Human stem cells alter the invasive properties of somatic cells via paracrine activation of mTORC1

Nat Commun. 2017 Sep 19;8(1):595. doi: 10.1038/s41467-017-00661-x.

Abstract

Controlled invasion is essential during many physiological processes, whereas its deregulation is a hallmark of cancer. Here we demonstrate that embryonic, induced pluripotent and amniotic fluid stem cells share the property to induce the invasion of primary somatic cells of various origins through insulin-like growth factor I (IGF-I)- or II (IGF-II)-mediated paracrine activation of mechanistic target of rapamycin complex 1 (mTORC1). We propose a model in which downstream of mTORC1 this stem cell-induced invasion is mediated by hypoxia-inducible factor 1-alpha (HIF-1α)-regulated matrix metalloproteinases. Manipulating the IGF signalling pathway in the context of teratoma formation experiments demonstrates that human stem cells use this mechanism to induce invasion and thereby attract cells from the microenvironment in vivo. In this study we have identified a so far unknown feature of human stem cells, which might play a role for the development of stem cell-derived tumours.Cell invasion is required for several physiological processes but it is unknown if stem cells induce invasiveness in other cells. Here, the authors show that human stem cells secrete insulin-like growth factor, which in turn activates the mTORC1 pathway, initiating invasive behaviour and attracting other cells.

MeSH terms

  • Carcinoma, Embryonal / metabolism*
  • Carcinoma, Embryonal / pathology
  • Cell Movement / drug effects
  • Cells, Cultured
  • Human Embryonic Stem Cells / metabolism*
  • Human Embryonic Stem Cells / pathology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor II / metabolism*
  • Insulin-Like Growth Factor II / pharmacology
  • Matrix Metalloproteinases / drug effects
  • Matrix Metalloproteinases / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / drug effects
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Neoplasm Invasiveness
  • Paracrine Communication* / drug effects
  • Signal Transduction
  • Teratoma / metabolism*
  • Teratoma / pathology

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IGF1 protein, human
  • IGF2 protein, human
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Mechanistic Target of Rapamycin Complex 1
  • Matrix Metalloproteinases