Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Hoefsmit, Esmée P.; Völlmy, Franziska; Rozeman, Elisa A.; Reijers, Irene L. M.; Versluis, Judith M.; Hoekman, Liesbeth; Akkooi, Alexander C. J. van; Long, Georgina V.; Schadendorf, Dirk; Dummer, Reinhard; Altelaar, Maarten; Blank, Christian U.

doi:10.1158/2767-9764.crc-23-0015

Cited by 7 publications

(6 citation statements)

References 61 publications

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“…High circulating LRG1 levels have been reported in many cancers, where LRG1 has been proposed, or used, as a prognostic and diagnostic marker. Indeed, high LRG1 levels in cancer patients' plasma correlate with poor prognosis and survival ( 59 – 61 ), and resistance to standard of care therapy ( 62 ). The involvement and roles of LRG1 in key vascular processes are the scope of this review and will be discussed in detail.…”

Section: Lrg1 In Homeostasis and Diseasementioning

confidence: 99%

Section: Lrg1 and Cancermentioning

confidence: 99%

“…LRG1 expression has been studied in a range of malignancies where it has been shown to be elevated and to associate with poor prognosis and survival (23,61,62,193,194). In addition, raised blood LRG1 levels have been established as a tumor biomarker with potential clinical value and also as a predictive marker for cancer onset (30,59,60,62,193,(195)(196)(197)(198)(199)(200). A growing number of studies support an integral role for LRG1 in cancer, where it has been shown to control cell viability and apoptosis, and promote epithelial cells to undergo EMT, a crucial step in tumor progression and metastasis (27,28,30,31,(80)(81)(82)(83)(84)(201)(202)(203).…”

Section: Lrg1 and Cancermentioning

confidence: 99%

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The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Dritsoula,

Camilli,

Moss

et al. 2024

Front. Cardiovasc. Med.

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The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-β signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.

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Section: Lrg1 In Homeostasis and Diseasementioning

confidence: 99%

Section: Lrg1 and Cancermentioning

confidence: 99%

Section: Lrg1 and Cancermentioning

confidence: 99%

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The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Dritsoula,

Camilli,

Moss

et al. 2024

Front. Cardiovasc. Med.

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“…The improvement of survival outcomes in patients with advanced melanoma due to the introduction of immune checkpoint inhibitors (ICIs) and targeted therapy (TT) for BRAF mutated melanoma, is undoubtedly very remarkable; nevertheless a proportion of patients still have poor prognosis [1][2][3]. Therefore, a growing line of research is focusing on the identification of potential biomarkers that may guide the treatment strategy [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy

Mallardo,

Fordellone,

White

et al. 2023

J Transl Med

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Background Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. Methods A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb–IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. Results The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFβ2, a marker of the N2 neutrophils with immunosuppressive activity. Conclusions These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.

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“…Therefore, a growing line of research is focusing on the identi cation of potential biomarkers that may guide the treatment strategy [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy

Mallardo

Fordellone

White

et al. 2023

Preprint

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Background Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. Methods A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb–IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. Results The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which is correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFβ2, a marker of the N2 neutrophils with immunosuppressive activity. Conclusions These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.

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Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Cited by 7 publications

References 61 publications

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy

CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy

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