Serum midkine as non-invasive biomarker for detection and prognosis of non-small cell lung cancer

Stern, Louisa; Mueller, Erik T.; Bellon, Eugen; Reeh, Matthias; Grotelueschen, Rainer; Guengoer, Cenap; Melling, Nathaniel; Goetz, Mara; Perez, Daniel; Izbicki, Jakob R.; Rawnaq-Möllers, Tamina; Ghadban, Tarik

doi:10.1038/s41598-021-94272-8

Cited by 9 publications

(10 citation statements)

References 29 publications

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“…High MDK expression was also associated with lower overall survival, in EGFR mutant and wild-type patient tumors ( p< 0.05) ( Figure 4E ). This observation aligns with a previous study where NSCLC patients displayed increased protein expression of serum MDK compared to healthy individual controls, and expression was associated with lower overall survival ( 65 ).…”

Section: Resultssupporting

confidence: 92%

“…This suggests that there may be distinct secretome profiles between pre-malignant and malignant stages of lung transformation. We assessed the top five over-expressed and under-expressed proteins in malignant vs non-malignant states for their potential as biomarker candidates and found that two, NPC2 and MDK - both of which are predicted to have a signal peptide and extracellular localization ( Supplementary Table 1 ) – have been found to be over-expressed in mouse LUAD plasma and NSCLC patient serum, respectively, confirming their secretion ( 64 , 65 ). We queried the 91 differentially expressed proteins for GO terms associated with biological processes, molecular functions, and cellular components ( Figure 2C ).…”

Section: Resultsmentioning

confidence: 97%

“…The secretome profile of the LUAD cell lines had a broad scope of biological functions ( Figure 3C ) which may be due to additional genetic changes specific to each NSCLC cell line, beyond EGFR and p53, such as p16 that can affect the secretome profile ( 90 , 91 ). Using transcriptome data, we found genes for 16 of these proteins which were expressed specifically in EGFR mutant LUAD, suggesting they may be biomarker candidates for this molecular subtype of lung cancer ( Figure 3D ) ( 65 , 78 ). A subset of these were also associated with patient survival in EGFR mutant LUAD, and we validated MDK, GDF15, and SPINT2 by ELISA, confirming their secretion and association with the malignant state.…”

Section: Discussionmentioning

confidence: 99%

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Characterizing the secretome of EGFR mutant lung adenocarcinoma

Luu,

Johnson,

Jajarmi

et al. 2024

Front. Oncol.

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BackgroundLung cancer is the leading cause of cancer related death worldwide, mainly due to the late stage of disease at the time of diagnosis. Non-invasive biomarkers are needed to supplement existing screening methods to enable earlier detection and increased patient survival. This is critical to EGFR-driven lung adenocarcinoma as it commonly occurs in individuals who have never smoked and do not qualify for current screening protocols.MethodsIn this study, we performed mass spectrometry analysis of the secretome of cultured lung cells representing different stages of mutant EGFR driven transformation, from normal to fully malignant. Identified secreted proteins specific to the malignant state were validated using orthogonal methods and their clinical activity assessed in lung adenocarcinoma patient cohorts.ResultsWe quantified 1020 secreted proteins, which were compared for differential expression between stages of transformation. We validated differentially expressed proteins at the transcriptional level in clinical tumor specimens, association with patient survival, and absolute concentration to yield three biomarker candidates: MDK, GDF15, and SPINT2. These candidates were validated using ELISA and increased levels were associated with poor patient survival specifically in EGFR mutant lung adenocarcinoma patients.ConclusionsOur study provides insight into changes in secreted proteins during EGFR driven lung adenocarcinoma transformation that may play a role in the processes that promote tumor progression. The specific candidates identified can harnessed for biomarker use to identify high risk individuals for early detection screening programs and disease management for this molecular subgroup of lung adenocarcinoma patients.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Characterizing the secretome of EGFR mutant lung adenocarcinoma

Luu,

Johnson,

Jajarmi

et al. 2024

Front. Oncol.

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“…Serum midkine (MDK), as a lymphangiogenesis-related biomarker, its overexpression has been identified in patients with NSCLC as a potential therapeutic target for its development, metastasis, and angiogenesis ( 82 , 83 ). Lymphangiogenesis, in addition to angiogenesis, mediates tumor vascularization, which meets the oxygen and nutrient requirements for tumor growth and metastasis ( 84 ).…”

Section: Pathogenesismentioning

confidence: 99%

A review of obstructive sleep apnea and lung cancer: epidemiology, pathogenesis, and therapeutic options

Yuan,

Hu,

et al. 2024

Front. Immunol.

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Despite undeniable advances in modern medicine, lung cancer still has high morbidity and mortality rates. Lung cancer is preventable and treatable, and it is important to identify new risk factors for lung cancer, especially those that can be treated or reversed. Obstructive sleep apnea (OSA) is a very common sleep-breathing disorder that is grossly underestimated in clinical practice. It can cause, exacerbate, and worsen adverse outcomes, including death and various diseases, but its relationship with lung cancer is unclear. A possible causal relationship between OSA and the onset and progression of lung cancer has been established biologically. The pathophysiological processes associated with OSA, such as sleep fragmentation, intermittent hypoxia, and increased sympathetic nervous excitation, may affect normal neuroendocrine regulation, impair immune function (especially innate and cellular immunity), and ultimately contribute to the occurrence of lung cancer, accelerate progression, and induce treatment resistance. OSA may be a contributor to but a preventable cause of the progression of lung cancer. However, whether this effect exists independently of other risk factors is unclear. Therefore, by reviewing the literature on the epidemiology, pathogenesis, and treatment of lung cancer and OSA, we hope to understand the relationships between the two and promote the interdisciplinary exchange of ideas between basic medicine, clinical medicine, respiratory medicine, sleep medicine, and oncology.

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“…An s-MK-positive status has been reported to be associated with poor prognosis in some solid tumors such as colorectal cancer [13] and nonsmall cell lung cancer [14], whereas an s-MK-positive status has been reported to be not a poor prognostic factor in esophageal [15] and gastric cancers [16]. The correlation between an s-MK-positive status and the prognosis of patients with HCC has not been published.…”

Section: Introductionmentioning

confidence: 99%

Prognostic and diagnostic effects of high serum midkine on patients with hepatocellular carcinoma

Okada,

Otsuka,

Kajiwara

et al. 2023

Preprint

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Background Midkine (MK) is a soluble cytokine, and its serum levels strongly correspond with protein expression levels in tumors. This study aimed to clarify the clinicopathological and prognostic significance of serum MK (s-MK) in patients with hepatocellular carcinoma (HCC).Methods Serum samples were obtained before surgery from 123 patients with HCC who underwent surgery between 2012 and 2020. Based on the receiver operating characteristics curve, the best cutoff value for s-MK in differentiating HCC from healthy cases was 426 pg/mL. Patients’ clinicopathological variables and overall survival were compared between the s-MK-positive group and the s-MK-negative group.Results The sensitivity, specificity, and accuracy of s-MK were 82.1%, 97.4%, and 88.0%, respectively. An s-MK-positive status was significantly associated with the number of tumors (≥ 2). The positivity rate of s-MK was significantly higher than that of α-fetoprotein and protein induced by vitamin K absence-II. In total, only 28% of the patients were positive for s-MK. The s-MK positive group showed significantly worse overall survival than the s-MK negative group. The multivariate analysis revealed that an s-MK-positive status was independently associated with poor prognosis.Conclusion s-MK was useful in detecting early HCC. A s-MK-positive status was associated with the number of tumors and was an independent prognostic risk factor.

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Serum midkine as non-invasive biomarker for detection and prognosis of non-small cell lung cancer

Cited by 9 publications

References 29 publications

Characterizing the secretome of EGFR mutant lung adenocarcinoma

Characterizing the secretome of EGFR mutant lung adenocarcinoma

A review of obstructive sleep apnea and lung cancer: epidemiology, pathogenesis, and therapeutic options

Prognostic and diagnostic effects of high serum midkine on patients with hepatocellular carcinoma

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