Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis

Abstract

Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no "cures" for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types. Cancer Res; 76(2); 188-92. Ó2016 AACR. Cancer Metastasis and the Importance of the Cellular MicroenvironmentThe spread of primary tumors to nonadjacent unrelated organs has proven to be a complex and difficult problem for researchers to tackle. This is because metastasis is a systemic process involving not only primary tumor cells, but also contributions from a vast and diverse range of nonmalignant host cells at both primary and secondary sites over varying timescales.Over the last two decades, it has become increasingly apparent in the field of cancer research that the genetic aberrations once seen as the primary drivers of cancer initiation and metastasis, can account for only a subset of the necessary steps required for progression. Additional contributions from the tumor microenvironment, dictated by both the tumor cells themselves, but more importantly by resident nonmalignant cells, provide an enormous repertoire of both soluble and insoluble cues, which facilitate metastasis. The dissemination of an isolated (and often surgically resectable) primary tumor to full-blown metastatic disease is a complex and reciprocal process, and it is currently unclear whether tumor cells or the microenvironment drives progression or they act equally. The deposition and posttranslational modification, as well as remodeling of the local extracellular matrix (ECM) has been shown to be critically important in metastasis both at primary and secondary sites. Similarly, the secretomes of cancer cells (and recruited host cells) have also been shown to be key in controlling the recruitment and response of nonmalignant host cells within the primary tumor microenvironment generating both feed-forward and feed-back signaling loops.The idea that a tumor can modulate not only the behavior of local cells and the re...

The Multiple Roles of Exosomes in Metastasis

“…They act as inducers of serum amyloid A3 (SAA3) which mediates accumulation of CD11 + myeloid cells via interaction with TLR4 and stimulation of NF-ĸB signaling (57). Recruitment of CD11 + myeloid cells to metastatic sites is further promoted by LOX activity which cross-links collagen type IV, thereby acting as a substrate for adherence of CD11 + myeloid cells (58,59). Deposition of FN, tenascin C, periostin and versican by recruited myeloid cells is another important step in formation of metastatic niches (52, [60][61][62].…”

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

“…ECM stiffening reflects an increase in protein abundance; particularly of fibrillar proteins such as collagens I and III, as well as their reorganization and posttranslation modifications that include lysyl oxidase -mediated cross-linking (Erler and Weaver 2009;Levental et al 2009;Egeblad et al 2010;Cox et al 2016). Although imaging elastography and unconfined compression analysis have consistently revealed an incremental increase in tissue stiffness as a function of tumor stage, grade atomic force microscopy (AFM) indentation analysis has also emphasized the heterogeneity of the ECM stiffness within a tumor (Evans et al 2012;Plodinec et al 2012;Yi et al 2013;Fenner et al 2014).…”

Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

“…Elevated LOX expression is linked to the disrupted collagen morphology and increased tissue stiffness often found in tumors, leading to aberrant cellular behavior (10,13). Activation of LOXs during cancer was also demonstrated to affect intracellular signaling pathways by modification of snail, (14) integrins (6), and repression of E-cadherin (15), leading to induction of epithelial-to-mesenchymal (EMT) transition.…”