Matrix Remodeling Stimulates Stromal Autophagy, "Fueling" Cancer Cell Mitochondrial Metabolism and Metastasis

Cell Cycle. 2011 Jun 15;10(12):2021-34. doi: 10.4161/cc.10.12.16002. Epub 2011 Jun 15.

Abstract

We have previously demonstrated that loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts is a strong and independent predictor of poor clinical outcome in human breast cancer patients. However, the signaling mechanism(s) by which Cav-1 downregulation leads to this tumor-promoting microenvironment are not well understood. To address this issue, we performed an unbiased comparative proteomic analysis of wild-type (WT) and Cav-1(-/-) null mammary stromal fibroblasts (MSFs). Our results show that plasminogen activator inhibitor type 1 and type 2 (PAI-1 and PAI-2) expression is significantly increased in Cav-1(-/-) MSFs. To establish a direct cause-effect relationship, we next generated immortalized human fibroblast lines stably overexpressing either PAI-1 or PAI-2. Importantly, PAI-1/2(+) fibroblasts promote the growth of MDA-MB-231 tumors (a human breast cancer cell line) in a murine xenograft model, without any increases in angiogenesis. Similarly, PAI-1/2(+) fibroblasts stimulate experimental metastasis of MDA-MB-231 cells using an in vivo lung colonization assay. Further mechanistic studies revealed that fibroblasts overexpressing PAI-1 or PAI-2 display increased autophagy ("self-eating") and are sufficient to induce mitochondrial biogenesis/activity in adjacent cancer cells, in co-culture experiments. In xenografts, PAI-1/2(+) fibroblasts significantly reduce the apoptosis of MDA-MB-231 tumor cells. The current study provides further support for the "Autophagic Tumor Stroma Model of Cancer" and identifies a novel "extracellular matrix"-based signaling mechanism, by which a loss of stromal Cav-1 generates a metastatic phenotype. Thus, the secretion and remodeling of extracellular matrix components (such as PAI-1/2) can directly regulate both (1) autophagy in stromal fibroblasts and (2) epithelial tumor cell mitochondrial metabolism.

Publication types

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

MeSH terms

  • Animals
  • Autophagy*
  • Breast Neoplasms / pathology
  • Caveolin 1 / metabolism
  • Cell Line, Tumor
  • Coculture Techniques
  • Extracellular Matrix / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Neoplasm Metastasis*
  • Neoplasms / pathology
  • Neoplasms / ultrastructure
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Plasminogen Activator Inhibitor 2 / metabolism
  • Stromal Cells / pathology*
  • Transplantation, Heterologous
  • Tumor Microenvironment

Substances

  • Caveolin 1
  • Plasminogen Activator Inhibitor 1
  • Plasminogen Activator Inhibitor 2