Cervical cancer is the fourth most common cancer in women and also is one of the leading causes of cancer related death in women [1]. Approximately 29,500 women die due to cervical cancer in China each year, accounting for approximately 11% of cervical cancer deaths worldwide [2]. Cervical fluid-based cytology and human papilloma virus (HPV) testing can effectively screen for cervical cancer. However, clinicians are always concerned about whether there may be a simpler and more convenient method, such as serum detection, that can detect cervical cancer early and help monitor tumor progression more effectively.

Recently, the angiopoietin (Ang)/tyrosine kinase receptor (Tie) system, the second largest angiogenic system after vascular endothelial growth factor; (VEGF), has attracted increasing attention because targeting VEGF has demonstrated limited efficacy in cervical cancer detection and monitoring [3]. Ang/Tie signaling mainly includes two ligands (Ang-1 and Ang-2) and two receptors (Tie-1 and Tie-2), which are expressed in endothelial cells (ECs). Ang-1 and Ang-2 both bind directly to Tie-2, thus playing a critical role in vascular development, physiological and pathological angiogenesis, and cancer cell invasion and metastasis [4,5]. Tie-1 and Tie-2 are homologous receptors, their extracellular amino acid sequence consistency is 33%, while that of the intracellular region is 76%. However, the ligand for Tie-1 has not been determined thus far [3,6], and research on its function and related mechanisms has been progressing slowly. Current studies suggest that Tie-1 may be a key factor in regulating the Ang/Tie pathway.

Most studies on Tie-1 have focused on its function and related mechanisms within endothelial angiogenesis. In physiological angiogenesis, Tie-1 can bind directly to Tie-2 to form polymers, reduce the internalization of phosphorylated Tie-2 (pTie-2) and protein degradation (lysosomal pathway), stabilize the phosphorylation signal for Tie-2, and positively regulate Ang/Tie-2 signaling to promote the survival and migration of endothelial cells [7]. In tumor angiogenesis, the deletion of the Tie-1 gene in ECs was found to inhibit the phosphorylation level at Tie-2 y1106 and reduce the migration ability of ECs [8]. Downregulation of Tie-1 expression in ECs can inhibit tumor growth, and Tie-1 depletion can improve the anti-tumor angiogenesis effect of Ang/Tie-2 targeted therapy [9].

However, research on the expression of Tie-1 in tumors and its association with the clinicopathological characteristics and prognosis of tumor patients, as well as the mechanisms mediating its role in tumor progression, have not been well studied. A few studies have demonstrated that Tie-1 is highly expressed in tumor cells in some cases of invasive ductal carcinoma of the breast, and is positively associated with the rate of lymph node metastasis [10]. In colorectal adenocarcinoma cells, Tie-1 expression is positively correlated with depth of invasion, tumor stage, and lymph node metastasis [11]. A recent study reported that high baseline circulating Tie-1 levels in breast cancer predict a worse prognosis [10]. Our previous studies have shown that Tie-1 is highly expressed in cervical squamous cancer cells as compared with normal squamous cells [5]. However, the clinical significance of circulating Tie-1 in cervical cancer remains unclear. Therefore, in this study, we investigated whether serum Tie-1 (sTie-1) is a valuable marker for predicting the progression and prognosis of cervical cancer.

We conducted a single-arm prospective study, with serum samples collected from 75 patients with cervical cancer, 40 cervical intraepithelial neoplasia (CIN) patients, and 55 healthy women (controls) presenting for primary care at the Department of Gynecology at the First Affiliated Hospital of Shihezi University School of Medicine between August 2017 and August 2020. The 75 cases of cervical carcinoma included 63 patients with cervical squamous cell carcinoma (CSCC) and 12 with cervical adenocarcinoma (CADC). The 40 cases of CIN included 17 cases of CIN2 and 23 cases of CIN3. Each diagnosis of cervical cancer was made by two or more clinicians (i.e., oncologists and pathologists) at the hospital. The prognostic value for sTie-1 in cervical cancer patients was evaluated according to the patients’ follow-up data as of October 2021. The median follow-up time was 30 months (range, 6–56 months). Among the 75 patients, 18 had a recurrence and 10 died. Patients with inflammation (i.e., abnormally elevated levels of C-reactive protein or procalcitonin), other types of cancer, connective tissue disease, or atherosclerosis (determined based on anamnestic data or abnormal imaging studies) were excluded from the current study. The average age and age range of patients of normal group were 53 (range, 28–72) years, the average age and range of patients in the CIN group were 51 (range, 41–69) years, and the average age and range of cervical cancer group were 55 (range, 35–83) years. There was no significant difference in the age of the three groups by one way ANOVA (F = 2.607, p = 0.077). This study was approved by the hospital ethics committee at our medical center (approval number: 201704001) and written informed consent was obtained from all enrolled participants. This research was conducted in accordance with the principles of the Declaration of Helsinki.

Cervical cancer is one of the most frequently occurring malignancies in women, particularly metastatic cervical cancer resulting in a poor prognosis [12,13]. In our study, we found that the expression of sTie-1 gradually increased with an increase in the severity of cervical lesions, and that a sTie-1 cut-off value of 1882.64 pg/ml could effectively distinguish cervical cancer patients from healthy controls. Patients with elevated sTie-1 levels showed statistically significant associations with advanced FIGO stage, larger tumor size, and pelvic lymph node metastasis, and higher sTie-1 levels predicted poorer prognosis for patients with cervical cancer. These results suggest that serum Tie-1 may be a valuable biological marker for predicting progression and prognosis in cervical cancer.

The mechanisms of action mediating the effects of Tie-1 in tumor growth and progression are currently a hot topic in the medical research community. Recent research has shown that acute and chronic inflammation leads to cleavage of the Tie-1 ectodomain in ECs, resulting in increased levels of the soluble extracellular domain of Tie-1 and decreased levels of the intracellular domain, transforming Ang-2 from a Ang-1/Tie-2 agonist to an antagonist and initiating a positive feedback loop through FOXO1-driven Ang-2 expression, thereby stimulating pathological angiogenesis [14]. It is well known that the systemic effects of tumors are similar to those of general inflammation. In a study on breast cancer, the median circulating plasma Tie-1 level of metastatic patients was statistically significantly higher than that of healthy controls [10], and our previous experiment showed that cervical cancer cell lines secrete soluble Tie-1 (similar to ECs) [5]. Consistent with these studies, we found that the median level of sTie-1 was statistically significantly increased in patients with cervical cancer as compared with CIN patients and healthy controls in the current study, and that cervical cancer patients with higher sTie-1 levels had poorer survival. A question of interest is that of the role of mediating mechanisms in cervical cancer, which may be similar to those seen in inflammation, with tumor conditions potentially leading to Tie-1 extracellular cleavage and activating the ANG/Tie-2 pathway, resulting in tumor angiogenesis. As mentioned above, previous studies have shown that cervical cancer cells can express Tie-1 at levels similar to ECs, leading to the question of whether Tie-1 cleavage mainly occurs in endothelial cells or in cancer cells. The specific mechanisms mediating these observations are worth exploring in depth in future research.

To the best of our knowledge, Tie-1 studies in human tumors are limited. In breast cancer, enhanced expression of sTie-1 is positively correlated with lymphatic metastasis and shorter survival [10] in hepatocellular carcinoma (HCC) patients, higher Tie-1 expression predicts poorer prognosis [15]. Our study demonstrates that cervical cancer patients with higher sTie-1 levels have larger tumors, more advanced progression, a greater likelihood of lymph node metastasis, and shorter PFS, and a multivariate-adjusted Cox proportional hazards model indicated that cervical cancer patients with high sTie-1 levels were 3.123 times more likely to have a recurrence than those with low sTie-1 levels. Additionally, previous research has found that Tie-1 deletion in experimental murine metastasis models prevents extravasation of tumor cells into the lungs and reduces metastatic foci [9]. These studies indicate that Tie-1 may play an independent role in tumor growth and progression, and may thus be an attractive novel target for cervical cancer therapy. Moreover, in colorectal cancer [11], Tie-1 positive cells were enriched in tumor cells with cancer stemness properties, suggesting that Tie-1 may have potential clinical applications in targeting cancer stem cells.

In the current study, we also showed that sTie-1 effectively distinguished CSCC from healthy controls and patients with CIN, and was especially efficacious in distinguishing cervical cancer patients from healthy controls. The role of sTie-1 concentrations in differentiating cervical cancer from CIN was likewise statistically significant. The AUC value of the ROC curve for sTie-1 (detecting cervical cancer as compared with healthy controls) was 0.846, which was higher than that of sAng-2 (0.769) and the sAng-1:sAng-2 ratio (0.719), as reported in our previous study [16]; the corresponding sensitivity and specificity values were 78.7 and 94.5%, respectively, indicating that, compared with sAng-2 and the sAng-1/sAng-2 ratio, sTie-1 levels may be a more sensitive and specific novel diagnostic measure for distinguishing healthy controls, CIN cases, and cervical cancer cases, with the strongest results observed for distinguishing cervical cancer patients from healthy controls. In metastatic breast cancer patients, plasma Tie-1 levels were statistically significantly decreased as compared with pre-operation after 6 weeks of chemotherapy [10], and a recent in vitro study indicated that the overexpression of Tie-1 in multiple ovarian cancer cell lines decreased cisplatin sensitivity indicating that this may be a key gene inducing platinum resistance [17]. Thus, we conclude that sTie-1 may be a potential novel serum marker for monitoring tumor progression in cervical cancer patients, similar to CA125 in ovarian cancer, and may be a marker for platinum resistance. These questions merit additional thorough investigation in future research.

In addition to the substantial strengths of our study, we acknowledge some limitations. First, the sample size in the current study was insufficient, especially for examining associations with cervical adenocarcinoma; this may have led to some selection bias and reductions in statistical power. Second, the follow-up time for our patients with cervical cancer was relatively short. In the future, expanding the sample size of enrolled patients and healthy controls and extending the follow-up time could effectively validate our results and provide more conclusive, rigorous, and generalizable findings.

Our findings revealed that, as the severity of cervical lesions increased, the level of serum Tie-1 gradually increased, and that sTie-1 levels can effectively distinguish cervical cancer patients from healthy controls. Thus, sTie-1 levels may be associated with the growth and progression of cervical cancer. We also found that high sTie-1 levels predict a poorer prognosis in cervical cancer patients. Therefore, sTie-1 may be a valuable biological marker for predicting the progression and prognosis of cervical cancer.