Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity

Sci Rep. 2016 Dec 20:6:39558. doi: 10.1038/srep39558.

Abstract

Tumor microenvironment has been recognized as a key determinant of tumor formation and metastasis, but how tumor microenvironment is affected by nanomaterials is essentially unknown. Here, we investigated whether carbon nanotubes (CNTs), a widely used nanomaterial with known carcinogenic potential, can affect cancer-associated fibroblasts (CAFs), which are a key component of tumor microenvironment that provides necessary support for tumor growth. We show for the first time that single-walled CNT and to a lesser extent multi-walled and its COOH-functionalized form induced CAF-like cells, which are non-tumorigenic in animals, but promote tumor growth of human lung carcinoma and CNT-transformed lung epithelial cells. The mechanism by which CNT-induced CAF-like cells promote tumor growth involved the acquisition of cancer stem cells (CSCs) in cancer population. Gene knockdown experiments showed that an expression of podoplanin on CAF-like cells is essential for their effects, indicating the functional role of CAF-like cells and podoplanin in CNT tumorigenic process. Our findings unveil a novel mechanism of CNT-induced carcinogenesis through the induction of CAF-like cells that support CSCs and drive tumor formation. Our results also suggest the potential utility of podoplanin as a mechanism-based biomarker for rapid screening of carcinogenicity of CNTs and related nanomaterials for their safer design.

Publication types

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

MeSH terms

  • AC133 Antigen / metabolism
  • Animals
  • Biomarkers, Tumor / metabolism
  • Cancer-Associated Fibroblasts / cytology*
  • Cell Count
  • Cell Line, Tumor
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Epithelial Cells / cytology
  • Humans
  • Lung / metabolism
  • Lung Neoplasms / metabolism
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nanotubes, Carbon / chemistry*
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / cytology
  • Signal Transduction
  • Tumor Microenvironment*

Substances

  • AC133 Antigen
  • Biomarkers, Tumor
  • Membrane Glycoproteins
  • Nanotubes, Carbon
  • PDPN protein, human
  • PROM1 protein, human