Bone tumors are rare but clinically consequential. Because survival rates are far higher when malignant disease is localized rather than metastatic, early diagnosis is critical. Yet the diagnostic pathway has long depended on imaging and histopathological evaluation, both of which rely on morphological changes that may be subtle or absent in the earliest stages of disease. Malignant bone tumors are particularly treacherous: their rarity and nonspecific symptoms often delay diagnosis, and late detection of primary malignant bone tumors is associated with poor prognosis. Benign lesions, which are far more common in everyday clinical practice, complicate the picture further, since imaging alone cannot always determine whether a lesion is non-aggressive.

This diagnostic gap is what motivated the research team to investigate ESM-1. The molecule is a soluble proteoglycan produced primarily by endothelial cells, the cells that line blood vessels, and it participates in endothelial activation and angiogenesis, the formation of new blood vessels. Both processes are highly relevant to tumor biology. Increased ESM-1 levels have been documented in tumor cells and in the vessels that feed tumors across a range of human cancers, and high levels are associated with poor prognosis in many malignancies. Growing evidence suggests ESM-1 facilitates tumor progression by enhancing cancer cell motility, proliferation, and cancer stem cell properties. It is also considered a potential immune-inflammatory marker, and it has been implicated in conditions ranging from neurological and cardiometabolic disorders to lung, kidney, and liver diseases.

The study enrolled 60 participants diagnosed with bone tumors at the Orthopedics Polyclinic of Atatürk University Research Hospital between August 2023 and December 2024, along with 30 healthy controls matched for age and gender. The tumor group was deliberately balanced, with 30 benign and 30 malignant cases; the malignant subgroup included both primary malignant tumors and bone metastases, all confirmed histopathologically. Participants undergoing active cancer therapy and those with obesity, metabolic syndrome, hypertension, coronary artery disease, or hepatic or renal insufficiency were excluded, since these conditions can themselves alter ESM-1 levels. Venous blood was drawn from all participants, and serum ESM-1 concentrations were measured using an enzyme-linked immunosorbent assay, with every specimen analyzed in duplicate.

The results were unambiguous at the group level. Mean ESM-1 in the bone tumor group was 246.63 ng/L, compared with 103.8 ng/L in healthy controls, a difference that was highly statistically significant. When the researchers applied receiver operating characteristic analysis, the area under the curve for detecting the presence of a bone tumor was 0.895, a value generally considered good diagnostic performance. Using a cut-off of 138.94 ng/L, the test achieved 78.3 percent sensitivity and 80.0 percent specificity. Binary logistic regression confirmed that ESM-1 was a significant independent predictor of tumor presence, with an odds ratio of 1.038 and an overall classification accuracy of 78.9 percent.

The most eye-catching results emerged when the researchers split the tumor group into benign and malignant subgroups. Mean ESM-1 was 142.63 ng/L in benign cases and 350.62 ng/L in malignant cases. In subgroup ROC analyses, ESM-1 perfectly discriminated malignant tumors from both benign tumors and healthy controls, with an area under the curve of 1.000 and sensitivity and specificity of 100 percent at cut-offs of 204.54 ng/L and 195.00 ng/L, respectively. Positive and negative predictive values likewise reached 100 percent in these comparisons. By contrast, distinguishing benign tumors from healthy controls was considerably harder: the area under the curve fell to 0.789, with sensitivity and specificity of 70.0 percent at a cut-off of 125.54 ng/L.

The study also examined conventional inflammatory markers. Erythrocyte sedimentation rate and C-reactive protein were both significantly higher in the malignant subgroup than in the benign subgroup, and ESM-1 levels correlated positively with both markers, with correlation coefficients of 0.570 for CRP and 0.561 for ESR. This pattern fits the emerging view of ESM-1 as a molecule that sits at the intersection of endothelial biology and inflammation. It also aligns with prior oncology findings: circulating ESM-1 has been shown to mediate EGFR-driven progression in non-small cell lung cancer, plasma levels can predict outcomes in triple-negative breast cancer, and high ESM-1 values forecast progression-free survival and recurrence in prostate cancer. In endometrial and ovarian disease, benign conditions did not raise ESM-1, while malignancies did.

The connection to bone metastasis is particularly intriguing. The skeleton is a preferred site of metastasis for common solid tumors, and bone metastases occur in up to 70 percent of patients with advanced breast or prostate cancer. Endothelial inflammation, glycocalyx disruption, and increased endothelial permeability are key early events in metastasis, and ESM-1, as a marker of endothelial function, appears to rise in the early stages of that process. The authors note that the molecular mechanisms by which metastatic cancer recognizes, infiltrates, and colonizes bone remain incompletely understood, and a circulating endothelial marker could offer a window into that biology.

Despite the headline-perfect numbers, the researchers themselves urge caution. An area under the curve of 1.000 with 100 percent sensitivity and specificity is extremely rare in real-world clinical settings, and the authors acknowledge that such excellent performance may reflect overfitting in a small, single-center sample of 90 participants. The heterogeneous nature of bone tumors also limits subtype-specific assessment, and the study lacked a direct comparison between ESM-1 levels and histopathological findings, which remain the reference standard for definitive diagnosis. Without an independent, multicenter validation cohort, the optimal threshold values reported here cannot yet be generalized to other populations.

Even so, the study demonstrates the potential clinical applicability of serum ESM-1 as a minimally invasive biomarker obtainable from a simple peripheral blood sample, complementing rather than replacing imaging and biopsy. The authors conclude that ESM-1 may have genuine diagnostic value in distinguishing both the presence and the malignancy of bone tumors, but that the findings must be confirmed in larger, more homogeneous populations across multiple centers. If those validation studies succeed, a routine blood draw could eventually become an early triage tool that flags which patients with suspicious bone lesions need urgent specialist attention, potentially shortening the diagnostic odyssey that so often delays treatment of malignant bone disease.

Subject of Research: Diagnostic value of serum ESM-1 (endocan) levels for detecting bone tumors and distinguishing malignant from benign lesions

Article Title: Diagnostic value of endothelial-specific molecule-1 levels in patients with bone tumors

Article References: Senocak, E., Ozturk, N., Keskin, A., Aygun, U., Dag, I., & Celik, M. (2026). Diagnostic value of endothelial-specific molecule-1 levels in patients with bone tumors. Acta Biochimica Polonica, 73, Article 17417. https://doi.org/10.3389/abp.2026.17417

Image Credits: AI Generated

DOI: 10.3389/abp.2026.17417

Keywords: ESM-1, endocan, bone tumors, biomarker, ELISA, ROC analysis, malignancy, diagnostic sensitivity, angiogenesis, endothelial cells, bone metastasis, C-reactive protein