RETRACTED ARTICLE: The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

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 hypoxia1. Tumour-secreted proteins play a crucial role in these interactions2-5 and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable6. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality6,7. 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 ER-negative breast cancer patients. 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 coloniseCorrespondence and requests for materials should be addressed to janine.erler@bric.ku.dk and a.gartland@shef.ac.uk.

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

“…A specific cellular and molecular repertoire within the organ characteristic local microenvironment predisposes the affected individuals to the appearance of the so-called pre-metastatic niches that might be the crucial step in the overall BM development [46]. This Bfertile^microenvironment actively supporting the cancer advancement is strongly promoted by systemic hypoxic effects frequently appearing in individuals with cardiovascular disease and related syndromes being a powerful stratification factor for the predisposed individuals as recently reviewed by O. Golubnitschaja et al [1].…”

“…In particular, systemic hypoxia strongly contributes to the Bfertile microenvironment^creating pre-metastatic niches in distant organs [46,67]. Therefore, it has been highly recommended to select and stratify potentially predisposed individuals who may suffer from the systemic hypoxic effects such as CVD patients and BFlammer syndrome^individuals, in order to predict and prevent particularly aggressive cancer types and fatal metastatic disease [68].…”

Postmenopausal breast cancer: European challenge and innovative concepts

“…Systemic hypoxic effects linked to the cardiovascular component create this fertile microenvironment playing the central role in progressive BC and metastatic disease [3,9,10]. Thereby, the appearance of the Bpremetastatic niches^may occur prior to the tumour onset resulting in the particularly aggressive metastatic disease developing at early stages of breast cancer [5].…”

“…FS prevalence evaluated by individual symptoms Figure 1 summarises the prevalence of individual Flammer syndrome symptoms (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) in two groups of comparison-the BPostmenopausal breast cancer^patients versus the reference group of BBC-free^individuals. Higher prevalence in postmenopausal breast cancer (red) has been demonstrated for altogether 11 symptoms.…”

Organotropic metastasis: role of tumor exosomes

“…In 2005, Dr Lyden and colleagues proposed a term of pre-metastatic niche to describe the phenomenon that primary tumor could promote its own metastasis by recruiting bone marrow-derived cells to the distant organ and establish supportive metastatic environments [4]. Besides, tumor-derived soluble factors such as lysyl oxidase [5] have been also reported to induce organ-specific metastasis by formation of pre-metastatic niche in certain sites. However, the exact mechanism for metastatic organotropism is still unclear.…”