Researchers from the University of Sheffield and University of Copenhagen identified a new mechanism of regulation of bone homeostasis and metastasis, paving the way to new therapeutic strategies with important clinical implications for breast cancer. The study is entitled “The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase” and was published in the journal Nature.
Tumor metastasis is a very complicated process involving interactions between cancer cells and host stroma at both primary and secondary sites, and is highly influenced by microenvironmental factors such as hypoxia. The proteins released by the tumors have a pivotal role in these interactions and are potential therapeutic targets. Metastasis of breast cancer to the bone occur in about 85% of patients with advanced disease and is usually untreatable. In particular, osteolytic bone lesions, where the bone is destroyed, lead to incapacitating skeletal complications and increased patient morbidity and mortality. However, the molecular interactions leading to the primary events of osteolytic lesion formation are not well understood.
In this study, the research team showed that hypoxia is specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. They identified the enzyme lysyl oxidase (LOX) as the protein associated with bone-tropism of tumor cells and tumor relapse. The authors observed that high expression of LOX in primary breast tumours or systemic delivery of LOX, led to osteolytic lesion formation while inhibition of LOX activity or abolishment of LOX expression blocked osteolytic lesion formation by the tumor. As such, LOX seems to favour tumor metastasis.
It seems that the enzyme lysYl Oxidase (LOX) released from the primary tumor function by causing holes in bone and preparing the bone for the subsequent colonization by tumor cells.
The authors treated a mouse model of breast tumor with bisphosphonates, an available class of drugs that can prevent the loss of bone mass commonly used as an osteoporosis therapy, and observed no bone alterations or metastasis in this model.
“We are really excited about our results that show breast cancer tumors send out signals to destroy the bone before cancer cells get there in order to prepare the bone for the cancer cells’ arrival” said Dr. Gartland, co-led author of the study, in a news release.
Dr. Gartland added that the team now wants to investigate the mechanisms by which tumor-secreted LOX can interact with bone cells, this way developing novel compounds to inhibit the formation of bone lesions, cancer metastasis or other bone diseases.
Study co-author Dr. Janine Erler explained that tumor invasion into the bone is very difficult to treat. She added that these findings can contribute towards a better understanding of the mechanisms by which tumor cells prepare (prime) the bone for the arrival of colonizing cells. If this process is blocked and can be translated into the clinic, breast tumor metastasis could be blocked enhancing patient overall survival.
Katherine Woods, from the Breast Cancer Campaign and Breakthrough Breast Cancer, said this study reinforces previous findings supporting the role of bisphosphonates to block metastatic breast cancer. “Our newly-formed charity is determined that by 2050, no one will lose their life to breast cancer and we’ll do this by ramping up our research efforts, in this area in particular, doing everything possible to achieve that goal,” she added.