Publication: Nature – Hypoxic breast cancer secretomes enhance bone metastasis through LOX

Thomas R. Cox, May 2015

The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

My research paper titled ‘The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase‘ which looked at how secreted factors from breast cancers can drive pre-metastatic niche formation in the bone to enhance tumour metastasis has just been published in Nature.

Breast Cancer Lysyl Oxidase LOX Bone Enzyme

Image: Nature – Schematic of Lysyl Oxidase (LOX)-mediated effects on bone homeostasis during breast cancer spread

The spread of breast cancer to the bone affects approximately 85% of breast cancer patients. Once breast cancer spreads to the bone it becomes largely untreatable and is accompanied by significant bone pain and other complications that typically lead to death.

In this paper we show that breast cancer cells can alter the behaviour of normal bone cells based on what they pump out into their surroundings. These tumour secreted factors cause changes to occur in the bone that actually go on to help the cancer cells make a new home in the bone.

We have discovered that certain types of breast cancer cells (Estrogen Receptor Negative [ER-]) produce large amounts of an enzyme called Lysyl Oxidase (LOX). This enzyme alters the way that bone cells behave leading to the generation of pre-metastatic niches. LOX works by increasing the number of bone destroying cells (called osteoclasts) and decreasing the number of bone-building cells (called osteoblasts). This leads to the generation of small holes in the bone, so called pre-metastatic niches. Pre-metastatic niches are defined as fertile microenvironments that form in an organ and go on to help the invasion, survival and/or proliferation of metastatic tumour cells. It is thought that these niches are a critical step in the spread of some cancers.

BoneRecon

Image: The generation of pre-metastatic lesions within the bone leads the formation of small holes that help tumour cells to make a new home in the bone

By blocking the action of LOX we can prevent the formation of pre-metastatic niches within the bone and in turn reduce the ability of breast cancer cells to spread to the bone. Furthermore, our findings show that in certain breast cancer patients, there may be a benefit in treating patients following diagnosis and surgery with bisphosphonates, an already approved drug in the clinic for the treatment of osteoporosis. Bisphosphonates work by blocking the action of bone destroying cells (osteoclasts). This also prevents cancer cell secreted LOX from generating pre-metastatic niches within the bone, and again reduces the ability of breast cancer cells to spread to the bone.

In summary, our insight into the very early mechanisms of bone metastases has identified a new step in bone metastasis and presents a new and exciting opportunity for therapeutic intervention.

Abstract
Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.

Links
View article on the Nature homepage
View abstract on PubMed
View the PDF

Citation
Cox TR,
Rumney RMH, Schoof EM, Perryman L, Høye AM, Agrawal A, Bird, D, Ab Latif N, Forrest H, Evans HR, Huggins ID, Lang G, Linding R, Gartland A, Erler JT. Hypoxic cancer secretomes induce pre-metastatic bone lesions through Lysyl Oxidase.
Nature (2015) doi:10.1038/nature14492

Funding
This research was supported by funding from Cancer Research UK, the Biotech Research and Innovation Centre (BRIC, University of Copenhagen), The University of Sheffield, The National Institute for Health Research Sheffield Clinical Research Facility, Breast Cancer Campaign, the Danish Cancer Society, The Lundbeck Foundation, Velux Foundations (VKR) and a Hallas Møller Stipendum from the Novo Nordisk Foundation.