Publication: New Article published in Cancer Cell on pre-metastatic niches in breast cancer

Thomas R. Cox, Jan 2009

Our recent work on the role of lysyl oxidase (LOX) in the formation of pre-metastatic niches has just been accepted in Cancer Cell.

CancerCell_Niche

Image: Immunofluorescence staining of LOX (green) and CD11b+ cells (red) in lung sections. Co-localization is indicated by yellow

In this paper we show that lysyl oxidase (LOX) is critical to the formation of pre-metastatic niches in breast cancer.

We show that LOX secreted by hypoxic primary tumour cells accumulates with fibronectin at sites of future metastasis. Here, it ability to crosslink collagen IV in the basement membrane increases adhesion of CD11b+ bone marrow derived cells which in turn produce MMP-2 to degrade collagen IV. The result is increased CD11b+ cell invasion into the lung tissue and the release of chemoattractive collagen IV peptides, thus attracting more CD11b+ cells in a positive feed-forward loop. This leads to increased accumulation of bone marrow derived cells, increased extracellular matrix remodeling, and creation of the premetastatic niche.

Importantly, formation of the premetastatic niche is critically dependent on the accumulation of enzymatically active LOX. Taken together, our data demonstrate a crucial role for LOX secreted by hypoxic tumor cells in formation of the premetastatic niche and in the enhancement of metastatic tumor growth. These data support targeting hypoxia-induced secreted LOX for the treatment and prevention of metastatic cancer.

Abstract

Tumor cell metastasis is facilitated by ‘‘premetastatic niches’’ formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for premetastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment andmetastatic growth. CD11b+ cells and LOX also colocalize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in premetastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease.

Links

View article on Cancer Cell homepage
View abstract on PubMed

Citation

Erler JT*, Bennewith KL*, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche
Cancer Cell; Jan 6;15(1):35-44 (2009) | doi: 10.1016/j.ccr.2008.11.012 

Funding

This research was supported by funds from the National Institutes of Health, the Canadian Institutes of Health Research, the Institute of Cancer Research, and Cancer Research UK