Lysyl oxidase mediates colon cancer metastasis in the skeleton

Caroline Reynaud, Floriane Pez, Delphine Goehrig, Géraldine Aimond, Pascal Sommer and Philippe Clezardin.

Metastasis is a multistep process involving dynamic interactions between tumor cells and the surrounding extracellular matrix (ECM), both at the primary tumor site and distant sites. ECM proteins are also known to participate in the formation of premetastatic niches in distant organs. In this respect, lysyl oxidase (LOX) is an ECM protein that could play a critical role during tumor progression. It catalyzes the cross-linking of collagens and elastin in the extracellular compartment, thereby regulating the tensile strength of tissues.

We have recently shown that LOX overexpression fosters primary tumor growth in a model of colorectal carcinoma (Pez et al., Cancer Research 2011). However, the impact of LOX on colon cancer metastasis incidence was still poorly understood. Here, using lentiviral transduction, LOX was either stably overexpressed or silenced in three different luciferase-expressing human colon carcinoma cell lines. Transduced cancer cell lines were then inoculated intravenously to immunodeficient mice and the occurrence of metastasis was monitored by noninvasive bioluminescence imaging of animals. In addition, animals were analyzed by radiography for the presence of osteolytic lesions in the skeleton. LOX overexpression in colon cancer cells substantially enhanced bone metastasis formation in animals. Conversely, LOX silencing drastically reduced the formation of osteolytic regions. Furthermore, we demonstrate that circulating and active LOX is involved both in the nidation of tumor cells in the bone marrow and in bone metastasis progression. We also provide evidence that LOX, by enhancing adhesion to COL1, regulates the attachment and colonization of colon cancer cells to the skeleton. In conclusion, our results suggest that LOX plays a critical role in mediating bone colonization by colon cancer cells.