Blocking Surgically Induced Lysyl Oxidase Activity Reduces the Risk of Lung Metastases

Abstract

SummarySurgery remains the most successful curative treatment for cancer. However, some patients with early-stage disease who undergo surgery eventually succumb to distant metastasis. Here, we show that in response to surgery, the lungs become more vulnerable to metastasis due to extracellular matrix remodeling. Mice that undergo surgery or that are preconditioned with plasma from donor mice that underwent surgery succumb to lung metastases earlier than controls. Increased lysyl oxidase (LOX) activity and expression, fibrillary collagen crosslinking, and focal adhesion signaling contribute to this effect, with the hypoxic surgical site serving as the source of LOX. Furthermore, the lungs of recipient mice injected with plasma from post-surgical colorectal cancer patients are more prone to metastatic seeding than mice injected with baseline plasma. Downregulation of LOX activity or levels reduces lung metastasis after surgery and increases survival, highlighting the potential of LOX inhibition in reducing the risk of metastasis following surgery.

ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis

“…ATP7A Is Necessary and Sufficient for Copper-Dependent Activity of LOX Family Members. The 4T1 cells were chosen as a model of metastatic human breast cancer because when orthotopically implanted into the mammary glands of mice, these cells readily metastasize to the lung in a LOX-dependent manner (7,23,26).…”

“…breast cancer | lung cancer | copper | lysyl oxidase | metastasis C opper is an essential micronutrient required as a catalytic cofactor for several metalloenzymes, including those involved in cancer-promoting activities (1). Copper-dependent enzymes with roles in tumor growth or metastasis include mitogen-activated kinase 1 (2,3), superoxide dismutase 1 (4), cytochrome c oxidase (5), and members of lysyl oxidase (LOX) family (6)(7)(8). The discovery that copper concentrations in serum and tumors are elevated in cancer patients and are correlated with disease severity has prompted speculation that copper delivery to oncogenic enzymes may be rate-limiting for tumor growth and metastasis (9)(10)(11).…”

Proinflammatory Macrophages Promote Multiple Myeloma Resistance to Bortezomib Therapy

“…Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001, using a two-tailed Student t test when comparing between two groups and one-way ANOVA followed by Tukey post hoc statistical test when comparing between more than two groups. Compelling data have shown that the major therapies for cancer, including chemotherapy, radiotherapy, and surgery, induce host effects (indirect effects) that may lead to enhanced tumor aggressiveness and subsequent relapsed disease (3,28,29). For example, several chemotherapeutic drugs have been shown to support the emergence of a tumor cell metastatic phenotype in lung carcinoma murine models, mainly by inducing the secretion of matrix-metalloproteinases from bone marrowderived cells (30).…”

Lysyl oxidase promotes neuronal ferroptosis exacerbating seizure-induced hippocampal damage

“…Nowadays, there is substantial evidence supporting that Lox family possesses multiple biological functions, in addition to the intra-and inter-molecular cross-linking of collagen and elastin fibers. It has been shown that Lox promotes cancer migration, adhesion and metastasis in multiple types of cancers including colorectal cancer, breast cancer and lung cancer (26,39,40). Blockade of Lox by a pharmacological inhibitor BAPN or CCT365623 is able to delay tumor progression and cancer metastasis (40,41).…”

“…It has been shown that Lox promotes cancer migration, adhesion and metastasis in multiple types of cancers including colorectal cancer, breast cancer and lung cancer (26,39,40). Blockade of Lox by a pharmacological inhibitor BAPN or CCT365623 is able to delay tumor progression and cancer metastasis (40,41). Moreover, the deleterious role of Lox in brain has been also observed in neuropathological states such as Alzheimer's disease and spinal cord injury (42,43).…”