Lysyl oxidase (LOX) is a secreted
copper-dependent
amine oxidase whose primary function is to drive
collagen crosslinking and extracellular matrix stiffness. LOX in
colorectal cancer synergizes with
hypoxia-inducible factor-1 (HIF-1) to promote
tumor progression. Here we investigated whether LOX/HIF1 endows
colorectal cancer cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary
tumors from patients with
colorectal cancer was associated with poor clinical outcome, irrespective of HIF-1 In addition, LOX was expressed by
tumor cells in the bone marrow from
colorectal cancer patients with bone
metastases. In vivo experimental studies show that LOX overexpression in
colorectal cancer cells or systemic delivery of the
conditioned medium from LOX-overexpressing
colorectal cancer cells promoted
tumor cell dissemination in the bone marrow and enhanced osteolytic lesion formation, irrespective of HIF-1 Conversely, silencing or pharmacologic inhibition of LOX activity blocked dissemination of
colorectal cancer cells in the bone marrow and
tumor-driven osteolytic lesion formation. In vitro,
tumor-secreted LOX supported the attachment and survival of
colorectal cancer cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX overexpression in
colorectal cancer cells also induced a robust production of
IL6. In turn, both LOX and
IL6 were acting in concert to promote RANKL-dependent osteoclast differentiation, thereby creating an imbalance between
bone resorption and bone formation. Collectively, our findings show that LOX supports
colorectal cancer cell dissemination in the bone marrow and they reveal a novel mechanism through which LOX-driven
IL6 production by
colorectal cancer cells impairs bone homeostasis.
Cancer Res; 77(2); 268-78. ©2016 AACR.