Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. Academic Article uri icon

Overview

abstract

  • Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.

publication date

  • February 9, 2015

Research

keywords

  • Adenocarcinoma
  • Carcinoma, Squamous Cell
  • Collagen
  • Lung Neoplasms
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase

Identity

PubMed Central ID

  • PMC4362236

Scopus Document Identifier

  • 84924045521

Digital Object Identifier (DOI)

  • 10.1172/JCI74725

PubMed ID

  • 25664850

Additional Document Info

volume

  • 125

issue

  • 3