“…This raises the possibility that LRG1 corrupts other key angiogenic processes which are responsible for vascular maturation and stability. For instance, data from our recent work on tumour vasculature [ 86 ] suggest that LRG1 may also disrupt the normal crosstalk between endothelial cells and pericytes, which is an essential prerequisite of vascular homeostasis, thus making vessels unstable and more prone to sprouting. Fig.…”
Section: Reviewmentioning
confidence: 99%
“…The effects of LRG1 on the cancer vasculature are therefore most likely inevitable and supportive of tumour progression. Indeed, we observed in a number of mouse tumour models that knockout of the Lrg1 gene, or its inhibition through a function-blocking antibody, delayed tumour growth and increased animal survival [ 86 ]. Moreover, in the absence or inhibition of LRG1, the tumour vasculature exhibited enhanced pericyte coverage and improved function suggesting that LRG1 prevents mature vessels from forming in the TME (Fig.…”
Section: Reviewmentioning
confidence: 99%
“…This has led to the hypothesis that restoring vessel function, a process referred to as vessel or vascular normalization , will reverse the pro-oncogenic TME and improve the delivery and effectiveness of current standards of care and immunotherapies [ 205 ]. In our recent study we demonstrated that vascular normalization, brought about by LRG1 inhibition with a function-blocking antibody, enhanced the effectiveness of cytotoxic (cisplatin), adoptive T cell and checkpoint inhibitor therapies [ 86 ]. In the case of immunotherapies, there was a significant switch from a less inflamed TME to a more inflammatory, or “hot”, tumour response.…”
The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.
“…This raises the possibility that LRG1 corrupts other key angiogenic processes which are responsible for vascular maturation and stability. For instance, data from our recent work on tumour vasculature [ 86 ] suggest that LRG1 may also disrupt the normal crosstalk between endothelial cells and pericytes, which is an essential prerequisite of vascular homeostasis, thus making vessels unstable and more prone to sprouting. Fig.…”
Section: Reviewmentioning
confidence: 99%
“…The effects of LRG1 on the cancer vasculature are therefore most likely inevitable and supportive of tumour progression. Indeed, we observed in a number of mouse tumour models that knockout of the Lrg1 gene, or its inhibition through a function-blocking antibody, delayed tumour growth and increased animal survival [ 86 ]. Moreover, in the absence or inhibition of LRG1, the tumour vasculature exhibited enhanced pericyte coverage and improved function suggesting that LRG1 prevents mature vessels from forming in the TME (Fig.…”
Section: Reviewmentioning
confidence: 99%
“…This has led to the hypothesis that restoring vessel function, a process referred to as vessel or vascular normalization , will reverse the pro-oncogenic TME and improve the delivery and effectiveness of current standards of care and immunotherapies [ 205 ]. In our recent study we demonstrated that vascular normalization, brought about by LRG1 inhibition with a function-blocking antibody, enhanced the effectiveness of cytotoxic (cisplatin), adoptive T cell and checkpoint inhibitor therapies [ 86 ]. In the case of immunotherapies, there was a significant switch from a less inflamed TME to a more inflammatory, or “hot”, tumour response.…”
The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.
“…19 Another study found that the administration of LRG-1 gene inhibitors successfully suppressed the tumor progression in mice and prolong its survival. 20 Another study showed that there was an increase in LRG-1 expression in colorectal cancer and pancreatic cancer tissue compared to the adjacent normal tissue. The LRG-1 contributes to inducting migration and invasion of cancer cells.…”
Objective: To determine if the level of LRG-1 in urine correlates with cervical cancer stage, histology type and histology gradingMethod: This cross-sectional study using ELISA to test urinary LRG-1 of 59 cervical cancer patients. Data were analyzed using Kruskal-Wallis test.Results: From the total of 59 samples, LRG-1 in urine ranged from 0.48 ng/mL to 170.43 ng/mL, with median value 58.42 ng/mL. A median value of 21.42±52.29 ng/mL was found in the urine at early stage and 115.32±59.36 ng/mL at advanced stage. Most patients had cervical cancer at advanced stage (69.4%), squamous cell carcinoma (66.1%), and grade cannot be assessed (45.8%). Median LRG-1 levels were highest in squamous cell carcinoma (66.42±60.89 ng/mL) and poorly differentiated (127.74 ±54.13 ng/mL). LRG-1 levels were significantly correlated with cervical cancer stage (p-value=0.045) but not histological type (p-value=0.940) or histopathological grade (p-value=0.488).Conclusion: The more advanced the cervical cancer stage, the more elevated urinary LRG-1 levels. LRG-1 contributes to angiogenesis and antiapoptotic processes in cancer. Further studies are required to identify and evaluate LRG-1 in urine as an important biomarker for making clinical decisions and developing potential treatments.Hubungan Kadar Protein Leucine-Rich-α-2-Glycoprotein-1 (LRG-1) Urine dengan Stadium, Tipe Histologis, dan Derajat Diferensiasi Kanker ServiksAbstrakTujuan: Untuk mengetahui hubungan kadar LRG-1 dalam urine dengan stadium, tipe histologis, dan derajat diferensiasi kanker serviks.Metode: Studi ini menggunakan desain penelitian cross-sectional pada 59 perempuan yang telah didiagnosis kanker serviks, kemudian diperiksa kadar protein LRG-1 dalam urine dengan metode ELISA. Uji statistik menggunakan Kruskal Wallis. Hasil: Dari total 59 sampel didapatkan kadar LRG-1 dalam urine terendah 0,48 ng/mL dan tertinggi 170,43 ng/mL, nilai median 58,42 ng/mL. Nilai median pada stadium awal 21,42±52,29 ng/mL dan stadium lanjut 115,32±59,36 ng/mL. Lebih banyak penderita mengalami kanker serviks pada stadium lanjut (69,4%), tipe histopatologis Squamous Cell Carcinoma (66,1%), derajat diferensiasi tidak dapat ditentukan (45,8%). Median tertinggi kadar LRG-1 pada tipe Squamous Cell Carcinoma (66,42±60,89 ng/mL), dan derajat diferensiasi yang buruk (127,74±54,13 ng/mL). Terdapat hubungan yang signifikan antara kadar LRG-1 dan stadium kanker serviks (nilai p = 0,045), tetapi tidak dengan tipe histologis (nilai p=0,940) dan derajat diferensiasi (nilai p=0,488).Kesimpulan: Semakin tinggi stadium maka semakin tinggi kadar protein LRG-1 dalam urine. LRG-1 berperan dalam proses angiogenesis dan antiapoptosis pada kanker. Diperlukan penelitian lebih lanjut agar identifikasi dan evaluasi biomarker LRG-1 urine dapat menjadi penanda penting yang membantu dalam pengambilan keputusan klinis, serta pengembangan terapi.Kata Kunci: Derajat diferensiasi, Kanker serviks, LRG-1, Stadium, Tipe histologis
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