Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

SIMPLE SUMMARY: Why do most drugs have limited effects in difficult-to-treat cancers such as mesothelioma? One explanation commonly given in response is that not enough drug can get into the tumor to generate an anti-tumor effect. Fibrosis is a common element of mesothelioma that causes the area around the cancer to stiffen. By itself, fibrosis makes breathing difficult and causes a poor quality of life, but it also acts as a barrier stopping drugs from getting into the tumor, and limits the immune system’s ability to detect and access the tumor to kill it. In this review, we discuss how a family of proteins called lysyl oxidases is associated with fibrosis in many disease settings, including solid tumors and mesothelioma, the current status of efforts to therapeutically target these proteins and how targeting this family may have therapeutic applicability in the treatment and management of mesothelioma. ABSTRACT: Immunotherapies (such as checkpoint inhibitors) and standard chemotherapies (such as cisplatin) have limitations in the successful treatment of malignant pleural mesothelioma (MPM). Fibrosis is the accumulation of collagen in the extracellular matrix (ECM) of tissues, making them denser than that of healthy tissues and thereby affecting drug delivery and immune cell infiltration. Moreover, fibrosis severely affects the patient’s breathing and quality of life. The production of collagen and its assembly is highly regulated by various enzymes such as lysyl oxidases. Many solid tumors aberrantly express the family of lysyl oxidases (LOX/LOXL). This review examines how LOX/LOXLs were found to be dysregulated in noncancerous and cancerous settings, discusses their roles in solid tumor fibrosis and pathogenesis and explores the role of fibrosis in the development and poor clinical outcomes of patients with MPM. We examine the current preclinical status of drugs targeting LOX/LOXLs and how the incorporation of such drugs may have therapeutic benefits in the treatment and management of patients with MPM.