Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis. Academic Article uri icon

Overview

MeSH

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Line, Tumor
  • Chemotaxis
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Homeodomain Proteins
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Receptors, CCR

MeSH Major

  • Adenocarcinoma
  • Chemokines, CC
  • Colorectal Neoplasms
  • Signal Transduction

abstract

  • Chemotactic cytokines (chemokines) can help regulate tumor cell invasion and metastasis. Here, we show that chemokine 25 (CCL25) and its cognate receptor chemokine receptor 9 (CCR9) inhibit colorectal cancer (CRC) invasion and metastasis. We found that CCR9 protein expression levels were highest in colon adenomas and progressively decreased in invasive and metastatic CRCs. CCR9 was expressed in both primary tumor cell cultures and colon-cancer-initiating cell (CCIC) lines derived from early-stage CRCs but not from metastatic CRC. CCL25 stimulated cell proliferation by activating AKT signaling. In vivo, systemically injected CCR9+ early-stage CCICs led to the formation of orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling inhibited CRC tumor formation in the native gastrointestinal CCL25+ microenvironment, while increasing extraintestinal tumor incidence. NOTCH signaling, which promotes CRC metastasis, increased extraintestinal tumor frequency by stimulating CCR9 proteasomal degradation. Overall, these data indicate that CCL25 and CCR9 regulate CRC progression and invasion and further demonstrate an appropriate in vivo experimental system to study CRC progression in the native colon microenvironment.

publication date

  • September 4, 2012

has subject area

  • Adenocarcinoma
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Line, Tumor
  • Chemokines, CC
  • Chemotaxis
  • Colorectal Neoplasms
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Homeodomain Proteins
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Receptors, CCR
  • Signal Transduction

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3428084

Digital Object Identifier (DOI)

  • 10.1172/JCI62110

PubMed ID

  • 22863617

Additional Document Info

start page

  • 3184

end page

  • 3196

volume

  • 122

number

  • 9