Tumour-derived laminin α5 (LAMA5) promotes colorectal liver metastasis growth, branching angiogenesis and notch pathway inhibition

Alex Gordon-Weeks*, Su Yin Lim, Arseniy Yuzhalin, Serena Lucotti, Jenny Adriana Francisca Vermeer, Keaton Jones, Jianzhou Chen, Ruth J. Muschel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
3 Downloads (Pure)

Abstract

Hepatic metastatic growth is dependent upon stromal factors including the matrisomal proteins that make up the extracellular matrix (ECM). Laminins are ECM glycoproteins with several functions relevant to tumour progression including angiogenesis. We investigated whether metastatic colon cancer cells produce the laminins required for vascular basement membrane assembly as a mechanism for the promotion of angiogenesis and liver metastasis growth. qPCR was performed using human-specific primers to laminin chains on RNA from orthotopic human colorectal liver metastases. Laminin α5 (LAMA5) expression was inhibited in colon cancer cells using shRNA. Notch pathway gene expression was determined in endothelia from hepatic metastases. Orthotopic hepatic metastases expressed human laminin chains α5, β1 and γ1 (laminin 511), all of which are required for vascular basement membrane assembly. The expression of Laminin 511 was associated with reduced survival in several independent colorectal cancer cohorts and angiogenesis signatures or vessel density significantly correlated with LAMA5 expression. Colorectal cancer cells in culture made little LAMA5, but its levels were increased by culture in a medium conditioned by tumour-derived CD11b+ myeloid cells through TNFα/NFκB pathway signalling. Down-regulation of LAMA5 in cancer cells impaired liver metastatic growth and resulted in reduced intra-tumoural vessel branching and increased the expression of Notch pathway genes in metastasis-derived endothelia. This data demonstrates a mechanism whereby tumour inflammation induces LAMA5 expression in colorectal cancer cells. LAMA5 is required for the successful growth of hepatic metastases where it promotes branching angiogenesis and modulates Notch signalling.

Original languageEnglish
Article number630
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume11
Issue number5
DOIs
Publication statusPublished - 1 May 2019

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Angiogenesis
  • Laminin
  • Liver metastasis
  • Matrisome
  • Microenvironment
  • Notch

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