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MUC1 Mediates Transendothelial Migration in vitro by Ligating Endothelial Cell ICAM-1

  • Jennifer J. Rahn
  • Jeffrey W. Chow
  • Garnet J. Horne
  • Brian K. Mah
  • Joanne T. Emerman
  • Pat Hoffman
  • Judith C. HughEmail author
Article

Abstract

MUC1 is a transmembrane glycoprotein expressed by normal breast epithelium and virtually all breast cancers. MUC1 is normally restricted to the apical surface of epithelia and loss of this polarized distribution in breast carcinomas is associated with lymph node metatases. Our previous work found that MUC1 can bind intercellular adhesion molecule-1 (ICAM-1), mediating adhesion of breast cancer cells to a simulated blood vessel wall, and also triggering a calcium-based signal in the MUC1-bearing cells. It is possible that the depolarized membrane distribution of MUC1 in breast carcinomas may facilitate interactions with stromal/endothelial ICAM-1 leading to adhesion and subsequent migration through the vessel wall. In the current study, we provide evidence that ICAM-1 can influence the migration of cells that express endogenous or transfected MUC1. Migration across a gelatin-coated Transwell membrane could be increased in a step-wise manner by the sequential addition of ICAM-1-expressing cells (endothelial cells and fibroblasts), and ICAM-1-inducing inflammatory cytokines (tumour necrosis factor-α and interleukin-1β). Antibodies against MUC1 or ICAM-1, but not a control antibody, could abrogate migratory increases. Cells that did not express MUC1 were unresponsive to ICAM-1. Our current findings build on our earlier work, by suggesting that the end result of the MUC1/ICAM-1-mediated cell–cell adhesion and calcium-based signal is migration. This has implications for the exit of circulating tumour cells from the vasculature, as well as tumour cell migration through fibroblast-containing stroma underlying the endothelial wall.

Keywords

breast cancer ICAM-1 MUC1 transendothelial migration transwell assay 

Abbreviations

DMEM

Dulbecco’s minimal essential medium

DPBS

Dulbecco’s phosphate buffered saline

ECGS

endothelial cell growth supplement

ECL

enhanced chemiluminescence

EGFR

epidermal growth factor receptor

ERK

extracellular signal-regulated kinase

FBS

fetal bovine serum

Grb2

growth factor receptor-bound protein 2

GSK3β

glycogen synthase kinase-3β

HMEC

human mammary epithelial cell

HUVEC

human umbilical vein endothelial cell

ICAM-1

intercellular adhesion molecule-1

IGF

insulin-like growth factor

IL-1β

interleukin-1β

LCA

leukocyte common antigen

MAPK

mitogen activated protein kinase

MIP-1

macrophage inflammatory protein 1

NBT/BCIP

nitroblue tetrazolium chloride/5-bromo-4-chloro-3-indolyl phosphate, toluidine salt

PCNA

proliferating cell nuclear antigen

PHEC

primary human endothelial cell

PI3-kinase

phosphoinositol-3-kinase

PKCδ

protein kinase C δ

RANTES

regulated upon activation, normal T-cell expressed and secreted

sc-uPA

single-chain urokinase-type plasminogen activator

SEM

standard error of the mean

Sos

son of sevenless

SYM

signal sequence-YFP-MUC1

TEME

transendothelial migration, specifically extravasation

TNF-α

tumour necrosis factor α

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Copyright information

© Springer 2005

Authors and Affiliations

  • Jennifer J. Rahn
    • 1
  • Jeffrey W. Chow
    • 1
  • Garnet J. Horne
    • 1
  • Brian K. Mah
    • 1
  • Joanne T. Emerman
    • 2
  • Pat Hoffman
    • 3
  • Judith C. Hugh
    • 1
    Email author
  1. 1.Department of Laboratory Medicine and Pathology, Cross Cancer InstituteUniversity of AlbertaEdmontonCanada
  2. 2.Department of Cellular & Physiological Sciences, Faculty of MedicineUniversity of British ColombiaVancouverCanada
  3. 3.ICOS CorporationBothellUSA

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