Fibronectin Regulation of Integrin B1 and SLUG in Circulating Tumor Cells

Cells. 2019 Jun 20;8(6):618. doi: 10.3390/cells8060618.

Abstract

Metastasis is the leading cause of cancer death worldwide. Circulating tumor cells (CTCs) are a critical step in the metastatic cascade and a good tool to study this process. We isolated CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) and a human xenograft mouse model of castration-resistant prostate cancer (CRPC). From these models, novel primary tumor and CTC cell lines were established. CTCs exhibited greater migration than primary tumor-derived cells, as well as epithelial-to-mesenchymal transition (EMT), as observed from decreased E-cadherin and increased SLUG and fibronectin expression. Additionally, when fibronectin was knocked down in CTCs, integrin B1 and SLUG were decreased, indicating regulation of these molecules by fibronectin. Investigation of cell surface molecules and secreted cytokines conferring immunomodulatory advantage to CTCs revealed decreased major histocompatibility complex class I (MHCI) expression and decreased endostatin, C-X-C motif chemokine 5 (CXCL5), and proliferin secretion by CTCs. Taken together, these findings indicate that CTCs exhibit distinct characteristics from primary tumor-derived cells. Furthermore, CTCs demonstrate enhanced migration in part through fibronectin regulation of integrin B1 and SLUG. Further study of CTC biology will likely uncover additional important mechanisms of cancer metastasis.

Keywords: SLUG; castration resistant prostate cancer (CRPC); circulating tumor cells (CTCs); epithelial-to-mesenchymal transition (EMT); fibronectin; hepatocellular carcinoma (HCC); immunomodulation; integrin B1; major histocompatibility complex class I (MHCI); metastasis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers, Tumor / blood
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Movement
  • Endostatins
  • Epithelial-Mesenchymal Transition
  • Fibronectins / metabolism*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immunomodulation
  • Integrin beta1 / metabolism*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice, Inbred BALB C
  • Neoplasm Metastasis
  • Neoplasm Proteins / metabolism
  • Neoplastic Cells, Circulating / metabolism*
  • Neoplastic Cells, Circulating / pathology
  • Snail Family Transcription Factors / metabolism*

Substances

  • Biomarkers, Tumor
  • Cadherins
  • Endostatins
  • Fibronectins
  • Histocompatibility Antigens Class I
  • Integrin beta1
  • Neoplasm Proteins
  • Snail Family Transcription Factors