Lysyl Oxidase Overexpressed in Mice that Undergo Surgery may Promote Metastasis

Tumor resection is one of the major treatment modalities for cancer. It is sometimes combined with chemo-radiation in order to reduce the risk of tumor re-growth or metastasis spread from existing residual disease. Yet, patients who undergo surgery may exhibit metastatic spread. Here we show that the host in response to radical surgery is vulnerable to metastasis seeding. Non-tumor bearing mice, which undergo surgery, succumb to LLC or EMT/6 lung metastasis earlier than control mice in an experimental lung metastasis assay. Similarly, mice injected with plasma from mice which underwent surgery were prone to metastasis seeding more than mice injected with plasma from control mice. Changes in primary tumor growth, angiogenesis and the colonization of bone marrow derived cells at the primary tumor site were documented following surgery. Importantly, increased LOX activity in the lungs of mice that underwent surgery resulted in lung extracellular matrix modulation. Consequently, the blockade of LOX family members by BAPN or by specific neutralizing antibodies reduced metastasis spread in the lungs of mice following surgery and increased their survival. Taken together, our results emphasize the modulation of the extracellular matrix in the pre-metastatic microenvironment induced by surgery, and suggest that LOX may contribute to surgery-induced metastasis. The study also offers new therapeutic intervention in combination with surgery to reduce risks of metastasis.