LOXL2 in Cancer: A Two-Decade Perspective

Abstract

Lysyl Oxidase Like 2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises five lysine tyrosylquinone (LTQ)-dependent copper amine oxidases in humans. In 2003, LOXL2 was first identified as a promoter of tumour progression and, over the course of two decades, numerous studies have firmly established its involvement in multiple cancers. Extensive research with large cohorts of human tumour samples has demonstrated that dysregulated LOXL2 expression is strongly associated with poor prognosis in patients. Moreover, investigations have revealed the association of LOXL2 with various targets affecting diverse aspects of tumour progression. Additionally, the discovery of a complex network of signalling factors acting at the transcriptional, post-transcriptional, and post-translational levels has provided insights into the mechanisms underlying the aberrant expression of LOXL2 in tumours. Furthermore, the development of genetically modified mouse models with silenced or overexpressed LOXL2 has enabled in-depth exploration of its in vivo role in various cancer models. Given the significant role of LOXL2 in numerous cancers, extensive efforts are underway to identify specific inhibitors that could potentially improve patient prognosis. In this review, we aim to provide a comprehensive overview of two decades of research on the role of LOXL2 in cancer.

The role of LOXL2 in tumor progression, immune response and cellular senescence: a comprehensive analysis

“…Our initial comprehensive examination of LOXL2 across various cancer types revealed its prevalent overexpression and association with unfavorable clinical results. Depending on this research, LOXL2 was markedly increased in numerous tumors when analyzing paired (16 types of tumors) and unpaired (27 types of tumors) samples at the mRNA level and 10 tumor types of unpaired protein samples, which aligns with previous reports [ 20 , 21 ], especially for liver, lung, breast, kidney, uterine, head and neck cancers. Cox and Kaplan–Meier curve analysis indicated a significant association between elevated LOXL2 expression and an increased incidence of poor OS (15 tumor types), DSS (17 tumor types), DPI (13 tumor types), and PFI (24 tumor types).…”

“…This phenomenon is also viable in the case of distant metastasis, as the secretion of LOXL2 upon reaching distant organs can stimulate the restructuring of the ECM and initiate the development of premetastatic niches [ 53 – 55 ]. However, the efficacy of LOXL2 -targeted therapy was found to be suboptimal, as evidenced by the unsatisfactory patient outcomes observed in multiple randomized phase II clinical trials involving the humanized LOXL2 antibody Simtuzumab [ 22 , 23 ], and more targeted agents and combinational regimens are needed to enter clinical studies [ 20 ]. The current understanding of molecular biology in LOXL2 is not yet complete.…”

“…LOXL2 gene mutations were all “Deep Deletion” in USC, DLBC, CHOL, and UM, but were all “Amplification” in PCPG and THYM. However, a report revealed that LOXL2 overexpression is more common than mutation [ 20 ], follow-up studies are required for specific cancer types. Variations in LOXL2 expression led to passenger mutations in APOB, USH2A, VPS13B, and KMT2D genes.…”

Lysyl oxidase-like 2 as a predictor of hepatocellular carcinoma in patients with hepatitis C virus after sustained virological response

“…Notably, the promoter region of LOXL2 contains the SMAD binding sequence, indicating that LOXL2 expression increases in parallel with virus-induced inflammation and subsequent TGF-β expression 17 . LOXL2 expression is also triggered by the hypoxia/hypoxia-inducible factor-1 (HIF-1) pathway, or by ECM stiffness followed by the activation of integrins, c-Jun N-terminal kinase (JNK)/c-Jun, or MEK1/2-ERK1/2 17 , 44 .…”

Understanding the matrix: collagen modifications in tumors and their implications for immunotherapy

“…Mutations in LOXL2 are identified in skin cutaneous melanoma and uterine corpus endometrial carcinoma. However, LOXL2 mutational burden does not impact the fitness of human tumors, although it is possible that specific mutations could be important in specific types of tumors [ 111 ].…”