasm Proteins
  • Thy-1 Antigens
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase