Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition
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 cell...
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| Format: | Article |
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MDPI AG
2019-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/5/630 |
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| author | Alex Gordon-Weeks Su Yin Lim Arseniy Yuzhalin Serena Lucotti Jenny Adriana Francisca Vermeer Keaton Jones Jianzhou Chen Ruth J. Muschel |
| author_facet | Alex Gordon-Weeks Su Yin Lim Arseniy Yuzhalin Serena Lucotti Jenny Adriana Francisca Vermeer Keaton Jones Jianzhou Chen Ruth J. Muschel |
| author_sort | Alex Gordon-Weeks |
| collection | DOAJ |
| description | 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<sup>+</sup> 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. |
| first_indexed | 2024-03-12T07:45:01Z |
| format | Article |
| id | doaj.art-74f68fb1b0e14a3c84b0f48e883f6c80 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:45:01Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-74f68fb1b0e14a3c84b0f48e883f6c802023-09-02T21:03:54ZengMDPI AGCancers2072-66942019-05-0111563010.3390/cancers11050630cancers11050630Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway InhibitionAlex Gordon-Weeks0Su Yin Lim1Arseniy Yuzhalin2Serena Lucotti3Jenny Adriana Francisca Vermeer4Keaton Jones5Jianzhou Chen6Ruth J. Muschel7Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX39DU, UKFaculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, NSW 2109, AustraliaCRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX37LE, UKCRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX37LE, UKCRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX37LE, UKCRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX37LE, UKCRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX37LE, UKCRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX37LE, UKHepatic 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<sup>+</sup> 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.https://www.mdpi.com/2072-6694/11/5/630liver metastasislamininangiogenesisNotchmicroenvironmentmatrisome |
| spellingShingle | Alex Gordon-Weeks Su Yin Lim Arseniy Yuzhalin Serena Lucotti Jenny Adriana Francisca Vermeer Keaton Jones Jianzhou Chen Ruth J. Muschel Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition Cancers liver metastasis laminin angiogenesis Notch microenvironment matrisome |
| title | Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition |
| title_full | Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition |
| title_fullStr | Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition |
| title_full_unstemmed | Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition |
| title_short | Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition |
| title_sort | tumour derived laminin α5 lama5 promotes colorectal liver metastasis growth branching angiogenesis and notch pathway inhibition |
| topic | liver metastasis laminin angiogenesis Notch microenvironment matrisome |
| url | https://www.mdpi.com/2072-6694/11/5/630 |
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