Alternatively activated macrophage-derived secretome stimulates ovarian cancer spheroid spreading through a JAK2/STAT3 pathway

Cancer Lett. 2019 Aug 28;458:92-101. doi: 10.1016/j.canlet.2019.05.029. Epub 2019 May 24.

Abstract

High-grade serous ovarian cancer (HGSOC) metastasizes when tumor spheroids detach from the primary tumor and re-attach throughout the peritoneal cavity. Once the cancer cells have implanted in these new sites, the development of metastatic lesions is dependent on the disaggregation of cancer cells from the spheroids and subsequent expansion across the collagenous extracellular matrix (ECM). As HGSOC progresses an increase in alternatively activated macrophages (AAMs) in the surrounding ascites fluid has been observed and AAMs have been shown to enhance tumor invasion and growth in a wide range of cancers. We hypothesized that soluble factors from AAMs in the peritoneal microenvironment promote the disaggregation of ovarian cancer spheroids across the underlying ECM. We determined that co-culture with AAMs significantly increased HGSOC spheroid spreading across a collagen matrix. Multivariate modeling identified AAM-derived factors that correlated with enhanced spread of HGSOC spheroids and experimental validation showed that each individual cell line responded to a distinct AAM-derived factor (FLT3L, leptin, or HB-EGF). Despite this ligand-level heterogeneity, we determined that the AAM-derived factors utilized a common signaling pathway to induce spheroid spreading: JAK2/STAT3 activation followed by MMP-9 mediated spreading. Furthermore, immunostaining demonstrated that FLT3, LEPR, EGFR, and pSTAT3 were upregulated in metastases in HGSOC patients, with substantial patient-to-patient heterogeneity. These results suggest that inhibiting individual soluble factors will not inhibit AAM-induced effects across a broad group of patients; instead, the downstream JAK2/STAT3/MMP-9 pathway should be examined as potential therapeutic targets to slow metastasis in ovarian cancer.

Keywords: MMP-9; Macrophages; Ovarian cancer; STAT3; Tumor microenvironment.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Cell Line, Tumor
  • Cystadenocarcinoma, Serous / immunology
  • Cystadenocarcinoma, Serous / metabolism
  • Cystadenocarcinoma, Serous / pathology
  • Female
  • Humans
  • Janus Kinase 2 / immunology
  • Janus Kinase 2 / metabolism*
  • Macrophage Activation
  • Macrophages / immunology
  • Macrophages / pathology*
  • Matrix Metalloproteinase 9 / immunology
  • Matrix Metalloproteinase 9 / metabolism
  • Middle Aged
  • Neoplasm Metastasis
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Receptors, Leptin / immunology
  • Receptors, Leptin / metabolism
  • STAT3 Transcription Factor / immunology
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Spheroids, Cellular
  • Up-Regulation
  • Young Adult
  • fms-Like Tyrosine Kinase 3 / immunology
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Receptors, Leptin
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • leptin receptor, human
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • JAK2 protein, human
  • Janus Kinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9